Mild, moderate and high levels of lymphocyte reactivity to metals in reactive subjects
+ Hallab, NJ; McAllister, K; Caicedo, M and Jacobs, JJ
Rush University Medical Center, Chicago, IL 60612
[email protected]
ACKNOWLEDGMENTS: NIH/NIAMS, Orthopedic Analysis LLC
REFERENCES:
1. Hallab N, Merritt K, Jacobs JJ. Metal sensitivity in patients with orthopaedic
implants. J Bone Joint Surg Am 2001 Mar;83-A(3):428-36.
2. Hallab NJ, Anderson S, Caicedo M et al. Immune responses correlate with
serum-metal in metal-on-metal hip arthroplasty. J.Arthroplasty 2004;19:88-93.
Figure 1. Percent of people reactive to each metal.
Figure 2. Average level of reactivity of subject reactive to each
metal, i.e. SI>2.
Cummulative percent of people Nickel reactive over the range
of reactivity levels.
(n=380 poeple tested n=150 reactive to Nickel)
100
90
80
70
60
50
20
10
high
30
mod
erate
40
mild
Percent of People Reactive
INTRODUCTION: Sensitivity to metallic implants is well documented
in case and group studies (1), yet, it remains a somewhat unpredictable
and poorly understood phenomenon. Other studies have shown elevated
lymphocyte reactivity is associated with failing and metal-on-metal
articulating total joint arthroplasties (2). However, it remains unknown
what metals are more immunogenic among metal-reactive pre-op and
post-op orthopedic populations and what levels of metal-specific
reactivity are associated with reactive individuals, as measured by
quantitative Lymphocyte Transformation Testing (LTT). Without a
clinical correlate, can it be determined what qualifies as high or low
lymphocyte reactivity in orthopedic patients? We hypothesized that
metal-sensitive orthopedic populations (pre- or post-op) will primarily
react to Nickel, and that Nickel will also elicit the greatest level of
response among metal reactive people. We tested this hypothesis using a
prospective longitudinal study of all-comer orthopedic patients
suspected of metal sensitivity and comparing metal specific reactivity
(e.g. proliferation responses) of primary lymphocytes to soluble metal
challenge (Al+3, Co+2, Cr+3, Fe+3, Mo+5, Nb+5, Ni+2, Zr+2, and V+3 chloride
solutions) at 0.01mM and 0.1mM.
MATERIALS AND METHODS: A single group of n=380 subjects
suspected of having metal reactivity (history of metal allergy or
idiopathic implant inflammation) was used in this investigation to
determine levels of metal-specific reactivity in “reactive” subjects:
human primary lymphocytes were isolated from 30 mls of blood (15-30
x 106 cells per subject) and incubated with DMEM and 10% autologous
serum with either no metal (plain media) as a negative control, 0.01
mg/ml phytohemagglutinin (PHA) as a positive control and Al+3, Co+2,
Cr+3, Fe+3, Mo+5, Ni+2, Zr+2, and V+3 chloride solutions at 0.01mM and
0.1mM. The amount of lymphocyte proliferation was normalized to that
of the negative “control” (no challenge agent), and this proliferation or
stimulation index, SI (or lymphocyte reactivity index), was used for
comparison. Statistical comparisons used students t-test for SI data,
where an “*” on the graphs indicates p<0.05 when compared to controls.
RESULTS: Incidence of Lymphocyte Reactivity: Of the n=380 subjects
tested, n=208 were reactive to at least one of the metals tested (SI>2 =
reactive), where n=177 subjects were reactive to one of the metals tested
at 0.01mM and n=143 were reactive at 0.1mM. Of the reactive metals,
nickel demonstrated the greatest reactivity, where n=150 of 208 reactive
people were nickel-reactive. Level of Lymphocyte Reactivity: This
increase in incidence of metal reactivity was also reflected in the average
levels of metal reactivity over time (Fig 3), where 1-2 years Group 2
samples tested at 0.01mM were statistically elevated over 2-4 months,
pre-op, and controls levels of reactivity to Al, Co, Cr, and Ni. The
highest levels of metal reactivity were to Ni at 1-2 years post-op.
Quartile Based Reactivity levels: Using the 150 people reactive to
Nickel a quartile division was used to delineate mild, moderate and high
reactivity. 50% of Nickel reactive people had an SI between 2 and 4 and
were characterized as mildly reactive. 25% of Nickel reactive people had
an SI between 4 and 8 and were characterized as reactive. The remaining
25% of subjects were characterized as highly reactive (SI> 8).
DISCUSSION: These results partially support our hypothesis that
Nickel was the most prevalently reactive metal (Fig 1), but average
Cobalt reactivity was equal to Nickel in level of metal of reactivity
elicited (Fig 2). This suggests that among metal-sensitive orthopedic
populations, reactivity to Cobalt may be more of a concern than Nickel
reactivity due to the prevalence of Cobalt in Co-alloy articulating TJA
surfaces. The dominance of Nickel as an immunogenic metal facilitates
its use as a marker of low, medium and high reactivity. On a quartile
basis, only 25% of reactive subjects had an SI>8, Fig 3. However this
scale is not based on clinical outcome and the relationship between level
of metal reactivity and implant performance is not established.
Currently efforts are underway using these finding to relate implant
performance of to this quartile based ranking system. Whether elevated
lymphocyte reactivity to metal is predictive of early or eventual revision
arthroplasty remains undetermined and is currently the subject of
continued follow-up study.
0
0
2
4
6
8
10 12 14 16 18 20 22 24 26 28 30 32 34 36
Level of Reactivity
Proliferation (Stimulation) Index (SI)
Figure 3. Quartile-based assessment of mild, moderate and
high levels of reactivity.
Poster No. 2166 • 56th Annual Meeting of the Orthopaedic Research Society