Sex and Risk of Hip Implant Failure

Sex and Risk of Hip Implant Failure: assessing the role of sex‐associated biomarkers

Lisa Torosyan, MD, PhDDivision of Epidemiology, OSB/CDRH

CDRH Health of Women (HoW) Program Launch June 25, 2013

Copyright ©

2012 American Medical Association. All rights reserved.

Sex and Risk of Hip Implant Failure:

Assessing Total Hip Arthroplasty Outcomes in the United States. Inacio et al. JAMA Intern Med. 2013;173(6):435-441.

Figure. Kaplan-Meier survival plot of primary total hip arthroplasty survival by sex. Log rank P

=

.005. Shaded areas: 95% CIs.

• Kaiser Permanente

Total Joint

Replacement Registry: ‐

35

140 operations ‐

46 medical centers ‐

319 surgeons

• Revision rates at

median follow‐up

of 3 years:

F 2.3%

M 1.9%

• When controlling for

potential confounders,

RR for women:

1.23 to 1.30

Gender‐dependent

reasons for revision:

•Aseptic revision:

F 0.57 M 0.44

•Aseptic loosening:

F 8.1% M 14.7%


Assessing Total Hip Arthroplasty Outcomes in the United States. Inacio et al. JAMA Intern Med. 2013;173(6):435-441.

More evidence on the sex‐dependent factors underlying MoM

THA failure

Various sex ratio in THA patients with aseptic loosening: Prosthesis? Patient demographics? 35,140 THAs:

F 8.1% vs.

M 14.7% P = .006 (Inacio et al 2013)1589 THAs: F 4.3% vs.

M 1.1% P = .0006 (Latteier et al 2011) 2049 THAs: F 3.8% vs.

M 0.9% P = .002 (Berend et al 2012)

Risk factors for aseptic loosening following THA MacInnes et al., Recent Advances in Arthroplasty, published online Jan 2012

• Patients vary in their

osteolytic response to

particulate wear debris

• In‐vitro macrophage

responsiveness to particulate

debris varies between

individuals

• PBMCs taken from patients

with a susceptibility to

osteolysis exhibit greater

cytokine responses

• Genetically‐determined

susceptibility and variable

responsiveness to THA AE

Degree of wear degree of aseptic loosening !

Wear debris or much more ?...

Currently identified candidate biomarkers for aseptic loosening

following THA

GNAS1 as a sex‐related candidate biomarker for aseptic loosening

• TT‐FEMALES: longer time to aseptic loosening compared to TC+CC (P = 0.022)

• CC‐MALES: longer time to loosening than TC and TT carriers (P = 0.018, P = 0.023), and

>11‐fold lower risk of loosening, HR 0.088 (95% CI: 0.02–0.50; P =0.006)

Gene Allele (MA)

Population MAF (95% CI)

White/ Caucasian MAF (95% CI)

White Hispanic MAF (95% CI)

Black African American MAF (95% CI)

Asian Hmong MAF (95% CI)

American Indian MAF (95% CI)

P value

GNAS C(T) 0.480 0.475-0.485

0.477 0.472-0.482

0.575 0.527-0.623

0.700 0.610-0.790

0.606 0.536-0.676

0.545 0.492-0.598 <0.0001

rs7121 20q13.3 GNASGeneID: 2778

Obesity, Cancer, ASEPTIC LOOSENING ?

GNAS1 rs7121:sex and ethnicity associations

Cross et al. BMC Genet 2010

1000 Genome project, Ensemble:

Caucasians – T allele; Asians – C allele

Population Genetics of GNAS1 rs7121 variance

> T‐allele in AFRICANS

> C‐allele in

EUROPEANS

GNAS1 as an example of putative sex/ethnicity‐related genetic

biomarkers for THA AE

Epidemiologic evidence:

A higher rate for revision due to aseptic loosening was found in

female THA patients

predominantly of Caucasian/European descent.

