Immune Response to Orthopedic Implants

Immune response to orthopedic hardware after implantation could be due to metal sensitivity or against other components, usually of bone cement.

The condition though rare, metal hypersensitivity should be considered.

In cases of recurrent pain and aseptic loosening related to implanted hardware.

The first report of cutaneous hypersensitivity caused by a metallic orthopedic implant was a 1966 case report by Foussereau and Laugier, which described a patient with eczematous dermatitis overlying the site of a metallic plate used for fracture fixation.

The metal hypersensitivity could also be seen in cardiovascular, dental, plastic and surgical implants and is not limited to the orthopedic device.

Most of these manifest in for of allergic skin reactions,  impaired wound healing, infection-mimicking reactions, effusions, pain, and implant loosening.

Metal sensitivity may also be associated with chronic fatigue syndrome, fibromyalgia, and autoimmune syndromes.

But, it could be difficult to reach at the diagnosis in a particular case.

Different metals in the implants, different manufacturing methods, small numbers of patients in the studies, and difficulty in achieving adequate diagnosis add to the confusion.

Moreover, the clinical spectrum overlaps with more frequent causes of allergy and the diagnosis in question can be reached at only by exclusion further adds to the difficulties.

Once the more common causes of implant failure have been excluded [Infection, non-union, aseptic loosening, other inflammatory conditions, mechanical failure of the implant, and malalignment issues]  the possibility of allergic reaction to the metal must be considered, evaluated, and if present, managed.

Metal Sensitivity and Implant Failure

In metal sensitivity, patients report hypersensitivity reactions to metals found in costume jewelry, belt buckles, or watches. The most common metal sensitivity in humans is against nickel. The others are beryllium, cobalt, chromium, tantalum, titanium, and vanadium.

The overall prevalence is estimated to be between 10% and 15%, higher in women than in men.

In contrast to cutaneous exposure to metals in the day to day life, metallic orthopedic implants are inserted deep but these metals can sensitize the body and provoke an immune reaction.

It has been found that circulating metal ions increase following joint replacement, especially in patients who have experienced implant loosening and is attributed to the continuous release of metal ions into the tissue surrounding the implant. This release occurs as a result of the corrosive process.

It is theorized that the accumulation of metal ions may trigger a localized inflammatory response that can lead to implant failure.

This proposed etiology is controversial though.

Metal hypersensitivity in patients with a failed implant is approximately six times more common than in the general population, and three times higher than in all patients with a metallic implant.

It is not known, however, whether this hypersensitivity is the cause or the result of implant failure, or whether separate autoimmune mechanisms may be responsible

Pathophysiology of Immune reaction of Implant

The hypersensitivity reaction is typically in an immune response mounted against metallic particles that are released as a result of implant wear or corrosion [it was seen more in metal on metal prostheses].

Loose metallic degradation products are known as haptens. These can complex with proteins and become capable of acting as antigens for circulating lymphocytes and induce an immediate humoral hypersensitivity response (type I, II, and III hypersensitivity reactions).

More commonly, these induce a cell-mediated delayed-type (type IV) hypersensitivity response via the activation of CD4+ T_H1 lymphocytes in the peripheral lymphoid tissues which release. pro-inflammatory cytokines (i.e., TNF-?, IFN-?, IL-1, and IL-2). These cytokines recruit macrophages to the site of the implant.

Significant levels of metal ions have been found in the periprosthetic tissues, the liver, spleen, lymph nodes, and urine/serum of hip arthroplasty patients. This shows that it is not just a local phenomenon.

As noted before, the hypersensitivity reaction can be to non-metallic components of the implant as well [even when metal hypersensitivity is not present], including allergens in the bone cement such as acrylates, benzoyl peroxide, N, N-dimethyl-p-toluidine, and gentamicin.

Another theory suggests that aseptic joint loosening may involve the proliferation of osteoclasts on metals such as titanium and vanadium and their subsequent degradation, uptake, and release of the metals from the device. This accounts for the high serum levels of metal in the systemic circulation and would serve as a potential mechanism for implant loosening.

This also induces a hypersensitivity reaction that exacerbates the loosening process.

Another proposed mechanism involves the haptenogenic stimulation of toll-like receptors in the periprosthetic tissue.

Still, others maintain implant loosening is primarily the result of a cytotoxic process in response to prolonged wear on the joint.

The nature of the implant alloy and the local exposure of the implant are important.
For example, implant-grade 316L (low carbon) stainless steel releases far less nickel than low-grade stainless steel suture.

