Unmet need in rheumatology: reports from the Advances in Targeted Therapies meeting, 2022.

To detail the unmet clinical and scientific needs in the field of rheumatology. After a 2-year hiatus due to the SARS-CoV-2 pandemic, the 22nd annual international Advances in Targeted Therapies meeting brought together more than 100 leading basic scientists and clinical researchers in rheumatology, immunology, epidemiology, molecular biology and other specialties. Breakout sessions were convened with experts in five rheumatological disease-specific groups including: rheumatoid arthritis (RA), psoriatic arthritis, axial spondyloarthritis, systemic lupus erythematosus and connective tissue diseases (CTDs). In each group, experts were asked to identify and prioritise current unmet needs in clinical and translational research, as well as highlight recent progress in meeting formerly identified unmet needs. Clinical trial design innovation was emphasised across all disease states. Within RA, developing therapies and trials for refractory disease patients remained among the most important identified unmet needs and within lupus and spondyloarthritis the need to account for disease endotypes was highlighted. The RA group also identified the need to better understand the natural history of RA, pre-RA states and the need ultimately for precision medicine. In CTD generally, experts focused on the need to better identify molecular, cellular and clinical signals of early and undifferentiated disease in order to identify novel drug targets. There remains a strong need to develop therapies and therapeutic strategies for those with treatment-refractory disease. Increasingly it is clear that we need to better understand the natural history of these diseases, including their 'predisease' states, and identify molecular signatures, including at a tissue level, which can facilitate disease diagnosis and treatment. As these unmet needs in the field of rheumatic diseases have been identified based on consensus of expert clinicians and scientists in the field, this document may serve individual researchers, institutions and industry to help prioritise their scientific activities.

2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases.

To update the European League Against Rheumatism (EULAR) recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) published in 2011. Four systematic literature reviews were performed regarding the incidence/prevalence of vaccine-preventable infections among patients with AIIRD; efficacy, immunogenicity and safety of vaccines; effect of anti-rheumatic drugs on the response to vaccines; effect of vaccination of household of AIIRDs patients. Subsequently, recommendations were formulated based on the evidence and expert opinion. The updated recommendations comprise six overarching principles and nine recommendations. The former address the need for an annual vaccination status assessment, shared decision-making and timing of vaccination, favouring vaccination during quiescent disease, preferably prior to the initiation of immunosuppression. Non-live vaccines can be safely provided to AIIRD patients regardless of underlying therapy, whereas live-attenuated vaccines may be considered with caution. Influenza and pneumococcal vaccination should be strongly considered for the majority of patients with AIIRD. Tetanus toxoid and human papilloma virus vaccination should be provided to AIIRD patients as recommended for the general population. Hepatitis A, hepatitis B and herpes zoster vaccination should be administered to AIIRD patients at risk. Immunocompetent household members of patients with AIIRD should receive vaccines according to national guidelines, except for the oral poliomyelitis vaccine. Live-attenuated vaccines should be avoided during the first 6 months of life in newborns of mothers treated with biologics during the second half of pregnancy. These 2019 EULAR recommendations provide an up-to-date guidance on the management of vaccinations in patients with AIIRD.

Unmet need in rheumatology: reports from the Targeted Therapies meeting 2019.

OBJECTIVES: To detail the greatest areas of unmet scientific and clinical needs in rheumatology. METHODS: The 21st annual international Advances in Targeted Therapies meeting brought together more than 100 leading basic scientists and clinical researchers in rheumatology, immunology, epidemiology, molecular biology and other specialties. During the meeting, breakout sessions were convened, consisting of 5 disease-specific groups with 20-30 experts assigned to each group based on expertise. Specific groups included: rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, systemic lupus erythematosus and other systemic autoimmune rheumatic diseases. In each group, experts were asked to identify unmet clinical and translational research needs in general and then to prioritise and detail the most important specific needs within each disease area. RESULTS: Overarching themes across all disease states included the need to innovate clinical trial design with emphasis on studying patients with refractory disease, the development of trials that take into account disease endotypes and patients with overlapping inflammatory diseases, the need to better understand the prevalence and incidence of inflammatory diseases in developing regions of the world and ultimately to develop therapies that can cure inflammatory autoimmune diseases. CONCLUSIONS: Unmet needs for new therapies and trial designs, particularly for those with treatment refractory disease, remain a top priority in rheumatology.