Genetic evidence:

GNAS1 rs7121 was identified as an independent factor determining

time to early

loosening following THA

Synthesis of epidemiologic and genetic evidence on GNAS1 rs7121 could provide

explanation for the higher risk of aseptic loosening in female THA patients in the

US:

A majority of THA patients are of European/Caucasian descent and, therefore, are expected

to carry the C‐allele associated with more favorable prognosis only in male THA patients;

Only patients of Asian, Hispanic, and especially African descent

are expected to carry the

T‐allele which was associated with more favorable prognosis in female THA patients.

SUMMARYDespite the enormous success of THA, patients face a number of

potential complications, many of them sex‐dependent.

Further studies on discovery of molecular signatures associated with unfavorable outcomes can clarify the reasons for variable individual

susceptibility to THA AE.

Biomarker‐based noninvasive diagnostic tests can enable early detection and therapeutic management of undesired THA outcomes in

sex‐, age‐, and ethnicity‐stratified patient subpopulations.

THANK YOU !

Questions or Comments?

[email protected]

ADDITIONAL SLIDES

Copyright ©


F vs. M:

•Women patients with THA were older

than men

•The race‐related gender difference

was found only in THA patients of Asian

decent:

F 4.1% vs.

M 2.7%

The following diagnoses were more

frequent in female THA patients:

•Osteoarthritis, the major underlying

cause fro THA•Rheumatoid arthritis•Dysplasia


Assessing Total Hip Arthroplasty Outcomes in the United States. JAMA Intern Med. 2013;173(6):435-441.

F vs.

M: •smaller femoral heads•more metal on XLPE

implants •less MoM bearings•more frequent use of

hybrid rather than

cementless fixation

Even after statistically

controlling for head

sizes, women had a

15% higher risk of

revision.


Assessing Total Hip Arthroplasty Outcomes in the United States. JAMA Intern Med. 2013;173(6):435-441.

Copyright ©


• 1589 primary MoM THA in 1363

patients, follow‐up ‐

60 months• Complications observed more frequently in women:

• cup revision (8.2% vs. 2.7%; P = .0000);• aseptic loosening (4.3% vs. 1.1%; P = .0006), similar to the analysis of 2049

THAs by Berend 2012: (3.8% vs. 0.9%, P = .002); and

• failure for metal‐bearing complications (2.2% vs. 0.6%; P = .0126).

Additional sex‐related differences:•Smaller cups and heads in women compared to men, but no significant difference in

size between failures and non‐failures in women.•A higher inclination angle in women compared to men, but no significant difference in

the inclination angle in failures vs. non‐failures in women.•Higher inclination angles in male failures due to metal complications, and a failure

increase with an inclination angle >45° only in men. •The need for further investigation of sex‐specific factors in THA failure

• The failure of MOM implants was almost twice as high for women than men, which is consistent with data from the England and Wales registries (5.1% vs 3.7% at 5 years) and from a smaller US study (8.2% vs 2.7% at 2 years, Latteier

et al, 2011).• NJR of England and Wales: higher occurrence of implant

failure in women with MoM implants after adjusting for age and femoral head size (Smith et al. Lancet 2012).

• Data on the risks and benefits of THA devices for women and men could allow better informed choices for the more

than 300

000 US patients undergoing THA annually, thus reducing the need for revision surgery and its concomitant

risk of myocardial infarction

Cross et al. BMC Genet. 2010; 11: 51.

Population based allele frequencies of disease associated polymorphisms in

the Personalized Medicine Research Project

• The allele frequencies for a panel of disease‐ associated 51 polymorphisms were determined

within the entire Personalized Medicine Research Project population based cohort.

• Differences in allele frequencies between self reported race, region of origin, and sex were

determined.• One of the three genes that exhibited sex

differences was GNAS.• GNAS was associated with different responses to

hip arthroplasty.

