(The following is a Commentary & Perpective review of the article on Aseptic Lymphocyte-dominated Vasculitis-Associated Lesions (ALVAL) and Metal-on-Metal Joint Replacements written by Craig Rineer, MD of the Brigham and Women’s Hospital on 01/27/2005)

by Joshua J. Jacobs, MD*,
Rush Medical College, Chicago, Illinois

Metal-on-metal hip arthroplasty is gaining popularity in the United States and abroad. Therefore, the study by Willert et al. concerning the phenomenon of hypersensitivity associated with failed metal-on-metal bearings is particularly timely. The concern about metal hypersensitivity leading to implant failure is not new—there were many studies published in the McKee-Farrar era during the 1970s that suggested this association¹. In the current era of “second-generation” metal-on-metal devices, there have been substantial improvements in metallurgy, manufacturing, and design; however, the concern about metal hypersensitivity as a mode of failure persists. The authors of the present study add to this growing body of literature by performing a careful histomorphological study on nineteen patients who underwent revision of a metal-on-metal hip replacement. The authors make a strong case for the role of hypersensitivity in implant failure; however, it must be recognized that the evidence presented is largely circumstantial because cause and effect have not been proven.

One of the more interesting aspects of the authors’ observations is that the delayed-type hypersensitivity-like reactions (which the authors term “aseptic lymphocyte-dominated vasculitis-associated lesion”) that were observed on histological analysis were associated with periprosthetic osteolysis—the very problem that metal-on-metal bearings were presumed to solve—in seven of the nineteen cases. The authors proposed a mechanism whereby the continuous release of metal ions facilitates and/or accelerates sensitization, resulting in an immunological response that leads to periprosthetic bone loss. This proposed mechanism should be seriously considered because the lead author is widely credited as being the first to propose that the cellular response to particulate wear debris was the cause of osteolysis and aseptic loosening. This was suggested more than twenty-five years ago² and is now generally accepted as the most plausible mechanism for this prevalent failure mode.

It is important to view the authors’ current findings with certain caveats. The observations were gathered from a small number of retrievals from an unknown population of patients undergoing total hip arthroplasty with metal-on-metal bearings. Thus, the true prevalence of implant failure attributable to Aseptic Lymphocyte-dominated Vasculitis-Associated Lesions (ALVAL) cannot be ascertained from the study. The authors suggest that implant failure due to this phenomenon is likely to be a low-probability event.

Another point worthy of note is that the analysis of the particles present in the periprosthetic tissue was limited to light microscopy. Recently, it has been recognized that most of the debris generated from metal-on-metal bearings is in the nanometer size range, which is well beyond the limit of resolution light microscopy³. A true accounting of the particulate debris in the periprosthetic environment would require techniques such as transmission electron microscopy. This fact may explain why the authors did not observe a correlation between the amount of particulate debris and the histological response. Another possibility is that the biologically active degradation products are metal-protein complexes⁴, which cannot be imaged even by electron microscopic techniques.

If hypersensitivity to metal degradation products is in fact a mechanism of failure in a small percentage of patients undergoing metal-on-metal hip replacement, is there a method by which individuals can be screened preoperatively to determine if they are at risk for the development of osteolysis? This is obviously a very important question, but one that cannot be answered definitively at this time. Both patch testing and the in vitro lymphocyte transformation testing have been described as ways to determine the presence of metal hypersensitivity¹. However, both methodologies have their drawbacks, including the fact that the specificity and sensitivity have not been defined for either technique. The development of preoperative screening tests as well as postoperative diagnostic tests for metal hypersensitivity is highly desirable and is an area under study. This requires prospective evaluation of large numbers of patients undergoing total joint arthroplasty, with use of currently available hypersensitivity testing methodology in correlation with clinical and radiographic outcomes.

This is an exciting era for the adult reconstructive surgeon who now has several bearing surface options that all promise to improve implant survivorship. Unfortunately, each bearing couple has potential drawbacks. The “Achilles’ heel” of metal-on-metal arthroplasty appears to be the biological reaction to metal degradation products, which can include the development of metal hypersensitivity. Metal hypersensitivity is likely to be more prevalent in patients with metal-on-metal bearings due to the fact that it has been well documented that systemic metal transport is greater in patients with well-functioning metal-on-metal total hip replacements than metal-on-polyethylene total hip replacements⁵. Further intermediate and long-term multicenter studies of patients with metal-on-metal bearings are required to establish the prevalence of this complication.

