The PID Odyssey 2030: outlooks, unmet needs, hurdles, and opportunities - proceedings from the IPOPI global multi-stakeholders' summit (June 2022).

IPOPI held its first Global Multi-Stakeholders' Summit on 23-24 June 2022 in Cascais, Portugal. This IPOPI initiative was designed to set the stage for a stimulating forward-thinking meeting and brainstorming discussion among stakeholders on the future priorities of the PID community. All participants were actively engaged in the entire Summit, bringing provocative questions to ensure a high level of discussion and engagement, and partnered in identifying the outlooks, unmet needs, hurdles and opportunities of PIDs for 2030. The topics that were covered include diagnosis (e.g., newborn screening [NBS], genomic sequencing- including ethical aspects on the application of genomics on NBS, the role of more accurate and timely diagnostics in impacting personalized management), treatment (e.g., the therapeutic evolution of immunoglobulins in a global environment, new therapies such as targeted therapies, new approaches in curative therapies), the interactions of Primary ID with Secondary ID, Autoinflammatory Diseases and other diseases as the field experiences an incessant evolution, and also the avenues for research in the field of humanities and human sciences such as Patient-Reported Outcome Measures (PROMs), Patient-Reported Experience Measures (PREMs), and Health-Related Quality Of Life (HRQoL). During this meeting, all participants contributed to the drafting of recommendations based on our common understanding of the future opportunities, challenges, and scenarios. As a collection of materials, perspectives and summaries, they are succinct and impactful and may help determine some of the next key steps for the PID community.

DRESS syndrome with thrombotic microangiopathy revealing a Noonan syndrome: Case report.

RATIONALE: The life-threatening drug rash with eosinophilia and systemic symptoms (DRESS) syndrome occurs most commonly after exposure to drugs, clinical features mimic those found with other serious systemic disorders. It is rarely associated with thrombotic microangiopathy. PATIENT CONCERNS: We describe the unique case of a 44-year-old man who simultaneously experienced DRESS syndrome with thrombotic microangiopathy (TMA) after a 5 days treatment with fluindione. DIAGNOSES: Clinical evaluation leads to the discovery of an underlying lymphangiomatosis, due to a Noonan syndrome. INTERVETIONS: The anticoagulant was withdrawn, and corticosteroids (1 mg/kg/day) and acenocoumarol were started. OUTCOMES: Clinical improvement ensued. At follow-up the patient is well. LESSONS: The association of DRESS with TMA is a rare condition; we believe that the presence of the underlying Noonan syndrome could have been the trigger. Moreover, we speculate about the potential interrelations between these entities.

Determination of rodenticides and related metabolites in rabbit liver and biological matrices by liquid chromatography coupled to Orbitrap high resolution mass spectrometry.

An analytical method based on ultra-high performance liquid chromatography (UHPLC) coupled to Orbitrap high resolution mass spectrometry was developed for the determination of rodenticides (bromadiolone, brodifacoum, difenacoum, chlorophacinone, diphacinone, coumachlor and warfarin) in liver matrix. Different extraction conditions were tested, obtaining the best results when the "dilute and shoot" method (acidified acetonitrile as extraction solvent) and a clean-up step with primary secondary amine (PSA) were used. The optimized method was validated, obtaining recoveries ranging from 60 to 120%. Repeatability and reproducibility were evaluated obtaining values lower than 20%, except for brodifacoum at 10µg/kg. Limits of quantification (LOQs) ranged from 0.1 to 0.5µg/kg, except for brodifacoum, which was 100µg/kg. Six liver samples were analyzed and diphacinone and chlorophacinone were detected in three samples at concentrations ranging from 4µg/kg to 13µg/kg. Moreover a retrospective screening of rodenticide metabolites in those samples and in animal forensic samples was developed based on Orbitrap capabilities. Brodifacoum was detected in three samples, and warfarin alcohol, which is a metabolite of warfarin, was also detected in one sample.

[Spontaneous hematoma of right angle of the transverse mesocolon: exceptional complication of anticoagulant therapy with vitamin K]. / Hématome spontané du méso de l'angle colique droit et du colon transverse compliquant un traitement par anti vitamine K: à propos d'un cas et revue de la littérature.

Spontaneous hematoma of transverse mesocolon is a rare complication of anticoagulant treatment with vitamin K. We report the case of spontaneous hematoma of right angle of the transverse mesocolon associated with a hemoperitoneum in a 32-year-old patient treated by fluindione for pulmonary embolism. The diagnosis must be made urgently. The abdominal ultrasound and the scanning confirm the diagnosis. It is important to note that surgery is indicated only in the case of complications such as the risk of rupture of the hematoma.

[Massive panniculectomy and bilateral subtotal mastectomy in a case of calciphylaxis: A case report and up date]. / Dermolipectomie abdominale et mastectomie bilatérale subtotale dans le cadre d'une calciphylaxie: à propos d'un cas et mise au point.

