Cutaneous and Systemic Hypersensitivity Reactions to Metallic Implants

Juliana L. Basko-Plluska; Jacob P. Thyssen; Peter C. Schalock

Dermatitis. 2011;22(2):65-79.

Abstract and Introduction

Abstract

Cutaneous reactions to metal implants, orthopedic or otherwise, are well documented in the literature. The first case of a dermatitis reaction over a stainless steel fracture plate was described in 1966. Most skin reactions are eczematous and allergic in nature, although urticarial, bullous, and vasculitic eruptions may occur. Also, more complex immune reactions may develop around the implants, resulting in pain, inflammation, and loosening. Nickel, cobalt, and chromium are the three most common metals that elicit both cutaneous and extracutaneous allergic reactions from chronic internal exposure. However, other metal ions as well as bone cement components can cause such hypersensitivity reactions. To complicate things, patients may also develop delayed-type hypersensitivity reactions to metals (ie, in-stent restenosis, prosthesis loosening, inflammation, pain, or allergic contact dermatitis) following the insertion of intravascular stents, dental implants, cardiac pacemakers, or implanted gynecologic devices. Despite repeated attempts by researchers and clinicians to further understand this difficult area of medicine, the association between metal sensitivity and cutaneous allergic reactions remains to be fully understood. This review provides an update of the current knowledge in this field and should be valuable to health care providers who manage patients with conditions related to this field.

Introduction

Contact Allergy to metals such as nickel, cobalt, and chromium is prevalent in the general population. It is estimated that up to 17% of women and 3% of men are nickel allergic, and that about 1 to 2% are allergic to cobalt, chromium, or both.^[1] Metal allergy is mainly caused by prolonged or repeated skin exposure to consumer items such as jewelry, cell phones,^[2] clothing fasteners,^[3] and leather goods.^[4] In some countries, a significant proportion of metal allergy derives from occupational exposure in the metal and construction industries.^[5] Independent of the primary cause of metal sensitization, the insertion of metallic implants may result in eczematous eruptions on the skin overlying the implant or in device failure caused by delayed-type hypersensitivity (DTH) (eg, chronic inflammation, pain, loosening of joint prostheses, or restenosis of cardiac stents). In an aging population, the putative association between metal allergy and device failure due to DTH may be a problem of growing significance.^[6] This review aims to update the reader on the general aspects of this complex topic and to briefly discuss future challenges.

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Abstract and Introduction
Compositions of Metal Implants
DTH Reactions
Implant-related Allergic Contact Dermatitis
Conclusions
References

Table 1. Some Metals and Metal Alloys Used in Implants
Implant Type	Stainless Steel	Metal Alloy							Copper
Implant Type	Stainless Steel	Co-Cr-Mo	Vitallium	Titanium	Mercury	Cr-Co-Ni	Gold	Nitinol	Copper
Orthopedic	+	+	+	+	—	—	—	—	—
Dental	+	—	—	+	+	+	+	—	—
Endovascular	+	—	—	+	—	+	+	+	—
Cardiac pacemaker	—	—	—	+	—	+	—	+	—
Gynecologic	+	—	—	+	—	—	—	+	+

Co = cobalt; Cr = chromium; Mo = molybdenum; Ni = nickel.

Table 2. Components of Selected Alloys Used in Metal Implants
Implant Alloy	Metal	Approximate %
316L stainless steel¹⁴	Nickel	8.3–35
	Chromium	20
	Manganese	2
	Molybdenum	2–3
	Nitrogen	0.1
	Carbon	0.03
	Sulfur	0.03
	Silicon	0.75
	Phosphorus	0.045
	Iron	Balance
Cobalt-chromiummolybdenum steel (ASTM F75)¹⁵	Chromium	27–30
	Molybdenum	5–7
	Nickel	< 0.5
	Iron	< 0.75
	Carbon	< 0.35
	Silicone	< 1
	Manganese	< 1
	Tungsten	< 0.2
	Phosphorus	< 0.02
	Sulfur	< 0.01
	Nitrogen	< 0.25
	Aluminum	< 0.1
	Titanium	< 0.1
	Boron	< 0.01
	Cobalt	Balance
Vitallium⁸	Cobalt	61
	Chromium	32
	Silicon	0.5
	Manganese	0.5
	Carbon	0.02
	Boron	0.1
	Molybdenum	5.6
	Iron	None
Titanium	Titanium	89.9
	Aluminum	5.5–6.5
	Vanadium	3.5–4.5
	Nickel¹⁰	Trace
Nitinol	Titanium	55
	Nickel	45
Oxinium	Zirconium (oxidized)	97.5
	Niobium	2.5
	Nickel	None

ASTM = American Society for Testing and Materials.

