Secukinumab retention rate is greater in patients with psoriatic arthritis presenting with axial involvement.

Psoriatic arthritis (PsA) is an inflammatory disease characterized by peripheral and axial involvement. Biological disease-modifying antirheumatic drugs (bDMARDs) are the mainstream treatment for PsA and bDMARDs retention rate is a proxy for the drug's overall effectiveness. However, it is unclear whether IL-17 inhibitors can have a higher retention rate than tumor necrosis factor (TNF) inhibitors, in particular in axial or peripheral PsA. A real-life observational study was conducted on bDMARD naïve PsA patients initiating TNF inhibitors or secukinumab. Time-to-switch analysis was carried out with Kaplan-Meyer curves (log-rank test) truncated at 3 years (1095 days). Sub-analyses of Kaplan-Meyer curves between patients presenting with prevalent peripheral PsA or prevalent axial PsA were also conducted. Cox regression models were employed to describe predictors of treatment switch/swap. Data on 269 patients with PsA naïve to bDMARD starting either TNF inhibitors (n=220) or secukinumab (n=48) were retrieved. The overall treatment retention at 1 and 2 years was similar for secukinumab and TNF inhibitors (log-rank test p NS). We found a trend towards significance in the Kaplan-Meyer at 3 years in favor of secukinumab (log-rank test p 0.081). Predominant axial disease was significantly associated with a higher chance of drug survival in secukinumab users (adjusted hazard ratio 0.15, 95% confidence interval = 0.04-0.54) but not in TNF inhibitor users. In this real-life, single-center, study on bDMARD naïve PsA patients, axial involvement was associated with longer survival of secukinumab but not of TNF inhibitors. Drug retention of secukinumab and TNF inhibitors were similar in predominantly peripheral PsA.

Efficacy of mud plus bath therapy as compared to bath therapy in osteoarthritis of hands and knees: a pilot single-blinded randomized controlled trial.

The primary objective of this study was to assess the efficacy of mud plus bath therapy in comparison to bath therapy alone in hand and knee osteoarthritis (HOA and KOA). We conducted a single-blinded randomized controlled trial (RCT). Patients were randomly assigned to either mud plus bath therapy (group 1) or balneotherapy (group 2). The primary outcome was a change in AUSCAN questionnaire for HOA and in WOMAC for KOA at month 12. Evaluations were performed at baseline (B), immediately after the interventions (week 2, W2) and after 3 (M3), 6 (M6), 9 (M9) and 12 (M12) months. 37 patients with KOA and 52 with HOA were randomized in the study. In HOA patients, AUSCAN pain improved more in group 1 compared to group 2 at M3, M6 and M12 (p<0.001, p=0.001 and p=0.038, respectively). AUSCAN stiffness improved more in group 1 at M3 (p=0.001). AUSCAN function improved more at M3, M6, M9 and M12 (p=0.001, p=0.001, p=0.014 and p=0.018, respectively). Regarding, KOA, WOMAC function decreased more prominently in group 1 compared to group 2 at M9 (p=0.007). The absolute values of WOMAC function at M6 and M9 were lower in group 1 compared to group 2 (p=0.029 and p=0.001, respectively). WOMAC pain absolute values were lower in group 1 at W2 (p=0.044) and at M9 (p=0.08). We conducted a RCT on the efficacy of mud plus balneotherapy over balneotherapy alone in HOA and KOA. We found that mud plus balneotherapy was more effective than balneotherapy alone on clinical outcomes of HOA. Differences in clinical outcomes of KOA were not significant, yet numerically higher.

Vitamin D and disease severity in coronavirus disease 19 (COVID-19).

The role of 25-OH-vitamin D in the assessment of coronavirus disease 19 (COVID-19) has not been investigated. We sought to investigate the prevalence of 25-OH-vitamin D deficiency among COVID-19 patients, and to determine the associations between 25-OH-vitamin D status and the severity of the disease. We have conducted a retrospective observational study of COVID-19 patients admitted to the University of Verona Hospital Trust. Demographic, clinical and biochemical parameters were collected at hospital admission, and serum 25-OH-vitamin D levels were measured. The following outcomes were assessed: arterial partial oxygen pressure (PaO2); C-reactive protein (CRP); length of hospitalization; requirement of oxygen therapy; non-invasive ventilation (NIV); mechanical ventilation; and death. Among 61 patients enrolled, 72.1% was 25-OH-vitamin D deficient (<20 ng/mL) and 57.4% had 25-OHvitamin D <15 ng/mL. Patients with arterial PaO2 <60 mmHg had significantly lower mean 25-OH-vitamin D levels compared to patients with PaO2 ≥60 mmHg (13.3 ng/mL vs 20.4 ng/mL respectively, p=0.03). Vitamin D deficiency was associated with 3-fold higher risk of having arterial pO2 <60 mmHg. 25-OH-vitamin D deficiency was associated with increased CRP and dyspnea. 25-OH-vitamin D deficiency was associated with more severe systemic inflammatory response and respiratory failure in COVID-19 patients.

