Impact of proactive of infliximab monitoring using the Bayesian approach in the maintenance phase in patients with inflammatory bowel disease / Impacto de la monitorización proactiva de infliximab en fase de mantenimiento mediante estimación bayesiana en pacientes con enfermedad inflamatoria intestinal

Background and objectives: There is increasing evidence that proactive monitoring is useful in improving the control of inflammatory bowel disease, although it remains controversial. The aim of this study was to evaluate the efficacy of proactive TDM based on the Bayesian approach to optimise the IFX dose compared with the standard of care dosing in patients with IBD. Methods: Retrospective observational cohort of inflammatory bowel disease patients>18 years. Patients were classified into two groups according to the strategy used to optimise the dose of IFX: a standard therapy group (ST-group) with clinically based dose adjustment and therapeutic drug monitoring group (TDM-group), with estimation of pharmacokinetic parameters calculated by Bayesian prediction. Results: A total of 153 patients were included. Of these, 75 were in the TDM-group. Clinical response at week 52 was evaluated in 114 patients. The proportion of patients who achieved clinical remission was higher in the TDM than in the ST-group (80.7% vs 61.4%, respectively, p=0.023). A total of 28 patients (24.6%) met the parameters for the composite variable ‘poor clinical outcome’ at week 52. The proportion of patients who reached this outcome was lower in the TDM-group than in the ST-group (12.3% vs 36.8%, respectively, p=0.002). Conclusions: Proactive therapeutic drug monitoring using Bayesian approach is associated with higher secondary response and fewer long-term complications.(AU)

Antecedentes y objetivos: Cada vez hay más evidencia de que la monitorización proactiva es útil para mejorar el control de la enfermedad inflamatoria intestinal (EII), aunque sigue siendo controvertida. El objetivo de este estudio fue evaluar la eficacia de la monitorización de fármacos terapéuticos (TDM) proactiva basada en el enfoque bayesiano en comparación con el manejo estándar en pacientes con EII. Métodos: Cohorte observacional retrospectiva de pacientes con EEI > 18 años. Los pacientes se clasificaron en dos grupos de acuerdo con la estrategia utilizada para optimizar la dosis de infliximab (IFX): un grupo de terapia estándar (grupo-ST) con ajuste de dosis basado en la clínica y un grupo de monitorización terapéutica del fármaco (grupo-TDM), con estimación de parámetros farmacocinéticos calculados mediante estimación bayesiana. Resultados: Se incluyeron un total de 153 pacientes. De estos, 75 estaban en el grupo-TDM. La respuesta clínica en la semana 52 se evaluó en 114 pacientes. La proporción de pacientes que alcanzaron la remisión clínica fue mayor en el grupo-TDM que en el grupo-ST (80,7 vs. 61,4%, respectivamente, p = 0,023). Un total de 28 pacientes (24,6%) cumplieron los parámetros de la variable compuesta «resultado clínico deficiente» en la semana 52. La proporción de pacientes que alcanzaron este resultado fue menor en el grupo-TDM que en el grupo-ST (12,3 vs. 36,8%, respectivamente, p = 0,002). Conclusiones: La TDM proactiva mediante el enfoque bayesiano se asocia con una mayor respuesta secundaria y menos complicaciones a largo plazo.(AU)

Comparative effectiveness and drug survival of biosimilar infliximab CPT-13 vs. reference infliximab in inflammatory bowel disease: A retrospective cohort study.

BACKGROUND: Studies have investigated the efficacy and safety of switching to the biosimilar infliximab (CT-P13) in patients with inflammatory bowel disease (IBD). However, there is limited research directly comparing the effectiveness, drug survival, and pharmacokinetic profiles of the reference infliximab (IFX) and CT-P13 in real clinical settings. OBJECTIVE: To compare the effectiveness and drug survival of CPT-13 and reference IFX at weeks 26 and 52, and to determine the pharmacokinetic profiles and safety profile in real-world settings. METHODS: A retrospective observational cohort analysis was conducted at a single center. The study compared the proportion of patients achieving clinical remission and experiencing poor clinical outcomes at weeks 26 and 52. The drug survival rate of CT-P13 and reference infliximab was also assessed during the follow-up period. RESULTS: A total of 153 patients were included in the study, 39.2% receiving CPT-13 and 60.8% reference IFX. At week 26, clinical remission rates were 66.7% (CPT-13: 74.4% vs. reference IFX: 62.3%, p=0.178), and at week 52, they were 64% (CPT-13: 85.4% vs. reference IFX: 63.0%, p=0.012). Subgroup analysis with therapeutic drug monitoring (TDM) found no significant differences at week 26 (CPT-13: 74.4% vs. reference IFX: 58.8%, p=0.235) or at week 52 (CPT-13: 85.4% vs. reference IFX: 68.8%, p=0.153). CONCLUSION: Our study demonstrates comparable efficacy, drug survival, pharmacokinetic profiles, and incidence of immunogenicity between both drugs in a real clinical setting. Further studies with greater statistical power are needed to validate these findings.