Table 3. Diagnostic Criteria for Metal-Induced Cutaneous Allergic Reactions
1. Chronic eczema beginning weeks or months after the implant
2. Eczema most severe around the implant site
3. Absence of other contact allergens or systemic cause
4. Patch tests positive or strongly positive for one of the metals in the alloy
5. Complete and rapid recovery after total removal of foreign metal implant

Adapted from Merle C et al.¹⁹

Table 4. Prospective Longitudinal Studies and Reviews*
Study or Review	Reference No.	Total Patients	Conclusions
Carlsson and Möller, 1989	20	18	Metal allergic patients, screened before receiving stainless steel orthopedic implants. None had issues despite confirmed allergy to one of the metals in their device (6-year follow-up).
Gawkrodger, 1993	7	N/A	"…it appears that most patients who are metal-sensitive can safely receive an orthopedic implant containing that metal without the risk of cutaneous or systemic complications."
Merritt and Rodrigo, 1996	115	22	< 1% develop cutaneous reactions versus 20–25% of patients who develop implant-induced metal sensitivity without any allergic skin manifestations
Hallab et al, 2001	9	N/A	Metals corrode in biologic systems, allowing for hapten formation. These degradation products of the implant may cause increased metal hypersensitivity and implant failure. Those with failed implants have a higher rate of dermal sensitivity.
Niki et al, 2006	21	92	26% of screened patients (n = 92) had positive lymphocyte stimulation tests to at least one metal (Ni, Co, Cr, Fe). In those with metal positives prior to implantation, 21% (5/24) developed cutaneous dermatitis at the site of implantation and (in some cases) widespread dermatitis; 5% of the total study group with metal orthopedic implants developed cutaneous allergic reactions.
Thyssen et al, 2009	41	356	The risk of surgical revision was not increased in patients with metal allergies, and the risk of metal allergy was not increased in patients who were operated on, in comparison with controls.
Eben et al, 2010	117	92	66/92 had symptoms (pain, reduced motion, swelling).
			Rates of allergy: nickel, patients (24.2%); cobalt, 6.1%; chromium, 3.0
			Symptomatic patients (31.8%) showed an allergic reaction to bone cement components (gentamicin 23.8%, benzoyl peroxide 10.6%, hydroquinone 4.5%)
			Sensitization rates in symptom-free patients: 3.8% for nickel, cobalt, chromium; 15.4% for gentamicin

Fe = iron; Co = cobalt; Cr = chromium; N/A = not applicable; Ni = nickel.
*List may not be exhaustive.

Table 5. Cutaneous Reactions after Insertion of a Metallic Orthopedic Implant*
Authors	Ref. No.	Patients	Procedure	Clinical Symptoms or Signs	Time to Appearance	Management and Outcome	Patch-Test Reactions
Thomas et al	8	37-year-old female s/p fracture of right wrist	Reduction and insertion of vitallium plate	Oozing, irritation around scar initially, then extended to right forearm and hands	10 weeks post surgery	Rash resolved after plate removal	Nickel +++
							Cobalt +++
Merle et al	19	57 M s/p fracture of left knee	Osteotomy with insertion of vitallium plate and screws	Generalized eczema	3 mo post surgery	Topical therapy unsuccessful; rash resolved after plate and screws removed	Cobalt ++
Rostoker et al	24	27 M s/p fracture of left tibia	Sherman plate (stainless steel alloy Al316)	Generalized eczema	7 mo post surgery, for 7-yr duration	Rash resolved within 1 mo of hardware removal	Nickel +++
Rostoker et al	24	56 F s/p fracture of left tibia	Intramedullary nail (stainless steel alloy Al316)	Generalized eczema	12 mo post surgery	Rash resolved within 15 days of hardware removal	Negative
		28 M s/p fracture of left clavicle	Osteosynthesis with screw (stainless steel alloy Al316)	Generalized urticaria	12 mo post surgery	Topical therapy unsuccessful; rash resolved within 1 mo of hardware removal	Negative
Kanerva and Forstrom	25	35 M s/p fracture of right ankle	Surgical realignment, metal plates & screws (made of Fe, Cr, Ni)	Eczema on hands	1 mo post surgery	Rash improved with hardware removal, but quickly relapsed	Nickel +++
							Budesonide +++
							Chromate +
Verma et al	118	15 patients (13 F, 2 M; 65–80 yr)	TKA	Localized eczema	1–3 mo post surgery	Rash resolved with topical steroids	Nickel + (4/15)
							Chromium + (2/15)
							Cobalt + (1/15)
Thomas et al	27	35 F s/p fracture of right tibia	Open reduction and plate fixation	Localized eczema	A few weeks post surgery	Ongoing eczema due to remaining metal fragments after plate removal	Nickel ++
							Cobalt +
Carboni et al	28	6 patients (53–72 yr)	PCA prostheses (4 hip, 1 knee, 1 patella removal)	Itching, pain (4 patients)	A few months post surgery	Not available Nickel	Nickel +++ (3/6)
				Eczema (2 patients))			Cobalt +++ (3/6)
							Imidazolidinylurea +++ (1/6)
							Ethylenediamine chlorhydrate (1/6)
Carboni et al	28	3 patients (45–70 yr)	ABG hip prostheses	Itching, burning	Not available	Not available	Negative
Carboni et al	28	2 patients (63 and 34 yr)	Arthroimmobilization	Diffuse eczema	Not available	Not available	Negative (1/2)
			Osteosynthesis with A0 prostheses				Nickel, cobalt +++ (1/2)
		73-yr-old with fractured leg	Left-leg prosthesis (acrylic cement) and potassium dichromate	Diffuse eczema	6 mo post surgery	Eczema completely resolved after prosthesis removal	Positive for certain allergens in the acrylic cement and for potassium dichromate
Ridley	29	78 F with OA	TKA with metal-onplastic prosthesis (Co-Cr alloy)	Initial localized swelling and pain	2 mo post surgery	Not available	Not available
				Eczematous reaction while being treated with antibiotics
Symeonides et al	30	30 M s/p fracture of right humerus	Open reduction and internal fixation with vitallium plate and screws	Generalized urticaria	2 mo post surgery	Urticaria completely resolved within 3 days of hardware removal	Nickel +
Gao et al	119	62 M with OA	TKA, Co-Cr-Mo alloy	Generalized eczema	6 mo post surgery	Eczema resolved within 2 mo of revision to zirconium-niobium alloy prosthesis	Chromium ++++
Handa et al	120	57 M	Total knee replacement with condylar knee	Exudative dermatitis	2 mo post surgery	Not available	Cobalt +
							Copper sulfate +
							Nickel −
Beecker et al	121	48 F with bilateral OA and allergy to Ni and Co	Bilateral TKA	Eczematous dermatitis that became generalized	1–2 mo post surgery	Skin findings managed with topical steroids, with good response	Nickel +++
							Cobalt +++