Different fracture risk profile in patients treated with anti-osteoporotic drugs in real-life.

In this retrospective study, we intended to investigate the baseline fracture risk profile in patients who started treatment with different anti-osteoporotic medications. We analyzed retrospectively the fracture risk calculated with DeFRA, a validated FRAX derived tool, in women who started an anti-osteoporotic treatment from 2010 to 2017. We analyzed baseline data of 12,024 post-menopausal women aged over 50 years. Teriparatide initiators had a baseline 10-year risk of major osteoporotic fracture of 82.1% with a Standard Deviation (SD) of 66.5%. Denosumab initiators and zoledronic acid initiators had a greater 10-year baseline risk of fracture (54.3%, SD 46.5% and 47.0%, SD 42.0 respectively) than patients initiated on alendronate (24.9%, SD 34.6%) and patients initiated on risedronate (23.9%, SD 24.1%). Using DeFRA, a FRAX™ derived tool, we showed significantly different fracture risk profiles in women who were started on various therapeutic agents for the treatment of osteoporosis in routine clinical practice.

Changes in Dkk-1, sclerostin, and RANKL serum levels following discontinuation of long-term denosumab treatment in postmenopausal women.

PURPOSE: The positive effects of denosumab (DMAb) on bone mineral density (BMD) are quickly reversible after its discontinuation. We investigated whether this rebound was associated with dysregulation of the Wnt canonical pathway and/or by the increase in the receptor-activator of nuclear factor-kappa B ligand (RANKL) serum levels. METHODS: The study included patients (n = 15) with postmenopausal osteoporosis to whom DMAb was administered for 78 months and then discontinued. We collected BMD data at baseline/month 0 (M0), M60, M84 (6 months after last DMAb administration, coinciding when the next DMAb dose would typically be due), and after 3 and 12 months of follow-up (FU-M3 and FU-M12, respectively). Serum C-terminal telopeptide of type 1 collagen (CTX-I), Dickkopf-1 (Dkk-1), and sclerostin were measured at M0, M60, M84, FU-M3, and FU-M12. Serum N-terminal propeptide of type 1 procollagen (PINP) and RANKL were dosed at M60, M84, FU-M3, and FU-12. RESULTS: We found a significant decrease in the T-score at all sites at FU-M12, when compared to M84 (-0.51 ±â€¯0.91 at the lumbar spine; -0.72 ±â€¯0.33 at the total hip; and -0.42 ±â€¯0.27 at the femoral neck, p < 0.05). After DMAb discontinuation (M84 vs FU M12) CTX-I, PINP increased already at FU-M3 (+0.921 ±â€¯0.482 ng/mL, +126.60 ±â€¯30.36 ng/mL, respectively, p < 0.01), RANKL increased at FU-M12 (+0.041 ±â€¯0.062 ng/mL, p < 0.05), while Dkk-1 and sclerostin decreased at FU-M12 (-10.90 ±â€¯11.80 and - 13.00 ±â€¯10.52 pmol/L, respectively, p < 0.01). No changes in BMD or any of the markers were found between M60 and M84. CONCLUSIONS: RANKL serum levels progressively increased after discontinuation of long-term DMAb while Dkk-1 and sclerostin serum levels decreased. The increase in RANKL serum levels supports the hypothesis of a sudden loss of inhibition of the resting osteoclast line after DMAb clearance, with a hyperactivation of these cells. Our results suggest that the changes in serum Wnt inhibitors after DMAb suspension might represent a mere feedback response to the increased bone turnover.

Inhibition of tumor necrosis factor-alpha (TNF-alpha) in patients with early rheumatoid arthritis results in acute changes of bone modulators.