Impact of proactive therapeutic drug monitoring of infliximab during the induction phase in IBD patients. A Bayesian approach.

BACKGROUND AND OBJECTIVES: there is increasing evidence that proactive therapeutic drug monitoring in induction is useful to improve the control of inflammatory bowel disease (IBD), although it remains controversial. The primary objective of the study was to assess the short-term outcomes of proactive Bayesian therapeutic drug monitoring (TDM) during induction, to optimize infliximab (IFX) maintenance dose. METHODS: retrospective observational cohort of IBD patients > 18 years. They were divided into two cohorts, standard therapy group (ST-group), with clinically based dose adjustment, and monitoring group (iTDM-group), with pharmacokinetic parameters calculated by Bayesian prediction at week 6 and individualized dosage regimens thereafter. In patients with an infliximab trough level (ITL) at week 6 below the optimal therapeutic range, the dose adjustment was performed at the first maintenance dose. RESULTS: a total of 153 patients were included, 40 in the iTDM-group. Median ITL at week 6 during the induction period was 12.8 µg/ml (IRQ: 12.7) in this group. Only 16 patients (40.0 %) had ITL ≥ 15 µg/ml. Half of the patients (50.3 %) received intensified maintenance therapy during the study period (57.5 % iTDM vs 47.8 % ST, p = 0.291). The proportion of patients achieving primary response at week 14 was 51.8 %. When comparing the two groups, this proportion was higher in the iTDM group (74.3 % vs 44.2 %, p = 0.002). With regards to the variable "poor clinical outcomes" at week 26, this proportion was lower in the iTDM group (3.3 % iTDM vs 21.1 % ST, p = 0.024). CONCLUSIONS: proactive therapeutic drug monitoring using Bayesian approach is associated with higher primary response rates and fewer short-term complications.

Impact of proactive therapeutic drug monitoring of infliximab during the induction phase in IBD patients. A Bayesian approach

Background and objectives: there is increasing evidence that proactive therapeutic drug monitoring in induction is useful to improve the control of inflammatory bowel disease (IBD), although it remains controversial. The primary objective of the study was to assess the short-term outcomes of proactive Bayesian therapeutic drug monitoring (TDM) during induction, to optimize infliximab (IFX) maintenance dose. Methods: retrospective observational cohort of IBD patients > 18 years. They were divided into two cohorts, standard therapy group (ST-group), with clinically based dose adjustment, and monitoring group (iTDM-group), with pharmacokinetic parameters calculated by Bayesian prediction at week 6 and individualized dosage regimens thereafter. In patients with an infliximab trough level (ITL) at week 6 below the optimal therapeutic range, the dose adjustment was performed at the first maintenance dose. Results: a total of 153 patients were included, 40 in the iTDM-group. Median ITL at week 6 during the induction period was 12.8 µg/ml (IRQ: 12.7) in this group. Only 16 patients (40.0 %) had ITL ≥ 15 µg/ml. Half of the patients (50.3 %) received intensified maintenance therapy during the study period (57.5 % iTDM vs 47.8 % ST, p = 0.291). The proportion of patients achieving primary response at week 14 was 51.8 %. When comparing the two groups, this proportion was higher in the iTDM group (74.3 % vs 44.2 %, p = 0.002). With regards to the variable “poor clinical outcomes” at week 26, this proportion was lower in the iTDM group (3.3 % iTDM vs 21.1 % ST, p = 0.024). Conclusions: proactive therapeutic drug monitoring using Bayesian approach is associated with higher primary response rates and fewer short-term complications (AU)

Biosimilar infliximab CPT-13 for inflammatory bowel disease in a real clinical setting: pharmacokinetic outcomes, immunogenicity, and drug survival.

