Dynamic Serial Cytokine Measurements During Intravenous Ca-DTPA Chelation in Gadolinium Deposition Disease and Gadolinium Storage Condition

Abstract

Purpose: The aim of this study was to investigate the feasibility of measuring early changes in serum cytokine levels after intravenous diethylenetriaminepentaacetic acid (Ca-DTPA) chelation in patients manifesting either gadolinium deposition disease (GDD) or gadolinium storage condition (GSC) and the possible usefulness of this method in further research. Methods: Four patients with recent-onset GDD (≤1 year) and 2 patients with long-standing GSC (4 and 9 years) underwent chelation with intravenous bolus administration of Ca-DTPA. Multiple blood draws were performed to measure serum cytokines: at T = 0 (before Ca-DTPA injection) and 1, 5, 10, 30, 60 minutes, and 24 hours after Ca-DTPA injection. Patients rated the severity of GDD symptom flare at 24 hours. The 24-hour urine Gd amounts were measured prechelation and for the 24 hours after chelation. Serum samples were analyzed blind to whether patients had GDD or GSC but with knowledge of the time points characterizing each sample. Results: Urine samples for both GDD and GSC patients showed increases in Gd postchelation. All GDD patients experienced flare reactions postchelation; the 2 GSC patients did not. Two cytokines, EGF and sCD40L, peaked at 30 minutes postchelation in at least 4 of the 6 participants. Three cytokines, ENA78/ CXCL5, EOTAXIN/CCL11, and LEPTIN, peaked at 24 hours in at least 4 of the 6 participants. Two participants were high outliers for a large number of cytokines across time points. No clear distinction between GDD and GSC was apparent from the cytokine patterns, although differences were present. Conclusions: This pilot study describes precise temporal resolution (in the range of minutes) after a cytokine-inciting event. Select cytokines exhibited peak values at different time points. At this preliminary stage of investigation, peak cytokine release seems to reflect the amount of Gd mobilized rather than the severity of the patient symptomatic reaction. Too few subjects were studied to support statistical analysis between GDD and GSC groups, although differences were observed through visual data analysis.

Use of Real-Life Safety Data From International Pharmacovigilance Databases to Assess the Importance of Symptoms Associated With Gadolinium Exposure

“…The same ranking was observed in FAERS despite different durations of commercialization and different numbers of safety notifications in the United States compared with Europe. As expected from the literature, 38 , 40 – 43 , 45 – 48 the linear agent displayed a higher SAGE weight than the macrocyclic ones. Unexpectedly, however, a twice greater SAGE weight was found for gadoteridol compared with the other macrocyclic GBCAs.…”

Severity of Flare Reactions in Diethylenetriamine Pentaacetate Chelations

“…Our rationale for the extended taper is that GDD symptoms themselves may develop a few days after the inciting GBCA injection, so we wanted to parallel this longer interval between inciting event and developing symptoms with a more extended postevent management of flare reaction. In our clinical practice, SAHT had been used as the first chelation in sufferers to see an unmodified flare, as flare to a strong chelator (in this case, Ca-DTPA) is the definitive clinical finding to substantiate GDD 4,6 . Subsequently, we have found that with initiating treatment after symptoms develop (SAHT), some individuals will also experience a more intense flare compared with those following EHMR (6 ± 1.3 vs 5 ± 1.1).…”

“…In our clinical practice, SAHT had been used as the first chelation in sufferers to see an unmodified flare, as flare to a strong chelator (in this case, Ca-DTPA) is the definitive clinical finding to substantiate GDD. 4,6 Subsequently, we have found that with initiating treatment after symptoms develop (SAHT), some individuals will also experience a more intense flare compared with those following EHMR (6 ± 1.3 vs 5 ± 1.1). Because our clinical experience has shown that flare is still observed with EHMR, and hence sufficient for diagnostic confirmation, essentially all current patients only receive EHMR, and no one has SAHT as the first chelation.…”

“…Previous reports have shown that Food and Drug Administration–approved GBCAs elicit a powerful cytokine release in isolated peripheral blood mononuclear cells 5 . Three recent investigations have shown that IV DTPA results in a release of cytokines in vivo in humans with GDD that differ from the cytokine profiles in a general population and/or those who have received GBCA injections but do not have the disease 4,6,7 . Therefore, this flare is believed to reflect a clinical manifestation of cytokine release and release of other immune system inflammatory products.…”

Commentary on the Association of Symptoms Associated With Gadolinium Exposure/Gadolinium Deposition Disease and Gadolinium-Based Contrast Agents

“…As in many autoimmune diseases, such as Crohn disease, we consider these likely tissue-resident memory T cells. An unexpected finding in our report on dynamic cytokine response to chelation 10 is that immune cells in GSC subjects do not simply ignore Gd. The intensity of total cytokine release was more related to the total body burden of Gd (reflecting the number of injections and the total amount of Gd retained) than the severity of flare.…”