OBJECTIVE: Dicckopf-1 (Dkk-1) is a potent inhibitor of the Wnt canonical pathway. In rheumatoid arthritis (RA), Dkk-1 is upregulated by tumor necrosis factor-α (TNF). Certolizumab pegol (CMZ) is a biologic TNF-inhibitor (TNFi) effective in RA and slows radiographic progression. Data on the immediate effects (≤1-8 weeks) of TNFi on Wnt modulators are lacking. This study investigated the acute influence of TNFi treatment on Wnt modulators (Dkk-1 and sclerostin) and bone turnover markers (BTM), including intact N-terminal propeptide of collagen type I (PINP) and C-terminal telopeptide of type I collagen (CTX-I). METHODS: This longitudinal, uncontrolled study involved female RA patients with inadequate response to conventional methotrexate who underwent treatment with CMZ. ESR, Dkk-1, sclerostin, BTM, parathyroid hormone (PTH), and 25OH-vitamin D levels were evaluated at baseline, week 1, week 4, and week 8. Radiographs of the hands and feet were obtained at baseline and the total and erosion scores were assessed using the Simple Erosion Narrowing Score method (SENS). RESULTS: Seventeen patients were enrolled. Dkk-1 and CTX-I significantly decreased after one week of treatment with CMZ (-49.1 ±â€¯17.1% and -25.0 ±â€¯20.6%, respectively, p < 0.01), whereas PINP increased (+43.2 ±â€¯31.5%, p < 0.01). These changes persisted at week 4 and 8. CONCLUSIONS: Our study showed that TNF-alpha inhibition with CMZ promptly results in a rapid decline of serum Dkk-1 levels, alongside decreased bone resorption and increased bone formation.

Brain functional and effective connectivity underlying the information processing speed assessed by the Symbol Digit Modalities Test.

Delayed Information Processing Speed (IPS) often underlies attention deficits and is particularly evident in patients with traumatic brain injury, Parkinson's disease, depression, dementia, and multiple sclerosis. Therefore, it is of interest to determine the brain network that is responsible for such essential cognitive function to understand IPS deficits and to develop effective rehabilitation programs. We assessed brain functional connectivity and effective connectivity during the performance of an adapted version of the Symbol Digit Modalities Test. Using dynamic causal modeling, we focused on obtaining a network model for IPS function in healthy subjects. Sixteen right-handed volunteers (seven women, age: 29.7 ±â€¯5.0 years) were included in the study after giving written consent for participating. Functional magnetic resonance images were acquired in a 3T scanner. According to our results, two systems interact during the IPS task performance. One is formed by frontoparietal and fronto-occipital networks, related to the control of goal-directed (top-down) selection for stimuli and response, while the second is composed of the temporoparietal and inferior frontal cortices, which are associated with stimulus-driven attention in the brain. Additionally, the default-mode network showed a significant correlation with networks positively associated with the task, mainly those related to visual detection and processing, indicating its relevant role in functional integration involving IPS. Therefore, an IPS-related network was proposed through a methodology that may be useful for future studies considering other cognitive functions and tasks, clinical groups, and longitudinal assessments.

Teriparatide and denosumab combination therapy and skeletal metabolism.

Several therapies are available for osteoporis. Understanding the bone turnover changes and their mutual realtionship gives an overall view and might lead to a target therapy INTRODUCTION: The aim of this study is to compare the changes in bone turnover markers in patients treated with either denosumab alone, teriparatide (TPTD) alone, or in a third therapeutic scheme, when TPTD was added to patients previously treated with denosumab. METHODS: Fifty-nine women over 65 years old with severe postmenopausal osteoporosis (evidence of at least two moderate-severe vertebral fractures) were enrolled in the study. Serum samples were collected every 3 months. They were assayed for intact N-propeptide of type I collagen (P1NP), C-terminal telopeptide of type I collagen (CTX), intact parathyroid hormone (PTH), 25 hydroxy-vitamin D (25 OHD), Sclerostin (SOST), and Dickkopf-related protein 1 (DKK1). Bone mass density was assessed by dual-energy X-ray absorptiometry at the lumbar spine and at the total hip. RESULTS: In the groups treated only with TPTD or with denosumab, bone turnover markers increased and decreased, respectively. In TPTD group, a later significant increase in DKK1 was observed, while in denosumab group, a progressive increase in SOST was associated with a progressive significant decrease in DKK1. In the group treated first with denosumab and in which TPTD was added 3 months later, both CTX and P1NP increased 3 months after the beginning of TPTD. The strong effect of denosumab on bone turnover seems to be reversed by TPTD treatment. CONCLUSIONS: In this study, we showed that TPTD is able to express its biological activity even when bone turnover is fully suppressed by denosumab treatment. The combination therapy is associated with significant increases in both DKK1 and SOST.

[Risk factors for hip fracture in elderly persons]. / Fattori di rischio per frattura di femore in persone anziane.