Implant properties may alter the amount of surface area available for metal ion release.

Plasma-spray coatings and grouting agents decrease ion release from the implant. Roughened, grit-blasted or grooved surfaces increase the surface area available for ion release from and thereby increase the local levels of dissolved metal.

Clinical Presentation

The patients may present with symptoms suggestive of non-union and hardware failure, including pain and motion at the fracture

Patients with joint replacements have symptoms of loosening, including pain and instability.

Local signs may be normal or very subtle. Sometimes, warmth, erythema, and swelling over the implant may be present [as in infection], though systemic complaints (eg, fever) are unlikely.

Metal hypersensitivity may also present as a skin rash at the site of the implant. The manifestations are usually subtle.

In the usual course of true postimplantation metal hypersensitivity, the symptoms develop over months to years. In the case of fracture fixation,  this may be long after the union renders the device dispensable.

In multipart devices, like prosthetic joints may be associated with periods of increased activity

There is also evidence that metal sensitivity may play a role in causing the conditions of chronic fatigue syndrome, fibromyalgia, and autoimmune/inflammatory syndrome induced by adjuvants (ASIA).

Differential Diagnosis

Infection should be ruled out.

Osteolysis due to implant loosening is always in the differential diagnosis.

The mechanism of osteolysis is primarily a local reaction to particulate debris,  which leads to a cascade of cellular reactions that eventually lead to increased osteoclastic activity around the prosthesis. Osteolysis is a reaction to local irritation, not an immune hypersensitivity response.

Diagnostic Workup

No workup is required in asymptomatic patients with a stable implant. The purpose of the workup is to confirm hypersensitivity to be a cause of implant failure.

In most of the fracture fixations, the hypersensitivity or implant loosening, if presents usually seen after a long time after union.

So the workup is required in cases of implant failure with non-union and prosthetic loosening.

It is important also to rule out non-allergic causes of implant failure which include aseptic osteolysis, infection, recurrent dislocation, and fracture.

 Blood Tests

Routine blood tests may show inflammatory mediators (eg, platelet count, C-reactive protein [CRP] level, and erythrocyte sedimentation rate [ESR]) are normal or mildly elevated.

Serum Levels of Metal

Concentrations of metal ions increase due to corrosion of the implant. These concentrations increase in loose implants.

Monitoring chromium and cobalt concentrations [every 6-12 months] have been suggested for patients with painful metal-on-metal hip replacements

The reference range for blood levels of cobalt and chromium are not defined but in the unexposed population, normal ranges are below 10 nmol/L and below 5 nmol/L, respectively.

They are in the range of 30 and 45 nmol/L, respectively, in unilateral well-functioning hip prostheses but increase to 6550 and 3400 nmol/L in failed prostheses.

Aspiration/Swabs

 The peoperative aspiration for cultures, to rule out infection. Tissue culture and swabs from the affected area would help to rule out infection as the cause but false positives and false negatives are common.

Biopsy

Biopsy of the synovial membrane at is the most accurate method for differentiating between infection and hypersensitivity reaction to the implant.

An arthroscopic biopsy with an intraoperative frozen section of the periprosthetic membrane is ideal for diagnosis.

There is an appearance a diffuse collection of perivascular lymphocytes, plasma cells, localized bleeding, necrosis, fibrin exudation, and presence of macrophages with drop-like inclusions

Imaging

X-rays may show

• Radiolucencies around the hardware
• Screw migration
• Change in position of the implant
• Cystic changes may be seen. [as seen in osteolysis]

Computed tomography (CT) is not especially helpful.

Magnetic resonance imaging may help to evaluate the status of the implant. Ultrasonography can also detect fluid but is nonspecific.

Tests for Hypersensitivity

Skin Patch Test

Skin patch testing has for metal hypersensitivity is cost-effective but the result of test needs to be considered in the context of a patient’s medical history and physical findings. 

 Many patients with implanted metal hardware have a positive skin test for those but are asymptomatic.

Patients who have a clear history of contact dermatitis to metal should be evaluated by patch testing prior to device implantation. But a positive patch test alone should not be used to justify the removal of the device. That decision to explant a device should be made on the basis of clinical factors and a risk-benefit analysis.

Patch testing in patients with a history of metal allergy helps to choose a less immunogenic device for implantation.

No causal relationship can be made between patch test reactivity and implant performance.

Lymphocyte transformation test

Some authors consider the lymphocyte transformation test to be the most reliable test.