ABG = Anatomique Benoist Giraud; Co = cobalt; Cr = chromium; F = female; Fe = iron; M = male; Mo = molybdenum; Ni = nickel; OA = osteoarthritis; PCA = porous coated monatomic; Ref. = Reference; s/p = status post; TKA = total knee arthroplasty.
*List may not be exhaustive.

Table 6. Cases of Aseptic Lymphocytic Vasculitis–Associated Lesions after Hip Arthroplasty*
Authors	Ref. No.	Patient	Procedure	Clinical Symptoms and Signs	Time to Onset	Management and Outcome	Periprosthetic Fluid Analysis and Biopsy Result
Mikhael et al	122	53 M	Bilateral MOM arthroplasty	Bilateral hip pain, intermittent lowgrade fever	Pain at time of surgery; persistent for 3 yr	Exchange of metal liner with cross-linked polyethylene liner led to resolution of pain and fever within 8 mo.	ALVAL
		55 M	Left MOM THR	Pain, swelling, limping	3 mo post surgery	Implantation of cross-linked polyethylene bearing surface led to symptom resolution in 3 mo.	ALVAL
Campbell et al	123	53 F	MOM hip resurfacing with Co-Cr alloy	Groin pain	4 mo post surgery	Revision to titanium THR with ceramic-on-ceramic bearing led to symptom resolution.	ALVAL
		47 F	MOM hip resurfacing with Co-Cr alloy	Groin pain, locking sensation, swelling	3 mo post surgery	Revision to cementless total hip with ceramic-onceramic bearing led to symptom resolution.	ALVAL
		54 M	Bilateral MOM hip resurfacing	Groin pain	1 yr post surgery	Revision to a ceramic-on-ceramic THR led to symptom resolution.	ALVAL
		56 M	MOM hip resurfacing	Groin pain	4 mo post surgery	Revision to titanium alloy with ceramic-on-ceramic bearing led to symptom resolution.	ALVAL
Jensen et al	124	71 F	THA, Co-Cr based	Groin pain	Months after surgery	Normal pelvic radiography. CT scan showed cystic collection of fluid with negative leukocyte scintigraphy. Large periprosthetic cystic mass removed surgically.	ALVAL
Counsell et al	125	40 F	Bilateral hip replacements	Lump in left groin associated with shooting pain	12 mo post surgery	Surgical exploration; pending revision.	ALVAL

ALVAL = aseptic lymphocytic vasculitis–associated lesions; Co = cobalt; Cr = chromium; CT = computed tomography; F = female; M = male; MOM = metal-on-metal; Ref. = reference; THA = total hip arthroplasty; THR = total hip replacement.
*List is not exhaustive.