Feasibility of Online Traumatic Brain Injury Prognostic Corticosteroids Randomisation After Significant Head Injury (CRASH) Model as a Predictor of Mortality.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of mortality in many countries. According to the World Health Organization, traffic crashes are a leading cause of death, with 1.25 million deaths worldwide in 2013. A 2013 global road safety report listed 68 low-to-middle income countries that had an increased mortality rate owing to traffic accidents. The aim of this study was to analyze feasibility of use of an online prognostic model from the Medical Research Council Corticosteroids Randomization After Significant Head Injury (CRASH) trial collaborators in our center. METHODS: This is a cross-sectional retrospective study of 229 patients with TBI who were admitted to the Neurosurgery Unit at Dr. Hasan Sadikin Hospital, Bandung, from July to December 2016. RESULTS: During the study period, 495 patients with TBI were admitted; 229 patients were included in the study. Several variables were analyzed using independent statistical methods before being included in the online CRASH calculator, including Glasgow Coma Scale score (P = 0.000), pupillary reaction to light (P = 0.000), major extracranial injury (P = 0.002), and interval following incidence (P = 0.000). Statistical analysis showed that the online CRASH prognostic model reliably predicted 14-day mortality rate (P = 0.000) with 91.6% sensitivity and 95.1% specificity. CONCLUSIONS: The online CRASH model is a good prognostic model that can be used for patients with TBI in many developing countries.

The unmet need in rheumatology: reports from the Targeted Therapies meeting 2016.

The 18th annual international Targeted Therapies meeting brought together over 100 leading scientists and clinicians from around the world in the field of rheumatology. During the meeting, breakout sessions were held consisting of 5 disease-specific groups each with 20-40 experts assigned to each group based on clinical or scientific expertise. Specific groups included: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis/spondyloarthritis, systemic lupus erythematous, and other connective tissue diseases (e.g. Sjögren's, Behçet's, others). In each group, experts were asked to identify unmet needs in 3 categorical areas: basic/translational science, clinical science and therapeutic development, and clinical care. Needs were prioritised as primary or secondary. Overall, similar primary unmet needs were identified within each disease foci. Within translational science, these included the need for better understanding the heterogeneity within each disease, such that predictive tools for therapeutic response could be developed. Within clinical science and therapeutic trials, the ability to prevent progression to disease onset in those at risk, and the ability to cure disease were identified. A further unmet need was to develop new and accessible therapeutics, as well as to conduct strategic trials of currently approved therapies. Within the clinical care realm, improved co-morbidity management and patient-centered care were identified as unmet needs. Lastly, it was strongly felt there was a need to develop a scientific infrastructure for well-characterised, longitudinal cohorts married with biobanks and mechanisms to support data-sharing. This infrastructure could facilitate many of the unmet needs identified within each disease area.

Laparoscopic sacrocolpopexy with a vaginal prosthetic adhesive.

STUDY OBJECTIVE: To evaluate the efficacy and safety of vaginal prosthetic adhesive (VPA) during laparoscopic sacrocolpopexy. DESIGN: Retrospective analysis of 35 first consecutive cases. SETTING: Gynecology Surgery Unit, Bouchard Clinic, Marseille, France. PATIENTS: Thirty-five women (age range: 35-85 years; average 60.8 years) presenting a genital prolapse assessed by a Pelvic Organ Prolapse Quantification (POP-Q) Score (stage 2 to 4). PROCEDURES: Modified laparoscopic sacrocolpopexy using a synthetic glue (Ifabond™, Peters Surgical(®)) to fix the mesh to the vagina (anterior and posterior) and to the levator ani. Two non-absorbable knots are used to secure the anterior mesh to the isthmus and to the promontory. MEASUREMENTS AND MAIN RESULTS: The average operating time was 68.4 minutes (45-115 min). No complications occurred during the procedure and early postoperative course. One patient (2.8%) experienced mesh exposure, and one patient (2.8%) experienced a subacute intestinal obstruction, which was resolved by a medical treatment. During a median follow-up at 13.2 months (range: 6-24.7 months), the surgical success rate (POP-Q<2) was 94.2% (two recurrences). The patient satisfaction rate was 87%. CONCLUSIONS: The VPA during laparoscopic sacrocolpopexy seems to be safe and effective at short term. This new procedure due to adhesive opens up a new path for the widespread use of sacrocolpopexy and for reduced operating times, which is often one obstacle with the dissection in the development of this technique.

