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.

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.

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.

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.

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.

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.

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.

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.

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.

The origin of the anticholinesterase-induced repetitive activity of the phrenic nerve-diaphragm preparation of the rat in vitro.

1. Action potentials have been recorded in contracting muscle cells of the phrenic nerve-diaphragm preparation from rats. After the organophosphorous anticholinesterase, ecothiopate, some cells fired repetitive action potentials. In 0.1 mM [Mg2+]o the repetitive activity was generated presynaptically or postsynaptically, and in 1 mM [Mg2+]o, probably only postsynaptically. 2. The repetitive action potentials in muscle were generated ectopically about 0.2 mm away from the usual site. 3. In 1 mM [Mg2+]o, spontaneous action potentials in muscle were generated presynaptically. These were often followed by repetitive action potentials generated either presynaptically or postsynaptically. 4. The initiation of centripetal action potentials in the phrenic nerve was coincident with the repetitive firing in the muscle. 5. The results are discussed in relation to the manner of generation of repetitive activity in nerve and muscle after anticholinesterases.

The origin of the effects of an anticholinesterase on the latencies of action potentials in mouse skeletal muscles.

1. Subcutaneous injection in mice of a single dose of an organophosphorous anticholinesterase, ecothiopate (0.5 mumol kg-1), produced increased variability in the latency (jitter) of indirectly-elicited action potentials in diaphragm muscles 5 days after treatment, but there was no effect on the variability of latencies of endplate potentials. This study was designed to elucidate the mechanism(s) of the increase in action potential jitter. 2. Action potentials evoked directly by electrical stimulation at one end of muscle fibres and recording near the other end had less jitter than indirectly-evoked action potentials and ecothiopate had no effect on directly-evoked action potentials. 3. In preparations with uncut fibres, pretreatment with ecothiopate reduced by about 20% both muscle fibre input resistance and the amplitude of spontaneous miniature endplate potentials. Ecothiopate had no effect on muscle fibre resting membrane potential or on the threshold potential for excitation. 4. In untreated preparations, indirectly-evoked action potentials recorded at the endplate had similar jitter to action potentials recorded at the tendon when latencies were measured at 10% of peak amplitude. However, when latencies were measured at peak, there was greater jitter of action potentials at the endplate. Ecothiopate increased jitter of action potentials recorded at the endplate at 10% of peak but did not significantly increase jitter of action potentials recorded at the endplate when measured at the peak. 5. In cut-fibre preparations, the first endplate potential of trains was significantly increased after ecothiopate but there was no effect of ecothiopate on the amplitude of plateau endplate potentials later in the train. Analysis of plateau endplate potentials showed that 5 days after administration, ecothiopateproduced an increase in the variance of endplate potential amplitudes and changes in the binomial parameters n and p.6. It was concluded that the increased jitter produced by ecothiopate is not a generalized effect on the plasma membrane and that none of the above observations could explain the increased jitter. The possibility is discussed that increased jitter is produced by variability in times to threshold of endplate potentials and/or by variability in the locus of generation of the action potential in the perijunctional area.

An electrophysiological study of the action of crude Enhydrina schistosa venom.

1 Electrophysiological studies on the rat diaphragm revealed that crude Enhydrina schistosa venom has a blocking action on postjunctional acetylcholine (ach) receptors. 2 This venom in concentrations of 0.125-1.0 microgram/ml abolished the extracellular endplate potential (e.e.p.p.) without altering the presynaptic spike. When the phrenic nerve was stimulated at a frequency of 1 Hz the degree of depression of successive e.e.p.ps was approximately the same in records made before and after treatment with venom. 3 In concentrations of 0.25 and 0.5 microgram/ml the venom reduced significantly the amplitude of miniature endplate potentials (m.e.p.ps). The frequency of m.e.p.ps did not increase but was decreased when the amplitue of the m.e.p.ps was much reduced. 4 The crude venom did not alter the resting membrane potential (RMP) of the muscle cell. 5 The venom inhibited the depolarization of the muscle membrane caused by carbachol. 6 It is concluded that an active component in the crude venom is responsible for a blocking action on postjunctional receptors.

Actions of bretylium tosylate at the neuromuscular junction.

1. The actions of bretylium tosylate on neuromuscular transmission in the rat phrenic nerve diaphragm preparation have been investigated by electrophysiological methods. Additional experiments have been made on the effect of the drug on the frog rectus preparation and on the acetylcholinesterase of erythrocytes.2. After bretylium, there was a reduction in the amplitudes of miniature end-plate potentials (mepps), endplate potentials (epps) and acetylcholine potentials recorded in the diaphragm, and also in the contractures of the rectus in response to acetylcholine (ACh) and to carbachol.3. After bretylium, there was a prolongation of the time courses of epps and ACh potentials. Under certain circumstances there was enhancement of the amplitudes of epps and ACh potentials and of the contractile responses to ACh but not to carbachol.4. Bretylium reduced the velocity of hydrolysis of ACh by erythrocyte ghosts. This inhibition was competitive and the Ki of bretylium was 0.053 mM.5. Bretylium did not cause a reduction in the mean quantal content of the epp in junctions blocked with Mg(++).6. It is concluded that bretylium exerts both facilitatory and inhibitory influences on neuromuscular transmission, which, exerted simultaneously, may give the false appearance that the drug has little action at this synapse.

