We live in an era where developments in DNA sequencing and proteomics are allowing researchers to make rapid advances in the understanding of complex disease processes.1 But this technology has not replaced the fundamentals of medical practice. The diagnoses of the most common diseases still rely upon history taking, clinical examination, basic blood tests and imaging. The ability of doctors to understand disease processes, classify them - and thus diagnose them clinically - has to a large extent been developed through the histopathological assessment of diseased tissues. Even in modern medicine, histopathology remains a cornerstone of correctly identifying – and therefore managing - diseases.2
Once a disease process is described and hallmark macro and microscopic features well defined, then further, more specific tests can be developed – either to make it easier for clinicians to diagnose a condition, to identify specific disease features associated with disease progression, or to direct specific treatments. Why is this relevant to the subject of metal allergy following arthroplasty?
Nickel has long been the focus when it comes to discussing metal allergy as a potential cause of arthroplasty failure.3 The diagnosis of nickel allergy has historically been made through the use of skin patch testing4 or lymphocyte transformation tests (LTTs).5 But, to date, there remains no clear understanding of how nickel allergy relates to periprosthetic tissue responses at a microscopic (in terms of well-defined histopathological features) or macroscopic level (the viability of periprosthetic tissues).6, 7 The published evidence supporting the clinical relevance of nickel allergy is at best, even after decades of research, equivocal.4, 6-10 The continued use of the term nickel allergy, and the persisting use of skin patch and LTT tests to identify this ill-defined condition, has led many surgeons to doubt the clinical relevance - if not the very existence - of metal hypersensitivity.11, 12
It could be argued that LTTs and skin patch testing came to be viewed as the gold standard to diagnose metal allergy, before the disease had been well defined (Figure 1) . If we look to specialties outside of orthopaedics, there are several hypersensitivity diseases which have been intensively studied over a number of years.13 These diseases have well defined pathological features, established risk factors, and detailed pathogeneses. In these conditions, it is a well-recognised issue that, in general, skin patch testing and serological studies (including LTTs), identify exposure to an antigen, rather than detecting clinically relevant disease.14 This is further discussed below.
Fig 1: Light microscopic images of CoCr alloy (a and b) and Ti alloy (c and d) tibial trays showing pitting on the superior surface. Red dotted lines on Ti alloy tray c indicate imprinting of the lot number marking of the polyethylene insert on the superior surface of the tray. Pitting is present on over 50% of explanted trays we receive at ExplantLab.
The failure of modern metal-on-metal hip arthroplasty was not a high point in the history of orthopaedic surgery.15 But one of the few positives that can be taken from the experience is the knowledge the orthopaedic community developed with regard to the understanding of immune responses to implants. Circa 2005, Willert and Davies provided a detailed description of the pathological responses seen in association with failed metal-on-metal hip prostheses.16 These pathological features included prominent perivascular lymphocyte infiltration, formation of high endothelial venules, accumulation of sheets of macrophages and surface membrane necrosis.
The acronym ALVAL (“aseptic lymphocyte dominated vasculitis associated lesion”) was coined. Clearly, ALVAL was a newly recognised condition.
As Davies wrote:
Following Willert et al’s publications, clinicians and researchers now had a defined disease, with defined pathological features that could be quantified on tissue specimens. Because of this, and in addition to the large number of patients who presented to clinics around the world experiencing complications from metal-related pathology, a substantial amount of knowledge was gained over a short period of time in the understanding of ALVAL. It is important to note, however, that in their seminal 2008 paper on pseudotumour development following metal-on-metal hip resurfacing, the Oxford group speculated that these (at times, catastrophic) periprosthetic reactions could be due to nickel allergy. To reiterate the point: metal-on-metal failure was originally proposed to be due to nickel allergy.18 It is also crucial to note that when the first reports of metal-on-metal hip failures began to emerge, blood metal ion testing was not routinely performed nor believed to be of benefit in patient management.