PPARß/δ promotes HRAS-induced senescence and tumor suppression by potentiating p-ERK and repressing p-AKT signaling.

Peroxisome proliferator-activated receptor-ß/δ (PPARß/δ) inhibits skin tumorigenesis through mechanisms that may be dependent on HRAS signaling. The present study examined the hypothesis that PPARß/δ promotes HRAS-induced senescence resulting in suppression of tumorigenesis. PPARß/δ expression increased p-ERK and decreased p-AKT activity. Increased p-ERK activity results from the dampened HRAS-induced negative feedback response mediated in part through transcriptional upregulation of RAS guanyl-releasing protein 1 (RASGRP1) by PPARß/δ. Decreased p-AKT activity results from repression of integrin-linked kinase (ILK) and phosphoinositide-dependent protein kinase-1 (PDPK1) expression. Decreased p-AKT activity in turn promotes cellular senescence through upregulation of p53 and p27 expression. Both over-expression of RASGRP1 and shRNA-mediated knockdown of ILK partially restore cellular senescence in Pparß/δ-null cells. Higher PPARß/δ expression is also correlated with increased senescence observed in human benign neurofibromas and colon adenoma lesions in vivo. These results demonstrate that PPARß/δ promotes senescence to inhibit tumorigenesis and provide new mechanistic insights into HRAS-induced cellular senescence.

Disseminated cutaneous infection due to Mycobacterium chelonae following hematopoietic stem cell transplantation.

This report describes two cases of disseminated cutaneous Mycobacterium chelonae after hematopoietic stem cell transplantation (HSCT).

Outcomes, infections, and immune reconstitution after double cord blood transplantation in patients with high-risk hematological diseases.

Double unrelated cord blood transplant (dUCBT) has been used to circumvent cell dose limitation of single UCBT; however, few data are available describing outcomes, infectious disease, and immune recovery. We analyzed 35 consecutive dUCBT recipients with high-risk malignant disorders (n=21) and bone marrow failure syndromes (n=14). Median follow-up was 32 months. Conditioning regimen was myeloablative in 14 and reduced intensity in 21 patients. Median infused nucleated cell dose was 4 × 10(7) /kg. Median time to absolute neutrophil count >0.5 × 10(9) /L was 25 days. Cumulative incidence (CI) of acute grade II-IV graft-versus-host disease was 47%. Estimated overall survival at 2 years was 48%. CI of first viral infections at 1 year was 92%. We observed 49 viral infections in 30 patients, 34 bacterial infections in 19 patients, and 16 fungal or parasitic infections in 12 patients. Lymphocyte subset analyses were performed at 3, 6, 9, and >12 months after dUCBT. Decreased T-cell and B-cell counts with expansion of natural killer cells were observed until 9 months post transplantation. Recovery of thymopoiesis measured by T-cell receptor excision circles was impaired until 9 months after dUCBT, when the appearance of new thymic precursors was observed. Delayed immune recovery and high incidence of infectious complications were observed after dUCBT in patients with high-risk hematological diseases.

New role for granulocyte colony-stimulating factor-induced extracellular signal-regulated kinase 1/2 in histone modification and retinoic acid receptor α recruitment to gene promoters: relevance to acute promyelocytic leukemia cell differentiation.