References

1. Hallab N, Merritt K, Jacobs JJ. Metal sensitivity in patients with orthopaedic implants. J Bone Joint Surg Am. 2001;83:428-36.
2. Willert HG. Reactions of the articular capsule to wear products of artificial joint prostheses. J Biomed Mater Res. 1977;11:157-64.
3. Doorn PF, Campbell PA, Worrall J, Benya PD, McKellop HA, Amstutz HC. Metal wear particle characterization from metal on metal total hip replacements: transmission electron microscopy study of periprosthetic tissues and isolated particles. J Biomed Mater Res. 1998;42:103-11.
4. Hallab NJ, Jacobs JJ, Skipor A, Black J, Mickecz K, Galante JO. Systemic metal-protein binding associated with total joint replacement arthroplasty. J Biomed Mater Res. 2000;49:353-61.
5. Jacobs JJ, Hallab NJ, Skipor AK, Urban RM. Metal degradation products: a cause for concern in metal-metal bearings? Clin Orthop. 2003;417:139-47.

DePuy Hip Implant Attorney

If you or a loved one have been injured as the result of a DePuy Orthopaedics – Johnson & Johnson hip replacement implant product, talk to a DePuy Hip Implant Attorney at the Willis Law Firm for legal advice about a potential DePuy hip replacement lawsuit. Please fill out the Free Case Evaluation at the right or call us toll-free at 1-800-883-9858.

IMPORTANT NOTE: If you are required to have a revision replacement surgery to remove and replace a faulty DePuy Hip Implant, notify your doctors that you want the hip implant to be preserved as evidence and NOT shipped or returned to the manufacturer, as it is critical evidence in a potential product liability lawsuit against DePuy and Johnson & Johnson.

 By Rita Rubin, USA TODAY - 3/13/2005 8:08 PM

Salvatore Ruggiero was puzzled. Over a three-year period, the jaws of dozens of patients who had undergone oral surgery at his hospital had failed to heal properly. Part of the jawbone had died and become exposed.

“We never saw this before in the jaw” except in patients who had received radiation therapy to that part of the face, says Ruggiero, chief of oral and maxillofacial surgery at Long Island Jewish Medical Center. “It just never existed.”

Further investigation revealed one common thread: All of the patients had been treated with at least one of a class of drugs called bisphosphonates.

Most were cancer patients who had received the intravenous bisphosphonates Zometa or Aredia or both for excessive calcium in their blood or bone tumors.

But about 10% were osteoporosis patients who had taken an oral bisphosphonate, mainly Fosamax.

In May, Ruggiero co-wrote a report on 63 patients with osteonecrosis — or bone death — of the jaw in the Journal of Oral and Maxillofacial Surgery. Six had taken Fosamax, and a seventh had taken Actonel, another oral bisphosphonate for osteoporosis.

The problem doesn’t appear to be as severe with oral bisphosphonates as it is with the IV drugs, Ruggiero notes. Patients who have been receiving IV bisphosphonates should avoid having teeth pulled “at all costs,” he says.

Based on his cases, a Food and Drug Administration review posted last week on the agency’s Web site suggests that osteonecrosis of the jaw (ONJ) is a risk of all bisphosphonates, not just the IV drugs.

Bisphosphonates remain in bone indefinitely. Ruggiero speculates that their long-term use could upset the delicate balance between cells that put calcium in bone and cells that take calcium away.

The FDA review concluded that all bisphosphonate labels should mention osteonecrosis.

Novartis, maker of Zometa and Aredia, added a precaution about ONJ to their package inserts in August, although the inserts note that cancer patients have other osteonecrosis risk factors, such as their malignancies.

Merck spokesman Tony Plohoros says his company is in the process of adding information about the ONJ cases to the Fosamax label. And Terri Pedone, spokeswoman for Sanofi-Aventis, which markets Actonel with Procter & Gamble, says, “We are currently addressing the FDA’s request to update the label” with information about ONJ.

Rugierro says he has now seen a total of 12 or 13 cases of ONJ in patients treated with an oral bisphosphonate. Robert Marx, chairman of the division of oral and maxillofacial surgery at Florida’s University of Miami, says he’s aware of at least 40 or 50 cases of ONJ nationwide in patients who had taken Fosamax.

That’s a infinitely small fraction of the approximately 3 million women in the USA who are taking the drug, although most experts agree that only 1% to 10% of adverse events linked to drugs are reported.

Interestingly, some doctors have prescribed IV bisphosphonates “off label” for osteoporosis. And Roche and GlaxoSmithKline announced in December that they are seeking FDA permission to market an IV form of their oral bisphosphonate, Boniva, for osteoporosis.

1. What is Tysabri?
   Tysabri is a monoclonal antibody that binds to a protein called alpha-4-integrin. Integrins are found primarily on the surface of white blood cells, and play a role in immune system activity.

 

2. What is Tysabri used for?
   Tysabri is approved to treat patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of exacerbations. It was approved based on results achieved after approximately one year of treatment in ongoing controlled trials.