Calciphylaxis or calcific arteriolopathy is a rare, life-threatening obstructive pathology of the small cutaneous and subcutaneous vessels. It mainly affects patients with chronic renal failure but it also has been described in patients with normal renal function. The principal risks factors apart from renal failure and phosphocalcic metabolism imbalance are: the female sex, obesity, peripheral vascular disease, diabetes and oral anti-coagulation. We present a very rare case of abdominal, mammarian and upper thighs calciphylaxis in a patient with normal renal function. She presented a severe obesity with a recent important loss of weight and had been treated by oral anticoagulants for a long time. She benefited of a multidisciplinary approach with dermatologists, plastic surgeons and anesthesists permitting a recovery in fourteen weeks. Multidisciplinary approach is necessary but the place of the surgery is not well defined. We report a case in which early and wide surgical approach permitted to obtain a favourable evolution of the pathology. Then, we propose a therapeutic strategy after review of the literature.

[Recurrent deep vein thrombosis and myeloproliferative syndrom: emergence of JAK2 mutation five years after the initial event]. / Thromboses veineuses à répétition et syndrome myéloprolifératif : positivité secondaire d'une mutation JAK2 cinq ans après l'événement initial.

JAK 2 mutation is the molecular event responsible for 95% of polycythemia cases and 50% of thrombocythemia vera and myelofibrosis cases. It can be used as a tool for the diagnosis of myeloproliferative disorders. We report a case illustrating the fact that a negative result does not definitively eliminate the diagnosis. A 40-year old woman, with a medical history of familial deep vein thrombosis, developed thrombosis of the inferior vena cava with extension to the suprahepatic veins and pulmonary embolism. No constitutional or acquired thrombophilia was diagnosed; search for JAK 2 mutation was negative. The patient was treated with fluindione. Five years later, she relapsed with popliteo-femoral and vena cava deep vein thrombosis. The etiological work-up included a PET scan which revealed diffuse uptake in bones and suspected neoplasic bone marrow invasion. Progenitor cell cultures were positive and JAK 2 mutation was confirmed. The bone marrow aspirate had the cytologic appearance of a myeloproliferative disorder. This case illustrates the fact that JAK 2 mutation can be identified several years after onset of a latent myeloproliferative disorder. Cases with a high clinical likelihood should lead to renewed search for this mutation. Secondary discovery of this mutation can be explained by a higher proportion of mutation expressing clones.

[Recurrent pyoderma gangrenosum-like ulcers induced by oral anticoagulants]. / Ulcérations récidivantes à type de pyoderma grangrenosum induites par les antivitamines K.

BACKGROUND: Other than the classic skin necrosis induced by oral anticoagulants (OAC) in patients with protein C and S deficiencies, other types of OAC induced-skin ulcers are little known. Herein, we describe an original case of recurrent pyoderma gangrenosum (PG)-like ulcers induced by OAC. PATIENTS AND METHODS: A 70-year-old female heart-transplant recipient presented deep, hyperalgesic and quickly-spreading necrotic ulceration of the right leg 6 weeks after starting oral anticoagulant therapy with fluindione. Histological analysis revealed dermal infiltrate containing polynuclear neutrophils, which accords with the histopathological diagnosis of leukocytoclastic vasculitis or PG. Infectious, autoimmune and thrombophilic causes were ruled out. Fluindione was withdrawn and the ulcer healed completely within a month. Six months later, right leg ulceration recurred two weeks after the patient resumed fluindione but healed within 1 month of discontinuation of the drug. An OAC from another chemical family (warfarin) was then introduced, with further recurrence of ulceration after 2 weeks of treatment. DISCUSSION: The chronology of events and the negativity of aetiological explorations allowed a diagnosis to be made of OAC-induced skin ulcer, a rare complication of which the pathophysiology is unclear. This is the first case of PG-like ulcers induced by OAC.

Pharmacokinetic and pharmacodynamic variability of fluindione in octogenarians.

In the PREPA observational study, we investigated the factors influencing pharmacokinetic and pharmacodynamic variability in the responses to fluindione, an oral anticoagulant drug, in a general population of octogenarian inpatients.Measurements of fluindione concentrations and international normalized ratio (INR ) were obtained for 131 inpatients in whom fluindione treatment was initiated. Treatment was adjusted according to routine clinical practice. The data were analyzed using nonlinear mixed-effects modeling, and the parameters were estimated using MONOLI X 3.2. The pharmacokinetics (PK) of fluindione was monocompartmental, whereas the evolution of INR was modeled in accordance with a turnover model (inhibition of vitamin K recycling). Interindividual variability (II V) was very large. Clearance decreased with age and with prior administration of cordarone. Patients who had undergone surgery before the study had lower IC50 values, leading to an increased sensitivity to fluindione. Pharmacokinetic exposure is substantially increased in elderly patients, warranting a lower dose of fluindione.