Ethnic composition in Iowa vs. USA

GNAS, rs7121 (1000 genomes, fragment)

• Areas of agreement SNPs overexpressed in patients with aseptic loosening and

periprosthetic osteolysis:– GNAS1– TNF‐238 A allele; TNF‐α

promoter (‐308G→A) transition– IL6‐174 G allele, IL6 (‐597) and (‐572)– MMP‐1‐promoting gene, C/C genotype for the MMP1, MT1‐MMP, MMP‐2– TGFB1 signal sequence (29T→C) transitions– A/A genotype for the OPG‐163, and MBL

He et al. International Orthopaedics (SICOT) (2013) 37:1025–1031

• Despite the enormous success rates of hip arthroplasty, patients face a number of potential

complications• Osteolysis and subsequent aseptic joint loosening is

the most common reason for joint revision• Diagnostic and prognostic biomarkers have the

potential:– to provide an early, accurate, and noninvasive diagnosis of

these undesired outcomes as well as help design interventions to prevent some of these complications,

especially AL.– Plasma level of multiple biomarkers in THA patients with

prosthetic AL were elevated compared to healthy controls and .

• 57 German Caucasian patients with revision for aseptic loosening

after THA• T393C polymorphism in GNAS1, the gene coding for the stimulatory

Gas subunit, a ubiquitous AMP‐

dependent G‐protein contributing to bone physiology

• Gas/cAMP pathways are involved in:– parathyroid hormone‐mediated osteoblastogenesis;– bone disorders such as McCune‐Albright syndrome, Albright hereditary osteodystrophy, and

functional defects of osteoblasts;

– IL6 activation in osteoblasts, macrophages and osteoclasts. • FEMALES: median time to aseptic loosening was not significantly associated with single T393C genotypes,

but it was longer in TT carriers compared to TC+CC genotypes (P = 0.022).

• MALES: the CC carriers had longer time to loosening than TC and TT carriers (P = 0.018, P = 0.023), and the

CC genotype showed a more than 11‐fold lower risk of loosening, with a hazard ratio of 0.088 (95% CI:

0.02–0.50; P =0.006).

• Compared with T393 homozygous males (reference group), heterozygous patients had a 6.25‐fold lower

risk with a hazard ratio of 0.160 (95% CI: 0.04–0.71; P =0.016).

• T393C polymorphism may have gender‐dependent effects on the aseptic loosening after THA. More

favorable prognosis is suggested for males with CC‐genotype and females with TT‐genotype.

The C‐allele of the GNAS genetic variance (rs7121) could have co‐modifying effect on the obesity and aseptic loosening in female patients with THA

Hahn S, Frey UH, Siffert W, Tan S, Mann K, Janssen OE. The CC genotype of

the GNAS T393C polymorphism is associated with obesity and insulin

resistance in women with polycystic ovary syndrome.

Eur J Endocrinol.

2006,

155:763‐70.

•Case control study of 278 German women with poly cystic ovary syndrome

and 820 controls.

•The C allele of the GNAS1 polymorphism T393C (rs7121) was associated with

a higher mean body weight, a higher BMI and a higher indices of insulin

resistance compared to women without a C allele.

Individual susceptibility to periprosthetic osteolysis is associated with altered

patterns of innate immune gene expression in response to pro‐inflammatory

stimuli. Gordon et al. J Orthop Res.

2010;28(9):1127‐35. (UK)

See also Gordon’s publications on SNP analysis in hip arthroplasty

(Gordon et al. 2008, ref.61, from MacInnes’

Risk factors for asept loos., not found)

Abstract Susceptibility to osteolysis after total hip arthroplasty (THA) varies between individuals. We

examined whether patients susceptible to osteolysis (group I, n = 34 subjects) after cemented Charnley

THA have quantitatively different innate immune responses to pro‐inflammatory stimuli versus patients

without this susceptibility (group II, n = 28 subjects) at a mean of 14 years after primary surgery.

Extracted peripheral blood mononuclear cells were stimulated for

3 h using endotoxin (LPS, 100

ng/mL), endotoxin‐stripped titanium particles (Ti) or endotoxin‐stripped particles with adherent LPS

added‐back (TI + LPS). Subjects returned 1 week later and the experimental protocol was repeated.

