Gadolinium (Gd) is a rare earth element. In its ionic form (+3), gadolinium is known to be highly toxic to humans. Gadolinium is strongly paramagnetic, which makes it a valuable contrast agent in for magnetic resonance imaging (MRI). The gadolinium is administered intravenously in a chelated form before MRI. In its chelated form, the ion is escorted out of the body through the kidneys before exposure to free Gd ion occurs. Or that was the theory.
Nephrogenic systemic fibrosis (NSF) is a rare, painful, incurable progressive connective tissue disease. NSF manifests with skin thickening and fibrosis, tethering, which means it cannot be pulled away from body. Some patients may develop extracutaneous fibrosis of muscle, lymph nodes, pleura, and other internal organs. Elana J. Bernstein, Christian Schmidt-Lauber, and Jonathan Kay, “Nephrogenic systemic fibrosis: A systemic fibrosing disease resulting from gadolinium exposure,” 26 Best Practice & Research Clin. Rheum. 489, 489 (2012).
As a diagnostic entity, NSF is a relatively recent discovery. The first case was noted in 1997, in California. Within a few years, the differential diagnostic criteria to distinguish NSF from other fibrotic diseases were developed. Centers for Disease Control, “Fibrosing skin condition among patients with renal disease–United States and Europe, 1997–2002,” 51 MMWR Morbidity and Mortality Weekly Report 25 (2002). Physicians identified the condition among patients with renal insufficiency who had received MRI with a gadolinium-based contrast agent (GBCA). Given the rarity of both the exposure (GBCA and renal insufficiency) and the outcome (NSF), the relationship between NSF and the use of gadolinium-containing contrast agents for magnetic resonance imaging (MRI) was discovered largely from case reports. A case registry is maintained at Yale University, and has identified 380 cases to date. Shawn E. Cowper, “Nephrogenic Systemic Fibrosis” at the website for The International Center for Nephrogenic Systemic Fibrosis Research (ICNSFR) [last updated June 15, 2013).
The little epidemiology that exists on the subject generally has found that all “cases” had exposure to Gd[1]. Or almost all. There have been occasional cases found without reported exposure to GBCA. Indeed, one case of NSF without prior GBCA was reported last month in the dermatological literature. C. Ross, N. De Rosa, G. Marshman, D. Astill, “Nephrogenic systemic fibrosis in a gadolinium-naïve patient: Successful treatment with oral sirolimus,” Australas. J. Dermatol. (2014); doi: 10.1111/ajd.12176. [Epub ahead of print].
In litigation, the usual scenario is that plaintiffs and their counsel and expert witnesses want to offer case reports or case series as probative of a causal association between an exposure and a particular disease outcome. In the silicone gel breast implant litigation, women, who self-characterized themselves “victims,” shouted outside courtrooms, “We are the evidence.”
When the outcome in question has a baseline rate, and the exposure is widespread, this strategy is usually illegitimate and most courts have limited or prohibited the obvious attempt to prejudice the jury by the use of evidence that has little or no probative value.
The causal connection between NSF and GBCA, described above, was postulated on the basis of case reports, but this is not really a rejection of the general rule about case reports. NSF is an extremely rare outcome, and GBCA administered to patients with serious kidney insufficiency is a fairly rare exposure. In addition, gadolinium ion has a known human toxicity, and the connection between renal insufficiency and Gd toxicity is rather straightforward. The insufficiency of the kidney function results in longer “in residence” times for the GBCA, with the consequence that the gadolinium disassociates from its chelating agent, and the free Gd ion does its damage. Furthermore, biopsies of affected tissues show an uptake of gadolinium in NSF patients.
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GE Healthcare manufactures Omniscan, a GBCA, for use as an MRI-contrast medium. Given the recently discovered dangers of GBCAs in vulnerable patients, Omniscan has been a magnet for lawsuits, with the peak intensity of the litigation field in the MDL courtroom of federal district courtroom of Judge Dan Polster. Judge Polster tried the first Omniscan case, which resulted in a verdict for the plaintiff. GE appealed, complaining about several of Judge Polster’s rulings, including the uneven handling of case reports. Last month, the Sixth Circuit affirmed. Decker v. GE Healthcare Inc., ___ F.3d ___, 2014 FED App. 0258P, 2014 U.S. App. LEXIS 20049 (6th Cir. Oct. 20, 2014).