Maintenance of anticoagulant and antiplatelet agents for patients undergoing peribulbar anesthesia and vitreoretinal surgery.

PURPOSE: To establish the prevalence of anticoagulation (vitamin K antagonists) and antiplatelet agent therapy in patients undergoing vitreoretinal surgery and to compare the outcome of peribulbar anesthesia and vitreoretinal surgery between users and nonusers. METHODS: We conducted a retrospective case series study in one academic center. No changes in the treatment regimen were made before surgery. Patients were divided into 3 groups: G1, patients with no anticoagulant or antiplatelet therapy; G2, patients treated with anticoagulants; and G3, patients treated with aspirin, clopidogrel, or both. RESULTS: Two hundred and six eyes (206 patients) were included. G1, 144 eyes (69.9%) without any anticoagulant or antiplatelet therapy (69.9%); G2, 12 eyes (5.8%) with anticoagulants; and G3, 44 eyes (21.4%) with antiplatelet agents. Six patients (6 eyes) (2.9%) received both anticoagulant and antiplatelet agents. The incidence of overall and mild postoperative hemorrhagic complications was similar between groups, P = 0.075 and P = 0.127, respectively. However, potential sight-threatening hemorrhagic complications were more frequent in patients receiving antiplatelet agents, P < 0.003. CONCLUSION: Peribulbar anesthesia for vitreoretinal surgery can probably be performed safely in patients receiving anticoagulants. However, retinal surgeons should be aware that severe bleeding complications are more frequent in patients receiving antiplatelet therapy.

[An atypical skin rash in a setting of antiphospholipid syndrome]. / Éruption cutanée atypique au cours d'un syndrome des antiphospholipides.

BACKGROUND: Antiphospholipid syndrome (APS) is characterised by arterial or venous thrombosis combined with the presence of specific antibodies known as antiphospholipids. It is commonly associated with cutaneous signs. Herein we report a case of atypical cutaneous eruption occurring during the course of APS and we discuss the possible mechanism. PATIENTS AND METHODS: A 45-year-old woman consulted twice within six months for an erythematosus papular eruption around the neckline. She was being followed-up for antiphospholipid syndrome treated with fluindione (Préviscan®), and her International Normalized Ratio (INR) was consistent with the prescribed anticoagulation target. Blood tests confirmed the presence of anticardiolipin and antiphospholipid antibodies, but no laboratory evidence of lupus was seen. Histopathological examination of a skin biopsy demonstrated the presence within the vascular lumen of a weakly eosinophilic anhistic substance positive for PAS stain. The patient was given acetone salicylic acid (Kardégic®) combined with fluindione, and four years later, she had presented no relapses. DISCUSSION: Despite a clinically evocative appearance, the diagnosis of lupus tumidus was ruled out in our patient by histopathological features, and associated systemic lupus erythematosus was repeatedly refuted on the basis of clinical and laboratory data. We suggest that the specific histological images of intraluminal deposits within the dermal vessels seen in this patient, although not typical of thrombosis, are associated with APS. The clinical remission seen from the start of antiplatelet treatment could be due to the action of these drugs against the obstruction of small-calibre dermal vessels.

[Skin necrosis during long-term fluindione treatment revealing protein C deficiency]. / Nécroses cutanées tardives sous fluindione révélant un déficit en protéine C.

BACKGROUND: Cutaneous necrosis is a rare complication of vitamin K antagonist therapy. It presents as cutaneous hemorrhagic necrosis and usually occurs at the start of treatment. We describe an atypical case of recurrent skin necrosis after two years of treatment with fluindione. CASE REPORT: A 70-year old woman with a history of venous thromboembolism and obesity presented with a large haemorrhagic necrosis of the abdominal wall. She had been treated with fluindione for two years. Genetic protein C deficiency was discovered. Resumption of vitamin K antagonist therapy was followed by recurrence of skin necrosis despite concomitant administration of heparin. Treatment with vitamin K antagonists could not be continued. DISCUSSION: This observation is unusual due to the late onset of skin necrosis. The condition usually begins shortly after initiation of vitamin K antagonist therapy, generally between the third and the sixth day of treatment. It is due to a transient hypercoagulable state in patients with protein C deficiency or, in rare cases, protein S deficiency. This late-onset skin necrosis, occurring many years after initiation of anticoagulant therapy, may be explained by a sudden worsening of pre-existing protein C deficiency due to infectious and iatrogenic factors.

A pharmacokinetic-pharmacodynamic model for predicting the impact of CYP2C9 and VKORC1 polymorphisms on fluindione and acenocoumarol during induction therapy.

