MetALLs: Metal Allergy Study. Health Sciences

Transcription

1 MetALLs: Metal Allergy Study Metal Mtl Allergy: Clinical relevance Karin Pacheco, MD, MSPH Division of Environmental & Occupational Health Sciences

2 Disclosures Karin Pacheco Nothing to disclose

3 Learning Objectives 1. Identify the three most common causes of joint replacement failures. 2. Define which allergens are important when considering sensitization as a cause of joint replacement failure. 3. Describe the different methods of making the diagnosis of an allergy to implant materials.

4 Outline of talk Brief history of joint replacements Current and future rates of joint replacement Rates and causes of joint revision Allergy to joint components as a cause of joint failure medical literature Methods of diagnosing g the allergy: pros, cons, and pitfalls Results from the MetALLs cohort

5 Limb replacements are not new Cairo Toe - between 1070 and 670 B.C. Wooden prosthesis: s: signs s of wear indicate use. Earliest artificial leg BC. Copper & wood; found in tomb in Capua, Italy. Joint replacements - required adequate anaesthesia. The first successful hip replacements (1948) were ivory. The artificial hinged knee was invented 1957.

6 Modern joint replacements Science & engineering of interacting surfaces in motion. Sir John Charnley: father of the 3-part hip replacement Stainless steel one piece femoral stem and head Polyethylene (originally Teflon) acetabulum Fixed to the bone using PMMA bone cement. Early titanium hip prosthesis, ceramic head, polyethylene acetabular cup.

7 Why talk about joint replacements? Because they re in the news, and the public has great interest. Wall St Journal April 2011

8 AND, demand d for joint replacement is rising ii Currently >1 million joint replacements/year. Main recipients y/o y/o, significant increase since 2000 If trends continue by 2015: 600,000 hip replacements/year 1.4 million knees/year By 2030: > 4 million joint replacements/yr

9 Joint replacements are cost effective THA vs. no surgery $10,402 per QALY (quality- adjusted life year) TKA vs. no surgery $13,000/QALY (payer) to $22,000/QALY (societal) Daigle ME. Cost-effectiveness of total joint arthroplasty: A systematic review of published literature. Best Practice & Research Clinical Rheumatology 2012;26:

10 Rates of hip and knee replacements are increasing in younger age groups HIP: KNEE: Ravi B. Changing demographics of total joint arthroplasty. Best Practice & Research Clinical Rheumatology. 2012;26:

11 Improved joint replacement outcomes: THA: Mdi Medicare data Length of stay: 9.1d 3.7d (p=0.002) 30d mortality: 0.7% 0.4% JAMA 2011;305(15): BUT: admit nursing home, 30d readmit rate 6% 8.5% TKA: volume: /10, revision rate: /10,000 Length g of stay: 7.9d 3.5d (p=0.001) JAMA 2012;308(12):1227=36. BUT: 30d readmit rate 4.2% 5% Comorbidity: AODM, CHF, Obesity, Renal Failure

12 Why talk about joint replacement failure? Because they go hand in hand with joint replacement, are also in the news, and the public has great interest. The High Cost of Failing Artificial Hips By Barry Meier December 27, 2011 The metal on metal hip made by DePuy was recalled in 2010 after having been implanted in 400,000 US patients. As of October 2011, some 3,500 patients had filed a lawsuit involving ing that t device. e Because e orthopedic outcomes ome are not formally tracked by government or by private companies, there are no data on the number of the all metal hips that failed prematurely.

13 How many yj joints need to be revised? Overall 10%. Joint failure first reported in the 1970 s. Rates have remained constant since then. Traditional causes of failure = infection, biomechanical problems. S Kurtz et al. J Bone Joint Surg Am. 2007;89:780-5

14 Implant Failure Presentation Chronic pain, chronic effusion, Instability, loosening Deep itching or burning, localized itchy rash (rare) Systemic symptoms (fatigue, low grade fever, malaise, pain) Rd Radiolucency around the prosthesis on X-ray May be foreign body reaction to polyethylene l or metal wear particles on biopsy

15 Joint replacement failure is now an active interest of the FDA F.D.A. Plans a New Review of Metal-on-Metal Hip Implants By REUTERS: March 29, 2012 The F.D.A. held an advisory panel meeting June 27-28, 28, 2012 to discuss safety concerns of metal on metal hip implants: Failure rates, metal ion testing, imaging methods, patient risk factors, follow-up surgery and complications. The meeting solicited input from scientists, researchers,,p patients and medical practitioners to help determine whether new testing standards and review requirements should be imposed.