General causation between GBCAs and NSF was apparently not disputed in Decker. Although plaintiffs in the GBCA litigation established the causality of GABC in producing NSF, by case reports, Judge Polster refused to permit GEHC’s expert witnesses to testify about their reliance upon case reports of gadolinium-naïve cases of NSF; that is, the court disallowed testimony about reported cases that occurred in the absence of GBCA exposure[2]. Id. at *9. Judge Polster found that the reported gadolinium-naïve case reports were “methodologically flawed” because they did not adequately show that the NSF patients in question lacked Gd exposure, with tissue biopsy or other means. Id. at * 10. The district court speculated that there may have Gd exposure from a non-MRI procedure, but never explained what non-MRI procedure would involve internal administration of GBCA. Nor did the district court address the temporal relationship between this undocumented, conjectured non-MRI gadolinium-based imaging procedure and the onset of the reported patient’s NSF.
Before trial defendant GEHC moved for reconsideration of the district court’s previous decision on defensive use of gadolinium-naïve case reports, based upon on a then recent publication of a “purported” case of gadolinium-naïve NSF. Id. at *8. A quick read of the late-breaking case study shows that it was more than a “purported” case. A.A. Lemy, et al., “Revisiting nephrogenic systemic fibrosis in 6 kidney transplant recipients: a single-center experience,” 63 J. Am. Acad. Dermatol. 389 (2010). The cited paper by Lemy had diagnosed NSF in a patient without GBCA exposure, and mass spectrometry testing of affected tissue revealed no Gd. The district court, however, dismissed the Lemy case as irrelevant unless GEHC’s expert witnesses could demonstrate that Lemy’s patient number 5 and the plaintiff were so clinical similar that “it was probable that Mr. Decker’s NSF was not caused by his 2005 Omniscan [exposure].”
The Sixth Circuit affirmed this “tails they win; heads you lose” approach to gatekeeping as all within the scope of the district court’s exercise of discretion. Lemy’s case number 5 and Mr. Decker both had NSF, and yet the courts do not describe clinical varieties among NSF, which vary based upon their relatedness to gadolinium exposure. It would seem that the courts were imposing an extremely heavy burden on the defense to show that the gadolinium-naïve cases were absolutely free of Gd exposure, and that they resembled the particular plaintiff’s NSF diagnosis in every respect. Without any evidence of diagnostic disease criteria sensitivity and specificity, and positive predictive value for the criteria, the district and the appellate courts seem to have accepted glib demands for absolute identity between the plaintiff’s NSF manifestation and any candidate Gd-free NSF case. Given that there is clinical heterogeneity among Gd-NSF cases, and that causality was basically inferred from cases and case series, the courts’ reasoning seems strained.
The appellate court also seemed blithely unaware of the fallacious circularity of permitting a diagnostic entity to be defined based upon exposure, thereby preventing any fair test of the hypothesis that all NSF cases are caused by gadolinium. This fallacy was advanced in the silicone gel breast implant litigation, where the litigation industry shrank from claims that silicone caused classic connective tissue diseases, in the face of exculpatory epidemiologic studies. The claimants retreated to a claim that silicone caused a “new” disease that was defined by mostly vague, self-reported symptoms [so very different from NSF in this respect], in conjunction with silicone exposure. The court-appointed expert witnesses, however, would have none of these shenanigans:
“The National Science Panel concluded that they do not yet support the inclusion of SSRD [systemic silicone-related disease] in the list of accepted diseases, for 4 reasons. First, the requirement of the inclusion of the putative cause (silicone exposure) as one of the criteria does not allow the criteria set to be tested objectively without knowledge of the presence of implants, thus incurring incorporation bias (27).”