BACKGROUND: efficacy and safety were evaluated after switching to a biosimilar infliximab (CPT-13) in patients with inflammatory bowel disease (IBD). However, few cohort studies compare the pharmacokinetic profiles, immunogenicity, and safety of the reference infliximab (IFX) and CPT-13 in a real clinical setting. OBJECTIVE: to compare the pharmacokinetic profiles and drug survival on the long term of reference IFX and CPT-13 at weeks 54 and 104. A secondary objective was to determine the long-term immunogenicity and safety profile of CPT-13 in patients with IBD in a real clinical setting. METHODS: a retrospective, observational cohort analysis was performed in a single center, including patients with IBD under treatment with reference IFX or CPT-13. Serum drug concentrations were compared to determine if there were any significant differences in pharmacokinetic outcomes between reference IFX and CPT-13 at 26, 54, 78, and 104 weeks. The drug survival of reference IFX and CPT-13 was determined at weeks 54 and 104. RESULTS: one hundred and six patients were included during the study period. Forty-five (42.5 %) patients received CPT-13 and 61 (57.5 %) received reference IFX. A total of 347 serum samples were analyzed and no significant differences were observed between reference IFX and CPT-13. The percentage of patients who achieved serum concentrations within the target therapeutic range was similar in both groups (74.1 % for reference IFX and 72.5 % for CPT-13, p = 0.741). At week 54, withdrawal rates for reference IFX and CPT-13 were 11.5 % and 20.0 %, respectively (p = 0.226), whereas at week 104 they were 26.2 % and 28.9 %, respectively (p = 0.761). CONCLUSION: the pharmacokinetic characteristics and incidence of immunogenicity of CPT-13 in a real clinical setting are comparable to those of the infliximab originator. The two products also have similar long-term drug survival and the same safety profile.

Association between ustekinumab trough concentrations and biochemical outcomes in patients with Crohn's disease. A real life study.

INTRODUCTION: numerous studies have shown a positive correlation between serum biologic drug concentrations and favorable therapeutic outcomes during the induction and maintenance period in patients with Crohn's disease (CD). To our knowledge, only a few and contradictory studies have determined the association between ustekinumab (UST) trough concentrations and biological outcomes. This study aimed to investigate the relationship between ustekinumab trough concentrations and biological outcomes in a real-world setting. METHODS: a cross-sectional cohort study was performed. All adult patients with CD who received maintenance therapy (≥ 24 weeks) with ustekinumab were included in the study. Clinical response was determined using the Harvey-Bradshaw Index. Biochemical remission was defined as a fecal calprotectin level < 150 µg/g in feces and a biochemical response as > 50 % reduction of fecal calprotectin. RESULTS: a total of 58 CD patients were included in the study and the median UST trough concentration was 1.78 µg/ml (IQR: 2.56). Differences in ustekinumab trough concentrations were observed for clinical (2.25 µg/ml vs 0.65 µg/ml; p = 0.006) and biochemical remission (2.33 µg/ml vs 1.03 µg/ml; p = 0.047). According to ROC analysis, a cut-off of 1.4 µg/ml (AUC: 077) and 2.0 µg/ml (AUC: 0.65) were identified for predicting clinical and biochemical remission, respectively. Likewise, ustekinumab trough levels were also higher in "composite clinical/biochemical remission" (2.38 µg/ml vs 1.08 µg/ml; p = 0.042). The trough level that was best associated with composite clinical/biochemical remission was 2.2 µg/ml (AUC: 0.69). CONCLUSION: this real-life study shows the association between ustekinumab trough concentration and clinical and biochemical remission and we suggest an optimal cut-off point higher than 2.2 µg/ml. Further studies are needed to confirm the findings and to identify the optimal cut-off in different disease outcomes and disease phenotypes.