16 AND joint revision is not cheap Sales of artificial hips & knees = $6.7 billion in /26/12: 2 Joint replacements are the #1 expenditure of Medicare. Revision costs paid by Medicare, insurance, & patients not the manufacturer.

17 Traditionally considered causes of joint replacement failure Infection Biomechanical issues Size Type Spacer Orientation/angle Metallosis a toxic/necrotic reaction to metal wear particles DVT / hemarthroses Obesity, cigarette smoking are risk factors

18 Causes of hip replacement failure 08% 12% Retrospective review of 1366 THAs at U Penn. Men=609 (44.5%) Women=757 (55.5%) Mean age=66 years 14% 51% 15% Aseptic loosening Ins tability Wear In fe ctio n Other Jafari SM et al. Clin Orthop Relat Res Aug;468(8): An allergy to hip components was not considered, but this can also present as aseptic loosening or instability.

19 Causes of knee replacement failure Survey of all 102 clinical members of The Knee Society Major causes of knee replacement failure included: Vascular: bleeding, wound complication, neural deficit, thromboembolic disease, vascular injury. Mechanical: Medial collateral ligament injury, instability, stiffness, mal-alignment, li extensor mechanism disruption, i patellofemoral dislocation, tibio-femoral dislocation. Deep joint infection. Implant degradation: bearing surface wear, osteolysis, implant loosening. Fracture: implant fracture/tibial insert dissociation Reoperation, revision, readmission, and death. NOT allergic/immune reaction to implant. Healy WL et al. Complications of TKA. Clin Orthop Relat Res January 2013 (epub)

20 Implants Joint replacement failure Implant allergy is not on the orthopedic radar: 94% do not routinely ask about metal allergy preoperatively. 82% would use cobalt/chrome or stainless steel implant even if a metal allergy were suspected. 71% would use cobalt/chrome, stainless steel implant even if patch test positive to cobalt, chromium, or nickel. A Razak et al. Knee Surg Relat Res 2013; 25(4): Metal allergy screening prior to joint arthroplasty and its influence on implant choice.

21 Why is this important? $$$ Numbers $$$ x Numbers

22 Frequent personal exposure and uses Jewelry Medical uses: Dental: orthodontic braces, bridges, implants Orthopedics: joint implants, screws, plates Cardiac: stents, patches for septal defects, valves GYN: IUDs cxvascular.com

23 Several sensitizing routes of exposure Skin Respiratory Blood and tissue Mortz CG Acta Derm Venereol 2002: 82: Route of 1 st exposure matters: N=1,501 8 th grade children in Odense, Denmark Ni patch test + in 8.6% Ear piercing first, then braces: 21% Ni patch + Braces first, then ear piercing: 2% Only braces: 3% Only ear piercing 12% org au None 3%

24 Multiple Sensitizers in Orthopedic Implants Implants Cobalt-Chrome Chrome Alloy: most common ~ 1% nickel ~ 30% chromium ~ 65% cobalt < 5% molybdenum Stainless Steel: 18% chromium, 10% nickel, 8% molybdenum Bone Cement: most knees, some hips & spines ~ 85% methacrylate component ~ 5% Benzoyl peroxide ~ 2-5% N,N-dimethyl dimethyl-p-toluidinetoluidine ~ 1% Hydroquinone

25 Scattered reports of metal & bone cement allergies causing joint replacement failure N=92 pts with hip or knee replacement: Nickel 66 w/complications n(%) 26 w/o n(%) Nickel 16 (24%) 1 (4%) Cobalt 4 (6%) 1 (4%) Chromium 2 (3%) Bone cement 21 (32%) 2 (3%) 1 (4%) Gentamicin 16 (24%) 4 (15%) Benzoyl peroxide 7 (11%) Hydroquinone y q 3 (5%) Eben R et al. Dtsch Med Wochenschr 2010; 135 (28-29):

26 Joint failure due to sensitization to bone cement THR Allergy to bone cement Early aseptic loosening 7 (47%) of hip prosthesis (n=15) Stable THR (n=25) 0 Awaiting i THR (n=25) 0 Infected THR (n=5) 0 Haddad FS et al. J Bone Joint Surg Br Jul;78(4):546-9.

27 MetALLs: Metal Allergy Study Division of environmental and occupational health h sciences Interest in allergy to metal and bone cement components of joint replacements: Experience in allergy and immunology Beryllium LPT: DOE Specification April High volume automated. Well established QA and validation.

