By Maureen Leahy

Patients with adverse reactions to metal debris, also referred to as adverse local tissue reactions (ALTR), from metal-on-metal (MOM) hip implants have markedly elevated levels of inflammatory cytokines in the periarticular fluid compared to patients with polyethylene-induced osteolysis, according to study data presented by Scott T. Ball, MD at the 2011 Annual Meeting.

“The literature has reported on the significant adverse reactions—including pseudotumors, large fluid collections, and necrotic bone and muscle around the hip—to wear debris generated by MOM bearings,” said Dr. Ball. “To our knowledge, however, the inflammatory cytokines (proteins) that drive these adverse reactions have not been previously investigated.”

The researchers hypothesized that the pattern of cytokine expression in patients with ALTR would differ from those in patients with polyethylene-induced osteolysis or osteoarthritis of the hip, thus defining a distinct ‘phenotype’ unique to ALTR.

“Furthermore, we hypothesized that the cytokine profile in patients with ALTR would vary with metal ion levels in the fluid and with the histologic grade found in sections of the periarticular soft tissues,” Dr. Ball explained.

Study methods
In this prospective, case control study, the researchers collaborated with numerous orthopaedic surgeons in a large metropolitan area to identify suspected cases of ALTR. Through laboratory tests and imaging studies, they confirmed 10 patients (11 joints) with ALTR from MOM hip implants in 2010.

“As a baseline control, we obtained synovial fluid from the hips of six patients with osteoarthritis (OA) who were undergoing primary hip replacement surgery,” said Dr. Ball. “Three patients undergoing revision for polyethylene wear and osteolysis served as a control for adverse reaction to other prosthetic material.”

Clinical data for each ALTR case, including patient age and sex, prosthesis type and implant position, time from index procedure to revision, and relevant laboratory data, were recorded. Intraoperative data, including the extent of soft-tissue destruction; presence, color, quality, and size of fluid collection; presence of bursa/pseudotumor; evidence of metallosis; and status of fixation of implants, were also noted.

At the time of revision, soft-tissue specimens from the involved joints were analyzed histologically for cell types and wear debris and were assigned an ALVAL (aseptic lymphocytic vasculitis-associated lesion) score. Periarticular fluid samples from each patient were collected and analyzed for cobalt and chromium levels and profiled for cytokine expression.

ALTR associated with elevated cytokine levels
The researchers found that periarticular fluid in the ALTR patients contained high levels of certain cytokines (Fig. 1).

“In particular, levels of the interleukins IL-6, 8, and 1ra, as well as levels of IP-10 (interferon-gamma-induced protein of 10 kDa) and tissue necrosis factor alpha (TNF-ɑ, were markedly elevated in patients with adverse reactions to metal debris,” said Dr. Ball. “The displayed levels of these cytokines in the ALTR cases were on average 15 times higher than those in the poly-ethylene/osteolysis patients, and 40 times higher than those in OA patients. This confirms an aggressive inflammatory response and may help to explain the aggressive soft-tissue destruction that is sometimes seen at the time of revision surgery in patients with ALTR.”

With the modest number of cases in this study, the researchers found no significant correlation between cobalt or chromium ion levels and the cytokine levels in the periarticular fluid. None of the implants in patients with ALTR had been recalled. In two patients, the acetabular cups were grossly malpositioned, and both patients had significantly elevated cobalt and chromium ion levels compared to the remainder of the cohort.

As the number of ALTR cases increases, the authors hope to establish a strong correlation among select cytokines, histologic appearance, and ALVAL score.

“Our findings may establish the groundwork for further study of better diagnostic modalities and prognosticating factors for ALTR using joint fluid analysis,” said Dr. Ball.

Dr. Ball’s coauthors of “Inflammatory Cytokines are Elevated in Patients with Adverse Reactions to Metal-on-Metal THAs” include Robert Scott Meyer, MD; Patricia A. Campbell, PhD; William Bugbee, MD; Joshua Hillman, MS; David Boyle, MS; and Gary S. Firestein, MD.

Disclosure information: Dr. Ball—DePuy, a Johnson & Johnson Company; Dr. Meyer—Bristol-Myers Squibb, Pfizer, Procter & Gamble; Dr. Campbell—Biomet, DePuy, a Johnson & Johnson Company, Wright Medical Technology, Inc., Zimmer, Smith & Nephew; Corin/Stryker, Inc., Journal of Arthroplasty; Dr. Bugbee—DePuy, a Johnson & Johnson Company, Zimmer, Smith & Nephew, Joint Restoration Foundation, Moximed, Advanced BioHealing, OrthAlign, NIH, Alter-G, Techniques in Knee Surgery; Dr. Firestein—no conflicts; Mr. Boyle—Pfizer Genentech; Mr. Hillman—no information.

Bottom Line

• Concern about adverse local tissue reactions in patients with metal-on-metal hip implants is increasing.
• Researchers found high levels of certain cytokines, including IL-6, IL-8, IL-1ra, IP-10, and TNF-α, in patients with adverse reactions to metal debris.
• In this small, prospective, case-control study, no significant correlation was found between cobalt or chromium ion levels and cytokine levels in periarticular fluid.

Maureen Leahy is assistant managing editor for AAOS Now. She can be reached at leahy@aaos.org