Encuesta nacional on-line sobre el consentimiento informado para la realización de paracentesis. ¿Lo tenemos? ¿Lo utilizamos? / No disponible

INTRODUCCIÓN: el uso del consentimiento informado es necesario en los procedimientos invasivos como documento garantizador de la relación sanitaria ética y de la seguridad del paciente. OBJETIVO: analizar si se poseen y utilizan los documentos de consentimiento informado para paracentesis en los centros sanitarios, así como obtener algunos datos de interés sobre la técnica. MATERIAL Y MÉTODO: realizamos un estudio observacional descriptivo mediante una encuesta transversal on-line difundida por redes sociales, destinada a los especialistas y residentes de aparato digestivo durante diciembre de 2019. RESULTADOS: incluimos 203 encuestas anónimas (55,2 % adjuntos y 44,8 % residentes) de 74 centros sanitarios de 34 provincias españolas. Noventa encuestados (44,3 %) tenían dicho documento en sus centros; de estos, 29 (32,2 %) lo entregaban siempre; 31 (34,4 %), algunas veces; y 21 (23,3 %), nunca. Setenta y dos profesionales (35,5 %) contestaron no tenerlo y 41 (20,5 %), ser desconocedores; de entre ellos, 77 (68,1 %) consideraban necesaria su creación, 31 (27,4 %) no lo creían así y cinco (4,4 %) no contestaron. En cuanto a la técnica, 173 facultativos (85,2 %) realizan la punción bajo visión directa y 30 (14,8 %), ecoguiada en la mayoría de las ocasiones. Ciento nueve (53,7 %) aplican siempre anestésico local, 80 (39,4 %) lo aplican en algunas ocasiones y 14 (6,9 %) no lo utilizan. Ciento sesenta y siete encuestados (82,3 %) consideraron que es una técnica sencilla, frente a 36 (17,7 %) que la consideran de complejidad intermedia. En cuanto al riesgo, 150 (73,5 %) lo consideran bajo y 52 (25,6 %), medio. Noventa y nueve de ellos (48,8 %) refieren haber tenido complicaciones menores y 37 (18,2 %), mayores. CONCLUSIONES: la paracentesis es una técnica habitual en los servicios de digestivo y, a pesar de ser considerada sencilla y segura, entraña complicaciones. Por ello consideramos necesaria la formación reglada en esta técnica, así como la creación, difusión y utilización de los consentimientos informados dada la importante variabilidad intra e interhospitalaria que presenta

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Spanish online survey on informed consent for the performance of paracentesis. Do we have it? Do we use it?

INTRODUCTION: informed consent is necessary for invasive procedures as a document that guarantees the ethical health relationship and patient safety. AIMS: to analyze whether we have and use informed consent documents for paracentesis in our hospitals and to obtain data on the technique. METHODS: a descriptive observational study was performed during December 2019, via a cross-sectional survey disseminated through social networks, aimed at specialists and residents of gastroenterology. RESULTS: two hundred and three anonymous surveys were included (55.2 % gastroenterologist and 44.8 % residents) from 74 hospitals in 34 Spanish provinces. Ninety respondents (44.3 %) stated that they had the document in their centers. Of these, 29 (32.2 %) always provided it, 31 (34.4 %) provided it sometimes and 21 (23.3 %) never. Seventy-two professionals (35.5 %) answered that they did not have it and 41 (20.5 %) selected "unknown". Of these, 77 (68.1 %) considered it was necessary to create this document, 31 (27.4 %) did not think it was necessary and five (4.4 %) did not answer. With regards to the technique, 173 (85.2 %) performed paracentesis under direct visualization and 30 (14.8 %) were eco-guided on most occasions. One hundred and nine (53.7 %) always applied local anesthetic, 80 (39.4 %) sometimes and 14 (6.9 %) did not. One hundred and sixty-seven respondents (82.3 %) considered it to be a simple technique versus 36 (17.7 %) who thought that it was of intermediate complexity. In terms of risk, 150 (73.5 %) considered it was low and 52 (25.6 %), medium. Ninety-nine (48.8 %) experienced minor complications and 37 (18.2 %) experienced major complications. CONCLUSIONS: paracentesis is a common technique in digestive services and could be associated with complications, even though it is considered to be simple and safe. Due to the important intra- and inter-hospital variability that this technique presents, we consider standardized training in this technique is necessary, as well as the creation, spread and use of informed consents.