At around the same period in time, in our hospital we began to see an ever increasing number of patients who developed ALVAL responses to their ASR hips.19 In an attempt to find answers, we established a retrieval laboratory to measure the volumetric material loss from the bearing and taper surfaces of explanted devices.20 These values were compared to synovial, blood and serum metal ion concentrations and, most importantly, to the associated periprosthetic tissue responses. From the results, it became clear that our patients were developing aggressive ALVAL responses to abnormally functioning prostheses.21
The issue of nickel allergy was still at the forefront of our thoughts, however. We carried out a small study to investigate the possibility that LTT testing may show that these patients were sensitive to nickel.21 We performed LTTs on blood samples obtained from a group of patients who had experienced failure of their ASRs secondary to ALVAL. We then compared these results to a control group who had elevated blood metal ion concentrations but were symptom free, with no abnormalities detected on cross sectional imaging. In the ALVAL group, only one of six patients tested positive for metal sensitivity on the LTT tests, whereas three of the five patients in the control group tested positive for sensitivity to a range of metals (all positive for nickel). The Oxford group, who had led the world in reporting their investigation of pseudotumours, carried out a similar study with larger numbers.22 Their findings were consistent with ours.
Since Davies and Willert published their work16, 17, there have been over a thousand papers published on ALVAL, submitted from hospital and research centres all over the world. This global effort has allowed the following facts to be established:
- ALVAL is a well-defined condition, in a histopathological sense.16 The pathological features are consistent with a delayed type hypersensitivity response and, as would be expected with delayed type hypersensitivity, reimplantation with cobalt-chrome alloy is ill advised, with symptoms returning after temporary alleviation.16, 19
- ALVAL varies in intensity; multiple grading systems exist.23-25 These grading systems largely agree with each other26, 27, as they are generally in unison on scoring the same parameters; the primary one being the presence of lymphocyte perivascular cuffing.16
- ALVAL has most frequently been identified in studies involving patients with metal-on-metal prostheses. However, a metal-on-metal bearing is not a prerequisite for the condition to develop28-30, and ALVAL has been frequently identified in tissues excised during knee revision surgery.31
- ALVAL is associated with abnormal fluid collections (which can build in pressure), and soft tissue and/or bone damage which can be extensive.30
- The grade of ALVAL correlates with the thickness of synovial lining on MRI32, the extent of surface membrane necrosis of the synovium33 and the level of pain reported by the patient prior to revision.34, 35
- ALVAL is associated with elevations in blood, serum and synovial cobalt and chromium concentrations.23, 25, 36
Regarding the final point, for over a decade we continued to collect data to study the interaction between patient and implant factors and the development of ALVAL in hundreds of patients. We found that while ALVAL was more common in devices generating excessive metal debris, beyond that, there appeared to be immunogenetic factors at play, with different patients displaying different tolerances before developing hypersensitivity.37
There are a host of hypersensitivity diseases which can afflict the human body. They tend to share certain features, however. As Friedmann made clear: “age, sex and genetic factors such as HLA haplotype can all influence whether and to what degree an individual reacts to a substance.”38
As just one example (there are many13), bird fancier’s lung is a common form of delayed type hypersensitivity pneumonitis that results from avian antigen exposure. It is related to the dose and duration of exposure39, 40, age and sex41, but also depends on an individual’s HLA genes.40, 42
Given the existing knowledge regarding hypersensitivity diseases, in 2017, after a decade of data collection, we set about identifying patients with extreme phenotypes in an attempt to identify HLA genetic variants associated with ALVAL. Extreme phenotypes in this respect referred to those patients developing high grade ALVAL reactions following relatively low metal exposure, versus those who appeared resistant to developing ALVAL despite long term exposure to large amounts of metal debris.