Table 7. Other Cases of Metal Reactions following Hip or Knee Arthroplasty*
Author	Ref. No.	Patient	Procedure	Clinical Symptoms and Signs	Time to Onset	Management and Outcome	Periprosthetic Fluid Analysis and Biopsy Results
Pandit et al	126	50 F	Bilateral MOM hip resurfacings (34 mo apart)	Hip pain	6 weeks post 2nd surgery	Revision to conventional THR led to resolution of pain.	Pseudotumor posterior to joint
		64 F	Bilateral hip arthroplasty	Groin pain; lump under scar	58 mo post surgery	Symptoms controlled with repeated joint aspirations.	Bilateral pseudotumors
		47 F	Bilateral hip arthroplasty	Bilateral hip pain	2 mo post 2nd surgery	Revision on one side. led to symptom resolution; awaiting revision on other side.	Bilateral pseudotumors anterior to joints (10 mo apart)
		65 F	Bilateral hip arthroplasty	Hip pain; femoral nerve palsy	6 mo post 2nd surgery	Staged revision resulted in pain relief, but nerve palsy did not recover.	Pseudotumors posterior to joints (4 mo apart)
Pandit et al	127	35–73 F (17 pts)	MOM hip resurfacings	Pain (15/17); lump (6/17); nerve irritation or palsy (5/17); dislocation (2/17); instability (2/17); rash (1/17); none (2/17)	Mean: 17 mo post surgery (0–66 mo)	13/17 underwent revisions to conventional THR; 8/13 with improved symptoms; 4/13 with complete resolution; 2/17 awaiting revision; 3/17 coping well.	Pseudotumors
Benevenia et al	128	63 M	Cementless TKR	Dull aching pain, swelling, followed by supracondylar fracture	6 yr post surgery	Surgical exploration, revision to LCS prosthesis with bone graft and PMMA cement.	Pseudotumor posterolateral to the joint
Dietrich et al	129	57–68 F (4 pts) with metal allergy	TKA with Co-Cr-Mo–based endoprostheses	Erythema, swelling, sterile effusions, pain with limitation of movement	Months to years post surgery	Changed to titaniumplated endoprostheses; symptoms resolved.	None

Co-Cr-Mo = cobalt-chromium-molybdenum; LCS = low contact stress; MOM = metal-on-metal; PMMA = polymethylmethacrylate; pts = patients; Ref. = reference; THR = total hip replacement; TKA = total knee arthroplasty; TKR = total knee replacement.
*List is not exhaustive.

Table 8. Common Bone Cement Allergens Used in Total Joint Arthroplasties
Allergen	Reference No.	Use	Approx. % Positive Reactions
N,N-Dimethyl-p-toluidine	47	Reaction initiator	10
Polymethyl methacrylate (MMA)	48	Cement base	25
Benzoyl peroxide	117, 130	Activator	8–10
Hydroquinone	117	MMA stabilization	5
Gentamicin	130	Antibiotic	17–24

Table 9. Studies Evaluating In-Stent Restenosis*
Authors	Reference No.	Total Patients	Conclusions
Koster et al	81	131	Prospective: 171 total stents; in-stent restenosis in 100% of patients with positive patch-test result but in only 57% of patients with negative patchtest results; no control group; only significant differences were for nickel and molybdenum.
Iijama et al	82	174	No difference in positive patch-test results between restenosis and nonrestenosis groups after stent implantation (9% vs 10%).
Hillen et al	83	34	Restenosis occurred predominantly in patients with negative patch-test reaction to nickel.
Norgaz et al	84	43	Patch-tested at time of stenting and again in 6 mo; 6.9% were nickel allergic, but 37% developed instent restenosis; 1/3 nickel-allergic patients developed diffuse in-stent restenosis.
Saito et al	85	> 1 stenosis = 60 (case) 1 stenosis = 68 (control)	Bare metal stainless steel 316L stents; 19% (24/128) of all patients were nickel positive; "24 nickel positives, 30% in study group, 9% in control group (p = .02)."
			Multivariate analysis: most significant predictor of chronic in-stent restenosis: reference vessel diameter (p = .0010), nickel positive (p =.0033), hyperlipidemia (p = .0305).
			Highest odds ratio for restenosis (5.41) were in nickel positives.
Hansen et al	86	10	No metal allergy was found in 10 patients with very late in-stent restenosis.
Svedman et al	87	338	Nickel-stented patients: difference in restenosis rate between "allergic patients with restenosis (n = 8, 17.8%) and not allergic with restenosis (n = 36, 12.3%) was not statistically significant (p > .3)."

*List may not be exhaustive.

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