28 CLINICAL: H & P Patch testing: Evaluation of patients metals (aluminum, chromium, cobalt, copper, manganese, molybdenum, nickel, niobium, tantalum, titanium, vanadium, zirconium). bone cement components (methyl methacrylates, ethyl acrylates, benzoyl peroxide, hydroquinone, n,n- n dimethyl-p-toluidine, bone cement A, and A+B). NiLPT Validated MetALLs: Metal Allergy Study RESEARCH: enrolled MetALLs study with consent RESEARCH: CoLPT, CrLPT, bone cement, outcomes

29 Case 1 62 year old man, had left TKA Jan 2010 Infected, treated with wt antibiotics. tbotcs. June 2010 prosthesis removed, replaced with antibiotic-impregnated impregnated spacer. effusion & pain, spacer replaced, more antibiotics Nov 2010: revision left TKA. Dec 2010 recurrent effusion with poor wound healing requiring skin graft. Jan 2011 admit for severe pain & effusion: C&S. Current symptoms: left knee pain, swelling, warmth, instability, mild lower leg itching.

30 Case 1: Patch testing day 1

31 Patch testing day 4 Commercial extract Methylmethacrylate y Final Diagnosis: Lf Left total knee replacement failure due to methacrylate allergy to both bone cement and spacer components. Bone Cement A Bone Cement A&B

32 Case 2 45 y/o woman right TKA March 2008 Post-op op pain, swelling, ROM. Summer 2010 knee aspirate grew staph sp. Treated with oral & IV antibiotics, knee hardware removed Dec 2010, antibiotic impregnated spacer placed. Operative p note during surgery > tibial component was loose and easily removed, with reactive bone changes and bone loss.

33 Placement of patches day 1

34 Day 3 Cobalt Cobalt Nickel Nickel Prior history of itching and burning rash to safety pins, dime store jewelry, pajama and jean snaps. The patient thought she was allergic to nickel, but had not told her surgeon. Knee prosthesis cobalt, chromium, molybdenum, 0.5-1% nickel. Dx: R TKA failure from a nickel and cobalt allergy to components of prosthesis.

35 Case 3 Along with pain and chronic effusions, bone cement allergy may present as poor wound healing.

36 Current measures to dx metal allergy Patch Testing Time consuming, needs expert trained in technique, many extracts not validated against positive standard Blood Testing Are they equivalent? LPT is only currently available test Easy to perform, may be performed remotely Most M t not validated d against any other standard d

37 Is implant allergy a form of internal contact dermatitis? YES Same process of ag take-up by APCs, followed by translocation to regional lymph node and presentation to circulating T cells, which then migrate back into the joint. Immune system is system wide can diagnose by patch testing NO APCs are different: Langerhans cells vs. dendritic cells. Can have organ specific response only identified locally, e.g. some cases of allergic rhinitis. Major contact of joint is with blood need to diagnose by blood testing

38 Nickel LPT assay set up Blood cells Stimulated with 8 concentrations of nickel, from 0.1 to 50 mcg/ml. Stimulation Index (SI) = Response (counts incorporated) at day 4 and day 6. Response of blood cells to nickel Background response in un-stimulated cells Test set-up: 1. Establish baseline SI in non-sensitized populations. p 2. Determine optimal range of nickel concentrations to differentiate sensitized from non-sensitized subjects.

39 Validation of NiLPT vs. Ni patch NiLPT Abnormal NiLPT Normal Patch Test Patch Test Total Positive Negative Total Sensitivity = Specificity = 63% 93%

40 Commercially available metal LPTs Orthopedic Analysis MELISA Not validated against any other standard National Jewish Health NiLPT validated against patch testing CoLPT & CrLPT available August 2014 MetALLs: Metal Allergy Study

41 Allergy Testing Hypotheses Sensitization to orthopedic implants in patients with joint failure, unexplained by infection or biomechanical issues, is common, and can be detected by patch and/or blood testing. A A preoperative history of skin reactions to metal will be associated with metal sensitization. MetALLs: Metal Allergy Study

42 Study Population Allergy Testing Patients referred by their orthopedic surgeon for clinical evaluation of potential implant sensitization: Enrolled n=311 into IRB-approved study (10/ / 2013) Preop patients reported a history of metal reactions, or Postop patients with implant failure not due to infection or biomechanical issues. Patch tested to standard panel of metals and bone cement components: Standard extracts obtained from Allergeaze Bone cement powder and liquid samples donated by orthopedic implant companies NiLPT Outcomes assessed at 1 yr using Knee Society Score Statistics: i chi-square analysis, significance ifi set at p=

43 Patch testing Allergy Testing Performed according to standard guidelines. Placed on upper back or forearms. Patches removed after 2 days. Read again in another 1 to 3 days. Scored according to International Contact Dermatitis Research Group scoring system. All reactions photographed and archived.