The test involves measuring the proliferative response of T lymphocytes upon 7-day incubation with and without the addition of metal antigen.

Lymphocyte transformation test is a helpful test in doubtful or questionable cases.. LTT more directly tests the immune components responsible for the hypersensitivity reaction in the periprosthetic tissue than the patch test

Lymphocyte transformation test has yet to earn widespread adoption among providers evaluating cases of suspected metal yet to be used widespreadly.

It is also technically sophisticated and expensive.

Lymphocyte transformation test is still not widely available, is not well standardized and some authors recommend against its routine use. 

Lymphokine Migration Inhibition Factor Test

This test selectively detects lymphokine migration inhibition factor, which, when present, indicate an active immune response and metal sensitivity. 

[Lymphokine migration inhibition factor acts to prevent lymphocytes from leaving a site where foreign antigens are present.]

The test is performed by isolating the lymphocytes and mixing  with solutions of specific metal ions, such as nickel, chromium, cobalt, or titanium

The test result is considered positive if the lymphocytes stay in the metal ion solution, indicating a cellular reaction to the metal dissolved in that solution. (No migration means positive test)

The test result is negative if the lymphocytes migrate away from the particular metal ion solution [This indicates that lymphocytes are not reacting to the dissolved metal.]

The lymphokine MIF is considered as the most useful clinical test for diagnosis of hypersensitivity reaction to orthopedic implants.

Cement wear particles are immunologically inert and have specifically been found not to cause a lymphocyte response in vitro. Thus, the lymphokine MIF result should be negative in osteolysis.

Other Tests

Luminex cytokine assays may more accurately reveal the qualitative and quantitive involvement of different cell types. Increased cytokine levels are found in patients with aseptic loosening.

Phase-contrast and laser scan confocal microscopy (LSCM) is another method of quantifying the number of positive cells involved in the immune reaction.

Treatment

There is no medical treatment is available. However, in patients where surgery is not to be done, a 21-day course of topical corticosteroids may sometimes control symptoms.  Analgesics including nonsteroidal anti-inflammatory drugs may control the symptoms.

Options for surgical treatment are

Revision Surgery

This is considered in joint replacement prosthesis or fracture implant that is still necessary for fracture stability.

An implant with titanium alloy or zirconium coating may be successful. Ceramic implants are chosen over the metal on metal implants. Use of implants with polytetrafluoroethylene-coated bearing surfaces is currently being investigated

Removal

For implant that is no longer necessary – Removal

Surgical removal of the culprit metal in these cases results in a clearing of the hypersensitivity reaction.

Prevention

In selected patients with known metal hypersensitivity, alternative prostheses or fracture fixation implants during preoperative planning may be considered for prevention of hypersensitivity.

However, routine preoperative screening in patients with no symptoms of metal hypersensitivity.

Testing is indicated in patients with known hypersensitivity reactions though there is no agreement on which specific patients require testing

Patients with known nickel allergy who, for example, may best be treated with titanium implants when such devices are available either in primary or revision surgery.

Before routine total hip or knee replacement, in patients suspected of having metal allergies, alternative prostheses may also be indicated, including ceramic implants, implants composed of different alloys, and coated implants.

References 

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2. Goldring SR, Clark CR, Wright TM. The problem in total joint arthroplasty: aseptic loosening. J Bone Joint Surg Am. 1993 Jun. 75(6):799-801. .
3. Merritt K, Brown SA. Metal sensitivity reactions to orthopedic implants. Int J Dermatol. 1981 Mar. 20(2):89-94.
4. Lachiewicz PF, Watters TS, Jacobs JJ. Metal Hypersensitivity and Total Knee Arthroplasty. J Am Acad Orthop Surg. 2016 Feb. 24 (2):106-12.
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6. Swiontkowski MF, Agel J, Schwappach J, et al. Cutaneous metal sensitivity in patients with orthopaedic injuries. J Orthop Trauma. 2001 Feb. 15(2):86-9.
7. Donati ME, Savarino L, Granchi D, et al. The effects of metal corrosion debris on immune system cells. Chir Organi Mov. 1998 Oct-Dec. 83(4):387-93
8. Lützner J, Hartmann A, Dinnebier G, Spornraft-Ragaller P, Hamann C, Kirschner S. Metal hypersensitivity and metal ion levels in patients with coated or uncoated total knee arthroplasty: a randomised controlled study. Int Orthop. 2013 Oct. 37 (10):1925-31.