 

3. What is Multiple Sclerosis?
   Multiple sclerosis (MS) is a serious disease in which the immune system attacks the person’s brain and spinal cord. The disease causes a wide range of symptoms including fatigue, difficulty walking, numbness, and vision problems. MS frequently progresses to severe disability and/or death. Relapsing MS is the most common form of this disease.

 

4. How is Tysabri given?
   Tysabri is given by intravenous infusion once every 4 weeks.

 

5. Why is marketing of Tysabri being suspended?
   A patient with MS in a long-term clinical trial of Tysabri recently died from progressive multifocal leukoencephalopathy (PML), a rare neurologic disease; a second patient with MS in the same trial who was receiving Tysabri has a confirmed diagnosis of PML. Because the relationship between use of Tysabri and PML is not clear, Biogen Idec, the manufacturer of Tysabri, has voluntarily suspended marketing, as well as dosing of Tysabri in clinical trials, until the relationship is better understood. The FDA concurs with this decision.

 

6. What other steps has the manufacturer taken?
   The manufacturer is notifying physicians of these cases and informing them that use of Tysabri should be discontinued until further notice. Similar notices are being sent to physicians who are studying Tysabri as part of a clinical trial. Biogen Idec is recommending that all patients who have received Tysabri and have signs and symptoms suggestive of PML be evaluated. Any potential case should be reported to Biogen Idec, or to the FDA’s MedWatch reporting system. The manufacturer is reviewing the records of all patients who have received Tysabri in a clinical trial and evaluating these patients to determine if there any other cases of PML in this population. Biogen Idec is also convening a panel of medical and scientific experts on this condition to give advice on appropriate steps, including how to assess patients who have received Tysabri and who may have developed undetected early-stage PML. The FDA will maintain close contact with the manufacturer during this process and issue further information as it becomes available.

 

7. What kinds and numbers of patients have received Tysabri?
   Patients have received Tysabri either in a clinical trial or, since its approval in November, 2004, through their personal physician. Clinical trials of Tysabri include patients with MS, Crohn’s disease, and rheumatoid arthritis. About 3000 patients have received Tysabri in clinical trials; over 1700 have received it for at least a year and approximately 1100 for over two years. Outside of a clinical trial, Tysabri is only approved for patients with MS. According to Biogen Idec, outside of clinical trials, approximately 5000 patients with MS have received Tysabri through their primary physician; however, because Tysabri was approved only recently, these patients have only received at most a few doses of Tysabri.

 

8. Have there been any cases of PML in the 5000 patients receiving Tysabri through their primary physician?
   There have been no cases of PML reported or detected in patients receiving Tysabri outside of a clinical trial and no cases outside of the trial in patients with MS.

 

9. How long will this suspension last?
   The availability of Tysabri in the future will depend on the analyses of the data being obtained by the drug’s manufacturer.

 

10. Why was marketing suspended because of just two confirmed cases of PML?
    Although these two confirmed cases of PML do not automatically mean that Tysabri causes PML, and additional information needs to be obtained to fully understand the connection, if any, between Tysabri use and PML, the FDA and Biogen Idec are concerned about the possibility that other patients who have received Tysabri may have developed undetected early-stage PML. PML is a very rare and potentially fatal condition that is not known to occur in patients with MS. Until this situation is better understood, the manufacturer has voluntarily suspended marketing of Tysabri and its use in clinical trials. The FDA concurs with this decision. The manufacturer is convening a panel of medical and scientific experts on this condition to give advice on appropriate steps, including how to assess patients who have received Tysabri and who may have developed undetected early-stage PML.

 

11. How common is PML?
    In the general population, PML is extremely rare, and virtually never occurs in individuals with normal immune systems. 1 – 5% of AIDS patients may be diagnosed during their lifetime; PML has also occurred in organ transplant recipients who have received immunosuppressive medications, as well as cancer patients.

 

12. What causes PML?
    PML is thought to be caused by a virus called JC virus (JCV). Most people are exposed to this virus in childhood and carry it in a dormant state but never develop illness. PML occurs almost exclusively in individuals with suppressed immune function who carry JCV. The immune suppression allows the virus to cause disease.

 

13. Is PML contagious?
    PML is not thought to be contagious, and isolation precautions are not needed.

 

14. Is there any treatment for PML?
    There is no known effective treatment for PML, although reversing immune system suppression may slow or arrest the progress of the disease.

 

15. Does Tysabri cause PML?
    At this point, the connection, if any, between Tysabri use and PML is not known.

 

16. Is PML more common in patients with MS?
    Although the symptoms of PML may appear similar to those of MS, there does not appear to be a direct relationship between these two diseases, and patients with MS are not thought to be at higher risk than the general population for development of PML.