44 Test Materials Allergy Testing Metals Aluminum Chromium Cobalt Copper Nickel Manganese Molybdenum Niobium Tantalum Titanium Vanadium Zirconium NiLPT Bone Cement Methyl methacrylate Hydroxy-ethyl methacrylate Hydroxy-propyl methacrylate Benzoyl peroxide N,N-dimethyl-p-toluidinetoluidine Hydroquinone Bone Cement liquid Bone Cement liquid & powder

45 Allergy Testing Patient Population Patients (n = 311) Seen October 2010 June 2013 Age 61.2 ( ) Female 214 (69%) Male 97 (31%) Post-Implant Evaluation 239 (77%) Knees 164 (69% of implants) Hips 48 (20% of implants) Age 61.7 ( ) Female 148 (62%) Pre-Implant Evaluation 72 (23%) p=ns Age 59.6 ( ) 84 Female 66 (92%) <

46 Allergy Testing Patch Test Results: Metals All Patients (n = 311) Patch Sensitized (%) Positive test for nickel Any metal patch 105 (34%) Nickel 80/105 (76%) Cobalt 54/105 (67%) Chromium 6/105 (6%) Any metal patch Copper 12/105 (11%) Nickel Cobalt Chromium -10% 10% 2% Copper 4% Sensitized to metal Perce nt of Patie nts 17% 30% 26% 34% 50% cobalt and cobalt sensitization cobalt nickel nickel

47 Metals test results: post-implant vs. pre-op Metal Test Results Post-Implant (n = 239) Pre-Op (n = 72) Allergy Testing op Metal Sensitized (%) Sensitized (%) p value Any metal 63/239 (26%) 42/72 (58%) < Nickel 40/239 (17%) 40/72 (56%) < Cobalt 35/239 (15%) 19/72 (26%) Chromium 4/239 (2%) 2/72 (3%) Chromi um Pre-op Post-op Cobalt Nickel Any 0% 10% 20% 30% 40% 50% 60%

48 Test Results: Bone Cement Allergy Testing All Patients (n = 311) Bone Cement Component Sensitized (%) Any bone cement 76/311 (24%) Methyl methacrylate 9/311 (3%) Benzoyl peroxide 38/311 (12%) 2-hydroxyethyl methacrylate 14/311 (4.5%) Bone Cement Liquid 43/311 (14%) Bone Cement Liquid & Powder 32/311 (10%) Ethyl-methacrylate Positive tests for sensitization to bone cement components 2-Hydroxyethyl methacrylate Bone cement

49 Allergy Testing Bone Cement Results: post-implant vs. preop Post-Implant (n = 239) Pre-Op (n = 72) Bone Cement Component Sensitized (%) Sensitized (%) p Any bone cement 68/239 (28%) 8/72 (11%) Mthl Methyl methacrylate lt 8/239 (11%) 1/72 (1%) Benzoyl peroxide 33/239 (14%) 5/72 (7%) hydroxyethyl methacrylate 13/239 (5%) 1/72 (1%) Bone Cement Liquid 39/239 (16%) 4/72 (6%) Bone Cement Liquid&Powder 28/239 (12%) 4/72 (6%) 0.183

50 Allergy Testing Summary Sensitization S i i i to metal or bone cement relevant to joint replacements was frequent in this population: Test Response Sensitized (%) Components Any positive n= /311 (51%) Pre-op n=72 45/72 (62.5%) p=0.03 Metals Post-implant n= /239 (47%) Bone cement

51 Allergy Testing Summary Rates of sensitization to metals are twice as high in pre-op vs. post-implant patients (p<0.0001): 0001): 58% in patients with a preoperative history of skin reactions to metal (typical history of rash or itching with jewelry, watchbands, jean snaps) 26% in patients with postoperative joint failure Rates of sensitization to bone cement are twice as high in post-implant vs. pre-op patients (p=0.003): 11% in preoperative patients 28% in postoperative joint failure Recommendations: based on allergy test results

52 Allergy Testing Conclusions Although we tested to all common metals used in implants, we detected sensitization s to only a few: Nickel, cobalt, chromium May in part be due to poorly sensitive extracts Bone cement was a frequent sensitizer in the post- implant population. NiLPT was a useful adjunct to testing Limitations: Cross-sectional sectional cohort Referral bias selected patients Are results directly related to outcomes?