Usefulness of population pharmacokinetics to optimize the dosage regimen of infliximab in inflammatory bowel disease patients

INTRODUCTION: infliximab is used in inflammatory bowel disease, which has a great inter-individual pharmacokinetic variability. Thus, it is necessary to individualize the therapy in many cases. The main objective of our study was to compare two methods of a dose adjustment strategy using therapeutic drug monitoring: a) based on an algorithm and b) based on Bayesian prediction, to achieve an optimal infliximab trough level in patients with inflammatory bowel diseases. The secondary objective was to evaluate the predictive performance of a population pharmacokinetic model of infliximab in patients with inflammatory bowel diseases and therefore, its clinical utility. Furthermore, the factors associated with a suboptimal adjustment of the model were analyzed. METHODS: a retrospective observational cohort analysis was performed of patients with inflammatory bowel disease and available serum levels of infliximab. The relationship between trough concentration and dosing strategy was compared in both groups. The external validation of a previously published population pharmacokinetic model was performed using the NONMEM software. The mean prediction error and mean absolute prediction error were calculated to evaluate the predictive performance of the model. RESULTS: a total of 94 infliximab serum samples were obtained from 47 patients. After the adjustment, a total of 30 patients (63.8 %) achieved optimal infliximab trough levels. A dosing strategy based on Bayesian was associated with optimal infliximab trough levels that were higher than the strategy based on an algorithm (OR: 8.94 [95 % CI: 2.24 - 35.6], p = 0.001). For the individual predictions, the mean prediction error was 0.118 Mug/ml (95 % CI: -0.149-0.384) and the mean absolute prediction error was 0.935 Mug/ml (95 % CI: 0.569-1.075). CONCLUSIONS: the application of a population pharmacokinetic model based on Bayesian prediction is an important advance in the optimization of infliximab dosage in the treatment of inflammatory bowel disease

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Usefulness of population pharmacokinetics to optimize the dosage regimen of infliximab in inflammatory bowel disease patients.

INTRODUCTION: infliximab is used in inflammatory bowel disease, which has a great inter-individual pharmacokinetic variability. Thus, it is necessary to individualize the therapy in many cases. The main objective of our study was to compare two methods of a dose adjustment strategy using therapeutic drug monitoring: a) based on an algorithm and b) based on Bayesian prediction, to achieve an optimal infliximab trough level in patients with inflammatory bowel diseases. The secondary objective was to evaluate the predictive performance of a population pharmacokinetic model of infliximab in patients with inflammatory bowel diseases and therefore, its clinical utility. Furthermore, the factors associated with a suboptimal adjustment of the model were analyzed. METHODS: a retrospective observational cohort analysis was performed of patients with inflammatory bowel disease and available serum levels of infliximab. The relationship between trough concentration and dosing strategy was compared in both groups. The external validation of a previously published population pharmacokinetic model was performed using the NONMEM software. The mean prediction error and mean absolute prediction error were calculated to evaluate the predictive performance of the model. RESULTS: a total of 94 infliximab serum samples were obtained from 47 patients. After the adjustment, a total of 30 patients (63.8 %) achieved optimal infliximab trough levels. A dosing strategy based on Bayesian was associated with optimal infliximab trough levels that were higher than the strategy based on an algorithm (OR: 8.94 [95 % CI: 2.24 - 35.6], p = 0.001). For the individual predictions, the mean prediction error was 0.118 µg/ml (95 % CI: -0.149-0.384) and the mean absolute prediction error was 0.935 µg/ml (95 % CI: 0.569-1.075). CONCLUSIONS: the application of a population pharmacokinetic model based on Bayesian prediction is an important advance in the optimization of infliximab dosage in the treatment of inflammatory bowel disease.

Usefulness of therapeutic drug monitoring of infliximab during the induction period in patients with inflammatory bowel disease

INTRODUCTION: previous studies have shown that higher infliximab trough levels are associated with favorable shortterm and long-term therapeutic outcomes in inflammatory bowel disease. There is a need to determine which patients could benefit from proactive therapeutic drug monitoring in the induction phase. The aim of this study was to evaluate the pharmacokinetic variability of infliximab, determine the factors associated with achieving target infliximab trough levels in the induction phase and analyze the clinical and biochemical response at week 26 of treatment. PATIENTS AND METHODS: a retrospective observational study was performed of patients with inflammatory bowel disease and data available on serum levels of infliximab during the induction period. The percentage of patients that achieved target infliximab trough levels at week 6 was determined. Clinical remission and response and biochemical remission were evaluated at week 26. RESULTS: thirty patients were included and only 13 (43.3 %) had infliximab trough levels > 15 μg/mL at week 6. A clinical response was observed during the maintenance period in 71.4 % of patients, their infliximab levels were significantly higher than in non-responders (6.3 μg/mL [IQR: 6.7] vs 1.0 μg/mL [IQR: 5.0], respectively; p = 0.016). Likewise, 53.6 % of patients achieved biochemical remission (responders 6.2 μg/mL [IQR: 5.2] vs non-responders 3.2 μg/mL [IQR: 5.0]; p = 0.031). CONCLUSION: less than half of patients had target infliximab levels during the induction period. Therapeutic drug monitoring during this period is related to the achievement of therapeutic levels of infliximab and may lead to a better clinical response in these patients