 

17. Did the patients who developed PML have other possible reasons to develop this disease?
    Neither patient had typical risk factors for PML. Both patients were receiving Avonex (interferon beta-1a), another approved treatment for MS, at the same time that they were being treated with Tysabri. Prior to approval, the manufacturer of Tysabri had studied its use in combination with Avonex; no cases of PML were observed in patients receiving the combination. The use of interferons, including Avonex, has not been associated with PML. FDA has analyzed data in its post-marketing database and not found any cases of PML reported in patients receiving a beta interferon. It is not known if Tysabri in combination with a beta interferon might cause PML.

 

18. How long has the FDA known about this situation?
    FDA was first provided with preliminary information about these cases by Biogen Idec late on the afternoon of Friday, February 18, 2005. Details of the cases became available over the next week.

 

19. What is the FDA doing about this situation?
    In addition to issuing this advisory, FDA has been in close contact with the manufacturer of Tysabri, and concurs with their decision to voluntarily suspend marketing of Tysabri and dosing of Tysabri in clinical trials. FDA is also imposing a clinical hold on trials of Tysabri, legally prohibiting further investigational use of Tysabri until more information is available. Although these events occurred in clinical trials, FDA has also been analyzing data from its post-marketing database to better understand any possible connection between Tysabri, Avonex, and PML. FDA is also working with the manufacturer to determine the best methods for assessing patients who have received Tysabri in order to assure their safety and understand the connection, if any, between Tysabri and PML. FDA will issue further information as it becomes available.

 

20. When was Tysabri approved?
    Tysabri received accelerated approval in November 2004.

 

21. What does it mean that Tysabri received accelerated approval?
    Accelerated approval is a program the FDA developed to make new drug products available for serious or life threatening diseases when they appeared to provide a benefit over available therapy. Tysabri was approved on the basis of a clinical study showing that Tysabri, when added to Avonex, reduced the risk of exacerbations by 54% compared to Avonex alone. Tysabri by itself reduced the risk by 66% compared to placebo in another clinical study. These results represented an important and meaningful benefit for patients with MS. At the time of approval, approximately 1,100 patients with MS had received Tysabri for one year or more. As a condition of approval of Tysabri, the manufacturer was required to continue these clinical trials through a period of two years to show that the drug continues to provide benefit. The two cases reported here occurred in patients in the continuation phase of these trials.

 

22. Why didn’t the FDA wait longer before approving Tysabri?
    The results shown in the clinical trials of Tysabri showed an important and meaningful benefit in the treatment of MS, a serious disorder that can lead to permanent disability or death. The efficacy results, in combination with the safety profile of Tysabri observed in clinical trials, supported accelerated approval. This allowed Tysabri to be made available to patients with MS earlier than would be the case for traditional approval. No cases of PML were observed in the clinical trials supporting the approval of Tysabri.

 

23. Shouldn’t the FDA have known this might happen?
    PML is a rare condition that does not occur even in the vast majority of patients, even those with suppressed immune systems. During the review of Tysabri, the FDA conducted an intensive analysis of possible adverse events that might be connected to effects of Tysabri on the immune system. No cases of PML were seen in the clinical trials that were the basis for approval of Tysabri, nor were infections characteristic of immunosuppression observed. However, for any approved therapy, new and unexpected adverse events may occur that were not seen in clinical trials. In the case of Tysabri, required post-marketing studies were ongoing and facilitated rapid reporting of and response to these events.

 

24. Are patients with MS at more risk of developing PML if they have been treated with Tysabri for a long time?
    The relationship, if any, between length of treatment with Tysabri and development of PML is not known at this time.

 

25. What are other adverse reactions have been reported with Tysabri?
    The most frequently reported adverse events with Tysabri in clinical trials were infections, severe or life threatening allergic reactions, depression (including thoughts of suicide), and gallbladder problems. These events occurred at rates ranging from 0.8% to 2.1%. No cases of PML were observed in the clinical trials used to support approval of Tysabri.

 

26. I’ve received Tysabri for my MS. Am I going to develop PML?
    Although the risk, if any, of PML in patients receiving Tysabri is not known, it is important to recognize that only two confirmed cases of PML have been identified from among over 8000 patients who have received Tysabri. Patients should, however, discontinue use of Tysabri until further notification.

(Note: The number of confirmed PML cases has risen significantly from the time that this article was initially published)

Tysabri PML Lawyer

If you or a family member has been diagnosed with PML, or been treated with Tysabri infusions, contact our law firm to speak to a PML lawyer about your legal options. Every attorney at our law firm is dedicated to fighting for the rights of those that have been harmed by dangerous and recalled drugs and medical devices. For over 25 years, Attorney David Willis has been a trial lawyer representing seriously injured clients in product liability and personal injury lawsuits such as defective drug litigation, class action drug lawsuits and medical device recall lawsuits. If Tysabri has harmed you, or a loved one, contact us right now to discuss your potential case in filing a Tysabri PML Lawsuit with an Attorney.