53 Outcomes Outcomes Hypothesis: If allergy test results are relevant, then revision based on allergy testing should result in improvement. If allergy tests do not reflect the process in the joint, then revision based on allergy testing should provide no better results than any revision not based on allergy tests.

54 Outcomes Outcomes Table 1. Patient Demographics: October 2010 September 2012 All (n=177) Follow-up (n=104) Lost to follow-up (n=73) Age (Range) 60.9 (19-88) 61.9 (42-83) 59.6 (19-88) 0.18 Male (%) 58 (33%) 35 (34%) 23 (32%) Female (%) 119 (67%) 69 (66%) 50 (68%) Pre-operative Evaluation (%) Post-implant Evaluation (%) 42 (24%) 24 (23%) 18 (25%) 135 (76%) 80 (77%) 55 (75%) p Positive: any metal (%) 62 (35%) 39 (38%) 23 (32%) 0.43 Positive: any bone cement (%) Any positive implant component test (%) 48 (27%) 31 (30%) 17 (23%) (55%) 61 (59%) 37 (51%) 0.36

55 Outcomes Outcomes Table 2. Implant type & prior history: all follow-up patients All (n=104) Pre-op Eval Post-Implant Eval Planned/Problem (n=24) (n=80) p Type of implant Planned Problem Knee 80 (77%) 19 (79%) 61 (76%) Other (shoulder, spine, etc.) Hip 20 (19%) 3 (13%) 17 (21%) 8 (8%) 2 (8%) 6 (8%) Pi Prior history of metal allergy Yes 22 (21%) 11 (46%) 11 (14%) No 46 (44%) 1 (4%) 45 (56%) Not sure 28 (27%) 10 (42%) 18 (23%) No response 8 (8%) 2 (8%) 6 (8%) <

56 Clinical relevance of allergy tests Outcomes

57 Table 3a. Patient Type Have you improved? Outcomes All Allergy Test Positive Patients (n =61) A lot Moderately A little Not at all No response Implant chosen based on allergy test results: YES (n=35) Index arthroplasty (n =15) 87% 7% 0% 7% 0% Revision arthroplasty (n = 20) 65% 10% 10% 15% 0% p Implant chosen based on allergy test results: NO (n=26) < No revision (n = 19) Revision not dictated by patch tests OR other surgery (spinal cord stim, scar tissue) (n=7) % 11% 21% 63% 5% % 14% 0% 71% 0% ns

58 Outcomes Table 3b. Patient Type Have you improved? All Allergy Test Negative Patients (n=43) A lot Moderately A little Not at all No response p Pre-op Evaluation (n =5 ) Index arthroplasty 80% 20% 0% 0% 0% Post-implant, no revision (n = 23) Minor surgery, no change in implant hardware % 9% 13% 52% 4% Revision (n = 15 ) Failure attributed t to biomechanical factors 53% 13% 0% 27% 7%

59 Outcomes Outcomes: are you better? A Lot Moderately A Little Allergy test dictates revision (n=21) Any other revision (n=23) p=0.05 Not at all No answer 0% 20% 40% 60% 80%

60 Outcomes Limitations Follow-up survey on only 60% of original cohort Patients w/ negative outcomes might be less likely to respond No differences in demographics or test results between those who responded and those who did not. Could miss sensitization due to limitations of test reagents. Or detected sensitization not clinically relevant. However, sensitization to components not present in the implant was rare. Improved outcomes after removal of allergenic components suggest that allergy tests were clinically relevant. Follow-up 9-12 months after visit ii is too short May have missed more long-term failure. Longer term follow-up will help address this limitation.

61 Outcomes Conclusions Sensitization to metal was more common in pre-op patients, whereas sensitization to bone cement was more prevalent in post-implant patients. All pre-op ppatients did well with implants. Post-implant patients found to be allergic to an implant component, and revised with other, non-allergic components, did significantly ifi better than: Those who were allergic but were revised with an allergenic component. Those who were revised for any other reason. Results suggest that testing for sensitization is relevant to joint implants.

62 Conclusions Who to test for metal sensitization? Pre-op testing history of metal reactivity. Post Post-Implant failure consider infection, biomechanical issues. If these are negative, & If considering a revision: Test for allergy to metal or bone cement before proceeding. If only concern is metal allergy, LPTs for nickel, cobalt, & chromium are the most relevant.

63 Thank you! Questions?

64 NJH CONTACTs: Samantha Erb Program Lead r Vijaya Knight Director, Clinical Immunology Lab Karin Pacheco Division of Environmental & Occupational Health Sciences