We quickly identified significant differences in the frequencies of specific HLA-DQ alleles, even with relatively small patient numbers. Not only that, but the peptide binding groove encoded by the primary HLA-DQ risk haplotype demonstrated an affinity for the N-terminal peptide fragment sequence of albumin, a recognised metal ion binding site.43 These binding affinities, along with patient (age and sex) and implant factors (duration in vivo, presence of modular junction) were entered into a machine learning algorithm which was trained and tested using the largest dataset of patients in the published literature.44 Extension of the genetic testing to include the whole genome did not identify genetic variants that improved the algorithm to any clinically relevant degree. The resulting commercial test "Orthotype” is now available for surgeons in the United Kingdom to use. The evidence validating Orthotype has been reviewed by the UK National Health Service and the test is provided by the NHS Blood and Transplant service. (Find out more)
Orthotype is a test which can be used pre- or post-operatively. It involves a routine blood draw, with samples placed in EDTA tubes and transported at ambient temperature.
With Orthotype Pre-Op, the patient’s HLA-DQ alleles are identified using next-generation sequencing. The resulting haplotypes are then inputted into a machine learning algorithm, along with patient age, sex and device type, to provide the clinician with a relative risk over time (compared to the background population) of the patient developing ALVAL in response to a cobalt-chrome implant.
Orthotype Post-Op can be used to monitor or investigate patients who have already received a cobalt-chrome implant. With this test, blood metal ion levels concentrations are measured using the same samples, and these results are added into the algorithm to provide the clinician with a result: ARMD positive or negative. If positive, a graph is outputted which allows the clinician to view the risk of ALVAL developing over time. The sensitivity and specificity for detection of ARMD post-op is 89% (84-93) and 90% (87-92), with a weighted mean survival probability error of 1.8% for pre-op prediction of ALVAL at 1.8% and 3.1% for post-op ALVAL.44
Orthotype was developed and validated using gold standard histopathological examination of tissue excised at revision surgery. The validation process was performed stepwise, with the candidate genetic variants identified first, then an algorithm developed and tested using prospectively collected data from three different countries. Histology results from 176 revision surgeries were included in the data set, along with clinical results from 430 patients followed up to a maximum of twenty years.44 The same methodology was used in the field of infectious disease to successfully identify genetic variants which confer protection from severe complications caused by COVID.45, 46
The originally published validation study included only patients with metal-on-metal THRs or resurfacings. However, a national study is currently being carried out to provide additional prospective data with patients implanted with other joint prostheses. The test is performing in line with the originally stated sensitivity and specificity values.
As discussed above, the phenomenon of “nickel allergy” has become inextricably linked with skin patch testing and LTTs. But the limitations of these tests as diagnostic tools are well recognised in other fields of medicine. For example, chronic beryllium disease is a pulmonary hypersensitivity disease resulting from exposure to the heavy metal, beryllium. In this HLA mediated condition, exposure to beryllium leads to a cell-mediated immune response where T-cells become sensitised to beryllium resulting in progressive lung damage.47 LTT screening of exposed workers commonly identifies individuals sensitised to the metal who have no evidence of lung disease. In other words, these “sensitised” subjects have a LTT beryllium specific response in peripheral blood, but no clinical or pathologic features of lung pathology.48 A positive LTT in beryllium disease therefore indicates sensitisation, rather than the presence of pulmonary disease.49 This effect is seen in other pulmonary hypersensitivity conditions, with positive skin patch and serological tests in up to 88% of exposed subjects who remain asymptomatic without evidence of disease.14
What is the implication of this? In orthopaedics, we may have used measures of exposure or sensitisation to diagnose disease, rather than identifying disease and then developing diagnostic tests to identify disease. If this is indeed the case, it would explain why these tests have not been proven to accurately identify ALVAL or tissue related complications necessitating revision. The damaging knock-on effect has been to create scepticism that metal hypersensitivity even exists. Rather than doubting the accuracy or appropriateness of the tests, the doubt has been cast on the disease.11
How can we unify the research findings and improve the terminology? If we restrict ourselves to using evidence derived from a classical approach to medicine (signs, symptoms, biochemistry, imaging and histopathology), then it is clear that the evidence indicates that it is ALVAL that is the condition which constitutes a clinically relevant meaningful disease process; the condition which we should be aiming to identify and eliminate moving forward.