The induction of the granulocytic differentiation of leukemic cells by all-trans retinoic acid (RA) has been a major breakthrough in terms of survival for acute promyelocytic leukemia (APL) patients. Here we highlight the synergism and the underlying novel mechanism between RA and the granulocyte colony-stimulating factor (G-CSF) to restore differentiation of RA-refractory APL blasts. First, we show that in RA-refractory APL cells (UF-1 cell line), PML-RA receptor alpha (RARα) is not released from target promoters in response to RA, resulting in the maintenance of chromatin repression. Consequently, RARα cannot be recruited, and the RA target genes are not activated. We then deciphered how the combination of G-CSF and RA successfully restored the activation of RA target genes to levels achieved in RA-sensitive APL cells. We demonstrate that G-CSF restores RARα recruitment to target gene promoters through the activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and the subsequent derepression of chromatin. Thus, combinatorial activation of cytokines and RARs potentiates transcriptional activity through epigenetic modifications induced by specific signaling pathways.

Association of drug metabolism gene polymorphisms with toxicities, graft-versus-host disease and survival after HLA-identical sibling hematopoietic stem cell transplantation for patients with leukemia.

Individual differences in drug efficacy or toxicity can be influenced by genetic factors. We investigated whether polymorphisms of pharmacogenes that interfere with metabolism of drugs used in conditioning regimen and graft-versus-host disease (GvHD) prophylaxis could be associated with outcomes after HLA-identical hematopoietic stem cell transplantation (HSCT). Pharmacogenes and their polymorphisms were studied in 107 donors and patients with leukemia receiving HSCT. Candidate genes were: P450 cytochrome family (CYP2B6), glutathione-S-transferase family (GST), multidrug-resistance gene, methylenetetrahydrofolate reductase (MTHFR) and vitamin D receptor (VDR). The end points studied were oral mucositis (OM), hemorrhagic cystitis (HC), toxicity and venoocclusive disease of the liver (VOD), GvHD, transplantation-related mortality (TRM) and survival. Multivariate analyses, using death as a competing event, were performed adjusting for clinical factors. Among other clinical and genetic factors, polymorphisms of CYP2B6 genes that interfere with cyclophosphamide metabolism were associated with OM (recipient CYP2B6(*)4; P=0.0067), HC (recipient CYP2B6(*)2; P=0.03) and VOD (donor CYP2B6(*)6; P=0.03). Recipient MTHFR polymorphisms (C677T) were associated with acute GvHD (P=0.03), and recipient VDR TaqI with TRM and overall survival (P=0.006 and P=0.04, respectively).Genetic factors that interfere with drug metabolisms are associated with treatment-related toxicities, GvHD and survival after HLA-identical HSCT in patients with leukemia and should be investigated prospectively.

Double cord blood transplantation in patients with high risk bone marrow failure syndromes.

Patients with bone marrow failure syndromes (BMFS) who reject a first allogeneic transplant or fail immunosuppressive therapy (IST) have an especially grim prognosis. We report 14 patients (eight adults, six children) transplanted with double cord blood transplantation (dUCBT) for BMFS. Neutrophil recovery was observed in eight patients, with full donor chimerism of one unit, and acute GVHD in 10. With a median follow-up of 23 months, the estimated 2 years overall survival was 80 +/- 17% and 33 +/- 16% for patients with acquired and inherited BMFS, respectively. Transplantation of two partially HLA-matched UCB thus enables salvage treatment of high-risk patients with BMFS.

Impact of comorbidity indexes on non-relapse mortality.

Comorbidity indexes (CI) have been reported to predict non-relapse mortality (NRM) and overall survival after allogeneic hematopoietic stem cell transplantation (HSCT) (Charlson's comorbidity index (CCI), hematopoietic cell transplantation CI (HCT-CI) and the pre-transplantation assessment of mortality (PAM) score). Which of these indexes best predict survival is unknown yet. We retrospectively studied 286 patients who underwent allogeneic HSCT. HCT-CI and PAM scores required grading according to pre-transplant pulmonary function tests (PFTs), which were lacking for some patients. We thus designed a reduced HCT-CI and an adjusted PAM, without results of PFTs. Using CCI, 25% of patients had indexes of 1 or more; median reduced HCT-CI score was 1; median adjusted PAM score was 24. The discriminative properties of the three CIs were rather low in our population. Comparison of patients and transplant characteristics between our and Seattle group's cohorts, however, revealed significant differences in more children, in more cord blood HSCT and in HSCT for Fanconi anemia in St Louis. Finally, multivariate analysis of scoring items revealed that age, matched unrelated or mismatched donor and hepatic disease were associated with NRM in our cohort. Translating use for patient's counseling or decision to proceed to transplant of these CIs will need prospective studies in a large independent cohort.