An anti-curare effect of hexamethonium at the mammalian neuromuscular junction.

1. Experiments were performed on the isolated phrenic nerve and diaphragm preparation of the rat.2. In preparations partly blocked with (+)-tubocurarine, the twitch amplitude increased after hexamethonium. This enhancement was not seen in preparations partly blocked with Mg(++) or with gallamine. High concentrations of hexamethonium produced failure of contraction.3. Extracellular endplate potentials were recorded from blocked preparations. The administration of hexamethonium resulted in an increased amplitude of these potentials only in curarized muscle.4. Hexamethonium had no anticholinesterase activity nor did it depolarize muscle cells or increase the quantal release of transmitter.5. It is concluded that hexamethonium exerts a specific anti-curare action. Experiments on the recovery of the twitch after washing out antagonists indicate that this process is limited by diffusion. The difference in rates of diffusion of hexamethonium and (+)-tubocurarine does not account for their interaction. The basis of the anti-curare action of hexamethonium is discussed.

The effects of anticholinesterases on the latencies of action potentials in mouse skeletal muscles.

1. The purpose of this investigation was to determine the long-term effects of a single dose of persistent anticholinesterases on muscle action potentials evoked by nerve stimulation. 2. Action potentials (APs), elicited by stimulation of the phrenic nerve, were recorded intracellularly in muscle fibres of mouse diaphragm. The time between stimulus and AP was measured and the variability of this latency was calculated during trains of APs. At the beginning of trains of APs there was an increase in latency, and this delay was also measured. 3. Within 3 h of subcutaneous injection, a single dose (500 nmol kg-1) of the anticholinesterase, ecothiopate produced about 90% reduction in the acetylcholinesterase activity of homogenates of mouse diaphragm muscle, but five days after injection, this activity was not different from values in untreated animals. The initial delay of APs and the variability of latencies were increased four fold and two fold respectively, remained at these maxima from the 1st to the 5th day after ecothiopate, and returned to the values in untreated animals between 15 and 27 days after ecothiopate. 4. These effects of ecothiopate on AP latency were dose-dependent and were also seen in extensor digitorum longus and soleus muscles. 5. Other anticholinesterases used were BOS (pinacolyl S-(2-trimethylaminoethyl)methylphosphonothioate), a quaternary compound, and diisopropyl fluorophosphate, a tertiary compound, which had effects similar to those of ecothiopate; the greater duration of the effects of this compound may be related to the greater duration of reduction in cholinesterase activity. 6. Ecothiopate had no effect on the delay or variability of latencies of endplate potentials which were recorded in cut-fibre preparations 5 days later. 7. It is concluded that the effects of ecothiopate on the latencies of indirectly-evoked muscle APs are postjunctional, may not be related to the degree of reduction in cholinesterase activity at the time of recording, and are not directly linked to necrosis.

Accumulation of extracellular calcium at the endplate of mouse diaphragm after ecothiopate in vitro.

1. Experiments were carried out to investigate the accumulation from the extracellular medium of 45Ca2+ by the endplate region of skeletal muscle. 2. Mouse diaphragm muscle was incubated in physiological saline labelled with 45Ca at 37 degrees C for periods of up to 1.5 h. 3. The muscle was divided into junctional and non-junctional portions and the Ca from the extracellular fluid accumulated at the endplate determined from the 45Ca content of the portions. 4. The accumulation of extracellular Ca at the endplate region of muscles incubated in pysiological saline alone was nil, but there was accumulation in the presence of the anticholinesterase ecothiopate iodide 0.5 x 10(-6) M (ECO). Stimulation of the phrenic nerve at 0.02 Hz caused no further increase in accumulation but reduced the amount of spontaneous fasciculation. In tetrodotoxin (TTX) 10(-6) M, the accumulation was halved, and in 3.5 mM Mg2+ the accumulation was nil. Carbachol 10(-4) M resulted in an accumulation of Ca similar to that in ECO. 5. It is concluded that there was an accumulation of extracellular Ca following excitation of the nerve by stimulation at a low frequency and during the spontaneous fasciculations, and about half of the accumulation of extracellular Ca after ECO in the experiments was due to the postsynaptic action of ACh released non-quantally from the nerve terminals.