Assays for mRNA induction for interleukin (IL)‐1alpha, IL‐1beta, IL‐1Ra, IL‐6, IL‐10, IL‐18, and tumor

necrosis factor (TNF) were made using quantitative real‐time PCR. Although baseline levels of mRNA

expression were slightly lower in group I, inducibility of mRNA expression was markedly greater in

group I versus group II for all cytokines in response to LPS or Ti + LPS, and for IL‐1alpha in response to Ti

(P < 0.05). LPS or Ti + LPS stimulation also resulted in an increase in the IL‐1/IL‐1Ra mRNA ratio in group

I versus group II (P < 0.05). mRNA induction was highly reproducible between subject visits (r > 0.7, P <

0.001). Osteolysis‐susceptible patients show repeatable, quantitatively different patterns of innate

cytokine gene expression in response to pro‐inflammatory stimuli versus THA patients who do not

display this susceptibility. These innate immune differences may

contribute to the variation in

osteolysis‐susceptibility observed clinically between individuals.

Suggestion: development of in vitro diagnostic/prognostic test for early detection and monitoring of

the proinflammatory immune response based on cytokine production

in hip transplant patients

Risk factors for aseptic loosening following total hip arthroplasty (MacInnes et al., from a book:

Recent Advances in Arthroplasty, pp.275‐294, published online Jan 2012)

Biologic effects of implant debris,

as reviewed in

Hallab and Jacobs, 2009 • Immune reactivity depends on:

– the dose, i.e., the concentration of

phagocytosable

particles per tissue

volume, which can be characterized by the

size distribution and amount of debris;– the shape: elongated particles (fibers) are

generally more proinflammatory than

round particles; – the material: metal particles are more

proinflammatory than polymers in vivo.

• Although to produce an in vitro

inflammatory

response, particles need to be <10µm, i.e.,

phagocytosable,

both soluble and particulate

debris derived from Co‐Cr‐Mo alloy implants can

induce monocyte/macrophage activation and

secretion of proinflammatory cytokines (IL1beta,

TNFalpha, IL6, IL8) by upregulating NFkB and

activating inflammasome danger signaling.

• Identification of new pathways of implant debris‐

induced inflammatory reactions, such as

activation of inflammasome‐mediated “danger

signaling”, provides new targets for improved

implant performance and therapeutic

intervention.

NALP3=NLRP3=PYPAF1=CIAS1 and genetic autoinflammatory syndromes,

or

Why NALP3 can mediate unprovoked systemic inflammation

which involves CNS, skin and joint and bone tissues • This protein interacts with ASC, which contains a caspase

recruitment domain, and is a member of the NALP3

inflammasome complex. This complex functions as an upstream

activator of NF‐kappaB signaling, and it plays a role in the

regulation of inflammation, immunity, and apoptosis.

• Mutations in this gene are associated with the cryopyrin‐

associated periodic syndromes:

‐

familial cold autoinflammatory syndrome (FCAS),

‐

Muckle‐Wells syndrome (MWS),

‐

chronic infantile neurological

cutaneous and articular

(CINCA)

syndrome, and

‐

neonatal‐onset multisystem inflammatory disease (NOMID).

• NOMID/CINCA

(or Prieur‐Griscelli syndrome) causes

uncontrolled inflammation including severe arthritis

and

neurologic

damage which may lead to the hearing loss. Joint

signs (35‐65%) can lead to unpredictable anomalies of growth

cartilage and long bones epiphyses suggestive of a

pseudotumour. Biopsy of skin lesions shows a perivascular

inflammatory infiltrate including granulocytes.

• NOMID has been successfully treated with anakinra (IL1‐

receptor antagonist).

• Activated NLRP3 inflammasome in mouse model caused

inflammation and abnormal skeletal development including

accelerated bone resorption and increased osteoclastogenesis

(Bonar et al. PLoS One 2012).http://a248.e.akamai.net/7/248/432/20101213115940/www.msdlatinamerica.com/

ebooks/ArthritisAlliedConditions/files/3b147cc82a21e2ab889fd76b34f4c516.gif

NOMID/CINCA symptoms which are similar to various clinical features attributed to the

metallosis

in hip transplant patients

Sex and Risk of Hip Implant Failure

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