Peter Tugwell, George Wells, Joan Peterson, Vivian Welch, Jacqueline Page, Carolyn Davison, Jessie McGowan, David Ramroth, and Beverley Shea, “Do Silicone Breast Implants Cause Rheumatologic Disorders? A Systematic Review for a Court-Appointed National Science Panel,” 44 Arthritis & Rheumatism 2477, 2479 (2001) (citing David Sackett, “Bias in analytic research,” 32 J. Chronic Dis. 51 (1979)).
Of course, NSF does not share the dubious provenance of SSRD, or SAD [silicone-associated disorder] as it was sometimes known. Still, the analytic studies that have shown that NSF cases all, or mostly, had GBCA exposure, explicitly refrained from defining the NSF case as including gadolinium exposure.
Decker is thus a curious case. The trial and appellate court talked about preventing the defense expert witnesses from relying upon case reports that were “methodologically flawed,” but the courts never mentioned Federal Rule of Evidence 703, which should have been the basis for such selective pruning of the expert witnesses’ reliance materials. And then there is the matter that even if GEHC were correct about Gd-free NSF cases, the attributable risk for NSF to prior Gd exposure is almost certainly very high, and the debate over whether NSF is a “signature” disease was not likely going to affect the case outcome.
Decker can perhaps best be understood as a dispute about specific causation, with established general causation, in which the relative risk of NSF from GBCA exposure is extraordinarily high among patients with renal insufficiency. If there are other causes of NSF, they are considerably more rare than GBCA/renal insufficiency exposed cases. In the face of this very high attributable risk, GE’s expert witnesses’ discussions of an idiopathic or other cause was too speculative to pass muster under Rule 702.
[1] Elana J. Bernstein, Tamara Isakova, Mary E. Sullivan, Lori B. Chibnik, Myles Wolf & Jonathan Kay, “Nephrogenic systemic fibrosis is associated with hypophosphataemia: a case–control study,” 53 Rheumatology 1613 (2014); T.R. Elmholdt, M. Pedersen, B. Jørgensen, K. Søndergaard, J.D. Jensen, M. Ramsing, and A.B. Olesen, “Nephrogenic systemic fibrosis is found only among gadolinium-exposed patients with renal insufficiency: a case-control study from Denmark,” 165 Br. J. Dermatol. 828 (2011); P. Marckmann, “An epidemic outbreak of nephrogenic systemic fibrosis in a Danish hospital,” 66 Eur. J. Radiol. 187 (2008) (reporting all patients had gadodiamide-enhanced magnetic resonance imaging and severe renal insufficiency before onset of NSF); P. Marckmann, L. Skov, K. Rossen, J.G. Heaf, and H.S. Thomsen, “Case-control study of gadodiamide-related nephrogenic systemic fibrosis,” 22 Nephrol. Dialysis &Transplant. 3174 (2007) (all 19 cases in case-control study had prior exposure to gadolinium (Gd)-containing magnetic resonance imaging contrast agents); Centers for Disease Control, “Nephrogenic Fibrosing Dermopathy Associated with Exposure to Gadolinium-Containing Contrast Agents — St. Louis, Missouri, 2002–2006,” 56 MMWR Morbidity and Mortality Weekly Report (Feb. 23, 2007).
[2] T.A. Collidge, P.C. Thomson, P.B. Mark, et al., “Gadolinium-Enhanced MR Imaging and Nephrogenic Systemic Fibrosis: Retrospective Study of a Renal Replacement Therapy Cohort,” 245 Radiology 168-175 (2007); I.M. Wahba, E.L. Simpson, and K. White, “Gadolinium Is Not The Only Trigger For Nephrogenic Systemic Fibrosis: Insights From Two Cases And Review Of The Recent Literature,” 7 Am. J. Transplant. 1 (2007); A. Deng, D.B. Martin, et al., “Nephrogenic Systemic Fibrosis with a Spectrum of Clinical and Histopathological Presentation: A Disorder of Aberrant Dermal Remodeling,” 37 J. Cutan. Pathol. 204 (2009).