Long-term outcomes after allogeneic stem cell transplantation for children with hematological malignancies.

We analyzed long-term outcomes and psycho-social aspects in 112 children with malignancies surviving 1 year after hematopoietic stem cell transplantation. At 10 years, overall survival was 75+/-5%, TRM 18+/-4% and relapse 14+/-3%; 10-year cumulative incidence of infections was 31+/-4%, cataract 44+/-4%, pulmonary dysfunction 20+/-4%, bone and joint complications 29+/-5%, hypothyroidism 36+/-4%, cardiac complications 11+/-3% and secondary malignancies 7+/-3%. Total body irradiation (TBI) was the most significant risk factor associated with cataract, pulmonary impairment, osteoarticular complications and hypothyroidism. Chronic graft-versus-host disease was associated with higher incidence of pulmonary dysfunction. The number of complications per patient increased with time. Half of the patients had psychological disturbance, 13 signs of depression and 16 a history of eating behavior disorders; 54% of patients with one or more long-term complications had psychological problems. Sixty-nine patients had learning difficulties and 36 achieved normal scholarship. With increased follow-up, development of late effects and of psycho-social disturbance are of major concern. While the use of single-dose TBI has now been abandoned, other risk factors are still of concern in the early 2000s.

Hematopoietic stem cell transplantation in severe congenital neutropenia: experience of the French SCN register.

Our objective was to study the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with severe congenital neutropenia (SCN). Among 101 cases of SCN included in the French Severe Chronic Neutropenia Registry, nine patients received HSCT between 1993 and 2003, in seven institutions. The indications were nonresponse to G-CSF therapy in four cases, bone marrow failure in one case, and myelodysplastic syndrome or leukemia in four cases. The conditioning regimen consisted of total body irradiation in two cases and chemotherapy alone in the other seven cases. Seven patients received stem cells from unrelated donors and two from identical siblings. Engraftment occurred in all but one of the patients. Three patients died. The respective causes of death were graft-versus-host disease, infection, and EBV post-transplant lymphoproliferative disease. Six patients are alive and in complete remission, with a median follow-up of 3.1 years. These results indicate that HSCT is feasible for patients with SCN who do not respond to G-CSF, who have malignant transformation, or who are at a high risk of malignant transformation, even if an HLA-identical sibling donor is not available.

Study of a predictive methodology for quantification and mapping of the radon-222 exhalation rate.

We propose a new methodology for predicting areas with a strong potential for radon (222Rn) exhalation at the soil surface. This methodology is based on the Rn exhalation rate quantification, starting from a precise characterisation of the main local geological and pedological parameters that control the radon source and its transport to the soil/atmosphere interface. It combines a cross mapping analysis of these parameters into a geographic information system with a model of the Rn vertical transport by diffusion in the soil. The rock and soil chemical and physical properties define the entry parameters of this code (named TRACHGEO) which calculates the radon flux density at the surface. This methodology is validated from in situ measurements of radon levels at the soil/atmosphere interface and in dwellings. We apply this approach to an area located in western France and characterised by a basement displaying a heterogeneous radon source potential, as previously demonstrated by lelsch et al. (J. Environ. Radioactivity 53(1) (2001) 75). The new results obtained show that spatial heterogeneity of pedological characteristics in addition to basement geochemistry--must be taken into account to improve the mapping resolution. The TRACHGEO forecasts explain the Rn exhalation variability on a larger scale and in general correlate well with in situ observations. Moreover, the radon-prone sectors identified by this approach generally correspond to the location of the dwellings showing the highest radon concentrations.