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Usefulness of therapeutic drug monitoring of infliximab during the induction period in patients with inflammatory bowel disease.

INTRODUCTION: previous studies have shown that higher infliximab trough levels are associated with favorable short-term and long-term therapeutic outcomes in inflammatory bowel disease. There is a need to determine which patients could benefit from proactive therapeutic drug monitoring in the induction phase. The aim of this study was to evaluate the pharmacokinetic variability of infliximab, determine the factors associated with achieving target infliximab trough levels in the induction phase and analyze the clinical and biochemical response at week 26 of treatment. PATIENTS AND METHODS: a retrospective observational study was performed of patients with inflammatory bowel disease and data available on serum levels of infliximab during the induction period. The percentage of patients that achieved target infliximab trough levels at week 6 was determined. Clinical remission and response and biochemical remission were evaluated at week 26. RESULTS: thirty patients were included and only 13 (43.3 %) had infliximab trough levels > 15 µg/mL at week 6. A clinical response was observed during the maintenance period in 71.4 % of patients, their infliximab levels were significantly higher than in non-responders (6.3 µg/mL [IQR: 6.7] vs 1.0 µg/mL [IQR: 5.0], respectively; p = 0.016). Likewise, 53.6 % of patients achieved biochemical remission (responders 6.2 µg/mL [IQR: 5.2] vs non-responders 3.2 µg/mL [IQR: 5.0]; p = 0.031). CONCLUSION: less than half of patients had target infliximab levels during the induction period. Therapeutic drug monitoring during this period is related to the achievement of therapeutic levels of infliximab and may lead to a better clinical response in these patients.

Paraganglioma abdominal. Ecoendoscopia como nueva herramienta diagnóstica / Abdominal paraganglioma. Endoscopic ultrasound as a new diagnostic tool

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Myelopathy secondary to copper deficiency as a complication of treatment of Wilson's disease

Wilson's Disease (WD) is an autosomal recessive disorder of copper metabolism resulting in a pathological accumulation of this metal, initially in the liver and later in other organs, mainly brain. Treatment with copper chelating agents and zinc salts results in a depletion of copper deposits and prevents or reverses the clinical manifestations. Copper deficiency may cause haematological and neurological changes, the latter principally being polyneuropathy and myelopathy. We report a patient with WD who developed a myelopathy associated with a deficiency of copper following prolonged treatment with D-penicillamine and zinc salts (AU)

La enfermedad de Wilson (EW) es una enfermedad autosómica recesiva del metabolismo del cobre que provoca la acumulación patológica de este metal, primero en el hígado y posteriormente en otros órganos, principalmente el cerebro. El tratamiento con agentes quelantes del cobre y sales de zinc conduce al agotamiento de los depósitos de cobre y previene o revierte las manifestaciones clínicas de esta enfermedad. El déficit de cobre puede causar alteraciones hematológicas y neurológicas, entre estas últimas principalmente polineuropatía y mielopatía. Se presenta un paciente con EW que ha desarrollado una mielopatía asociada con la deficiencia de cobre tras un tratamiento prolongado con D-penicilamina y sales de zinc (AU)

Myelopathy secondary to copper deficiency as a complication of treatment of Wilson's disease.

Wilson's Disease (WD) is an autosomal recessive disorder of copper metabolism resulting in a pathological accumulation of this metal, initially in the liver and later in other organs, mainly brain. Treatment with copper chelating agents and zinc salts results in a depletion of copper deposits and prevents or reverses the clinical manifestations. Copper deficiency may cause haematological and neurological changes, the latter principally being polyneuropathy and myelopathy. We report a patient with WD who developed a myelopathy associated with a deficiency of copper following prolonged treatment with D-penicillamine and zinc salts.