ALVAL is present in approximately 30% of tissue samples taken from patients undergoing revision of their knee arthroplasties29, 31, 35 and the grade of ALVAL correlates to the levels of pain reported by patients prior to their revision procedures.34, 35 There is even evidence that ALVAL may masquerade as culture negative prosthetic joint infections, just as was the case with the first metal-on-metal ALVAL reactions encountered by unsuspecting surgeons.31, 50 So why is this condition still viewed with scepticism? Why is ALVAL apparently siloed in the world of failing metal-on-metal hips, and what are the obstacles preventing it gaining attention in other areas of arthroplasty?
The issue of diagnosis
ALVAL is diagnosed through histopathology. Being a relatively novel condition, many non-specialist units may not be aware that ALVAL exists nor have the relevant expertise to identify it. In the UK, most knee surgeons do not send a periprosthetic tissue sample at revision for histological examination. The incidence and clinical significance of ALVAL therefore by definition cannot be determined (in the UK at least) within the bounds of current clinical practice.
A lack of awareness of evidence and persisting, inaccurate beliefs
There is no established culture in current knee arthroplasty practice to measure blood metal ion concentrations post-operatively, and metal hypersensitivity is regarded as a diagnosis of exclusion.51 In these respects, there are striking parallels with the early management of patients with metal-on-metal hips. There remains a fixed belief that metal debris generation from a contemporary knee arthroplasty is clinically insignificant. However, a cursory examination of the literature on the subject identifies evidence to challenge these assumptions. Blood metal ions are frequently elevated to clinically relevant concentrations post knee arthroplasty.52-55 Sceptics may suggest that these elevations only occur with defective or failing devices. Yet evidence shows that even in the idealised environment of a knee simulator, approximately 12 % by weight of the wear products generated from a knee arthroplasty is metallic.56 Furthermore, concerns have been expressed that the increased wear resistance of contemporary polyethylene changes may alter force transmission through the links of the arthroplasty chain, resulting in a change in the magnitude of wear debris generated at each interface.57
The unexplained phenomenon of nickel allergy in knees versus cobalt-chrome associated ALVAL in hips
It is now clear that excessively wearing cobalt-chrome hip components precipitate high rates of ALVAL.37, 58The standard cobalt-chrome alloy used in metal-on-metal hips (ASTM 75) is identical to that used in the vast majority of knee prostheses.59 These cobalt-chrome alloys rarely contain more than 0.2% nickel by weight, compared to up to 65% of cobalt - amounting to a three hundred fold difference. To place nickel under scrutiny seems questionable. As another comparison, an Exeter hip contains fifty times the amount of nickel compared to a cobalt-chrome component. Global clinical experience has demonstrated which devices are more likely to provoke an ALVAL response. That is not to say that nickel associated ALVAL doesn’t exist - far from it – but, just as with other diseases, histopathological analysis should form a cornerstone of the diagnostic process.2
To summarise, the available evidence indicates that ALVAL is the histopathological manifestation of delayed type metal hypersensitivity. Evidence also indicates that debris produced from cobalt-chrome alloy is the most relevant sensitising agent from a clinical perspective. Could it be cobalt, chromium, nickel or perhaps one of the other elemental constituents of cobalt-chrome alloy (such as molybdenum) that is the major culprit? Does it matter? The most relevant clinical question seems to centre on other orthopaedic biomaterials, most notably titanium alloy. At our unit, and as part of the ongoing national Arthrogenex study, we are actively investigating titanium associated ALVAL. It certainly exists.
Reassuringly, it appears that the genetic risk factors associated with ALVAL secondary to cobalt- chrome exposure are not the same as those associated with titanium-induced ALVAL. Does this mean that future surgical practice may be based on biomaterial selection guided by an individual’s DNA profile? Why not? This is already happening in other specialties to guide pharmacological treatment regimes.60-63
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