BACKGROUND AND OBJECTIVE: Vitamin K epoxide reductase complex, subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) polymorphisms are taken into account when predicting a safe oral dose of coumarin anticoagulant therapy, but little is known about the effects of genetic predictors on the response to fluindione and acenocoumarol. The aims of this study were to characterize the relationship between fluindione and acenocoumarol concentrations and the international normalized ratio (INR) response, and to identify genetic predictors that are important for dose individualization. METHODS: Fluindione concentrations, S- and R-acenocoumarol concentrations, the INR and genotype data from healthy subjects were used to develop a population pharmacokinetic-pharmacodynamic model in Monolix software. Twenty-four White healthy subjects were enrolled in the pharmacogenetic study. The study was an open-label, randomized, two-period cross-over study. The subjects received two doses of an oral anticoagulant: 20 mg of fluindione (period A) or 4 mg of acenocoumarol (period B). The pharmacokinetics and pharmacodynamics were studied from day 2 to day 3. RESULTS: A two-compartment model with a first-order input model was selected as the base model for the two drugs. The pharmacodynamic response was best described by an indirect action model with S-acenocoumarol concentrations and fluindione concentrations as the only exposure predictors of the INR response. Three covariates (CYP2C9 genotype, VKORC1 genotype and body weight) were identified as important predictors for the pharmacokinetic-pharmacodynamic model of S-acenocoumarol, and four covariates (CYP2C9 genotype, VKORC1 genotype, CYP1A2 phenotype and body weight) were identified as predictors for the pharmacokinetic-pharmacodynamic model of fluindione. Because some previous studies have shown a dose-response relationship between smoking exposure and the CYP1A2 phenotype, it was also noted that smokers have greater CYP1A2 activity. CONCLUSION: During initiation of therapy, CYP2C9 and VKORC1 genetic polymorphisms are important predictors of fluindione and acenocoumarol pharmacokinetic-pharmacodynamic responses. Our result suggests that it is important to take the CYP1A2 phenotype into account to improve individualization of fluindione therapy, in addition to genetic factors.

Acute and chronic nephropathy induced by fluindione must be addressed.

BACKGROUND: Among the vitamin K antagonists (VKA), indanedione-derived VKA is suspected to induce an immunoallergic risk. One indanedione-derived VKA, fluindione, is still being used in France. The aim of this study was to evaluate the contribution of VKA to acute and chronic nephritis. METHODS: Twenty-four cases of biopsy proven acute interstitial nephritis (AIN) were retrospectively selected, based on a first intake of VKA within the previous 12 months as well as an increase of at least 50% of the basal level of serum creatinine. The 24 cases were all treated with fluindione VKA and not with coumarinic VKA. RESULTS: The subjects studied included 20 men and 4 women, with a mean age of 73.0±9.3 years (range: 44-84). The delay between fluindione introduction and the appearance of an AIN, proven by biopsy when available, was 11.9±6.9 weeks (range: 3-28). Creatinine increased from 123.0±56.4 µmol/L (range: 56-335) at fluindione introduction to 460.7±265.3 µmol/L (range: 109-1200) at the time of AIN discovery. The treatment then consisted of stopping the fluindione and introducing steroids for 21 patients. If a VKA was necessary, fluindione was replaced by a coumarinic VKA. After 6 months, 1 patient died and 15 patients presented severe chronic kidney disease (CKD Stages 4-5). Two patients still required chronic dialysis after 6 months and five patients after 3 years. Patients with pre-existing kidney disease were more prone to develop severe CKD with fluindione. CONCLUSION: In this large study, arguments are presented to incriminate fluindione in the induction of acute and chronic nephritis.

Characterization and stability of ternary solid dispersions with PVP and PHPMA.

The effect of adding a third polymer to immiscible binary solid dispersions was investigated. The model actives griseofulvin (GF), progesterone (PG) and phenindione (PD) were selected because they exemplify a key property of many poorly soluble molecules of having at least one hydrogen bonding acceptor moiety while not having any hydrogen bond donating moieties. Ternary solid dispersions of the drug, PVP (polyvinylpyrrolidone) (proton acceptor) and PHPMA (poly[2-hydroxypropyl methacrylate]) (proton acceptor and donor) were prepared by spray drying. Stability results showed that binary solid dispersions (API and PVP) of GF and PVP crystallized quickly while the amorphous form was not possible to prepare for PG and PD. The amorphous form was prolonged upon the incorporation of PHPMA in the solid dispersion (API, PHPMA and PVP). Based on measuring the melting points, the energy of mixing the drug with the polymer was calculated using the Flory-Huggins theory. The results showed that GF had the lowest free energy followed by PG and finally PD which agreed well with the stability results. These results suggest that the addition of a third polymer to immiscible binary solid dispersions can significantly improve the stability of the amorphous form.