OBJECTIVE: The aim of this observational study, promoted by the Health Authorities of the Regione Veneto (Italy), is to assess the prevalence of the most relevant environmental and individual risk factors in subjects with a recent hip fracture. METHODS: Patients aged more than 60 years of both genders with a recent hip fracture not associated with malignancies, were administered questionnaires on dietary habits, sun exposure, and disability score. A complete family, pharmacological and pathology history was collected together with information on previous falls, details of the fracture index, and anthropometric data. In all subjects, blood was taken for the measurement of serum 25 hydroxy-vitamin D (25OHD). RESULTS: The study included 704 patients (573 women and 131 men). Mean age was 81 ± 8 years (range 60-102). Severe pre-fracture disability was a common feature (58%) associated with multiple co-morbidities (84%), more frequently cardiovascular and neurological diseases, and specific medications. In a large proportion (86%) of the patients, environmental or individual risk factors for falling were found. Vitamin D insufficiency (serum 25OHD levels < 75 nmol/l) was quite common (70%), particularly in the regional Health Districts were strategies for preventing vitamin D deficiency were not implemented (91%). Only a small proportion (17%) of the study population had been evaluated and treated for osteoporosis. CONCLUSIONS: In senile patients with a recent hip fracture, pre-existing disability, multiple co-morbidities, high risk of falling and inadequate intake of calcium and vitamin D is relatively common. Community and case-finding interventions aimed at selecting subjects at high risk of osteoporosis, preventing vitamin D and dietary calcium deficiency, and increasing awareness on the environmental risks of falling are highly warranted.

Stem cell factor (c-kit ligand) enhances the interleukin-9-dependent proliferation of human CD34+ and CD34+CD33-DR- cells.

We have studied the effects of recombinant human interleukin-9 (IL-9), alone and combined with stem cell factor (SCF, c-kit ligand), IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) on the clonogenic proliferation of highly enriched human hematopoietic CD34+ and CD34+CD33-DR- progenitor cells. Colony assays were performed under serum-containing and serum-free conditions. IL-9, as a single agent, did not support colony formation. The addition of erythropoietin (Epo) to IL-9 induced the growth of erythroid progenitors (BFU-E) derived from both CD34+ and CD34+CD33-DR- cells. The IL-9-dependent growth of BFU-E derived from CD34+ cells was increased in an additive manner by SCF and, to a lesser extent, by IL-3, whereas CD34+CD33-DR- erythroid precursors were also responsive to GM-CSF in combination with IL-9. The addition of SCF to IL-9 did stimulate the development of CD34+ and CD34+CD33-DR- macroscopic, multicentered BFU-E and multilineage colonies (CFU-GEMM). When IL-9 was used in serum-free conditions, the growth of CD34+ and CD34+CD33-DR- BFU-E was observed in the presence of Epo. Moreover, a marked synergy on BFU-E colony formation was evident when IL-9 was combined with SCF, and their activity was enhanced by the addition of IL-3. IL-9 showed a negligible proliferative activity on colony-forming units-granulocyte/macrophage (CFU-GM). However, it increased the number of CD34+CD33-DR- CFU-GM responsive to IL-3 (37% of the colonies generated by phytohemagglutinin-stimulated lymphocyte conditioned medium [PHA-LCM]). The effects of IL-9 on CD34+CD33-DR- cells were also studied in a short-term suspension culture system, which evaluates the proliferation of progenitors earlier than day 14 CFU-C (Delta assay). In this system, IL-9 had a minimal activity on its own. In combination with SCF, however, it induced a nine-fold expansion of CD34+CD33-DR- cells, which generated a greater number of CFU-GM than BFU-E in secondary methylcellulose cultures. These experiments indicate that IL-9 induces the proliferation of very primitive human erythroid cells, and this effect is potentiated by SCF and other cytokines. Furthermore, IL-9 synergizes in vitro with the c-kit ligand in expanding the pool of early pluripotent hematopoietic progenitor cells.

Toxicity of high-dose busulphan and cyclophosphamide as conditioning therapy for allogeneic bone marrow transplantation in adults with haematological malignancies.

The toxicity of the conditioning regimen high-dose busulfan (BU) 16 mg/kg followed by cyclophosphamide (CY) 200 mg/kg has been analysed in 60 adult patients (mean age 36 +/- 9 years) with haematological malignancies, a third of whom had advanced disease, all received the graft from fully HLA-identical siblings. Significant nausea and vomiting were rare during BU administration but occurred in 44% of the patients with CY. Severe mucositis occurred in 30% of patients. Haemorrhagic cystitis occurred in 16% of patients; interstitial pneumonia occurred in 3 patients and was fatal in one. Veno-occlusive disease of the liver occurred in 2 patients and was fatal in one: however, increase of bilirubin of at least twice the baseline value and/or isolated weight gain > 5% of pre-transplant value occurred in 28% of patients. These signs of liver toxicity disappeared in all patients after appropriate therapy. Normalisation of bilirubin levels took twice as long as normalisation of body weight: median 35 and 18 days, respectively. Hyperpigmentation of the skin, mainly involving flexural and pressure areas, occurred in 47% of patients and was manageable topically. Eight patients died of relapsed disease; 15 died of transplant complications but in six the original malignancy persisted or had recurred at the time of death. Overall transplant-related mortality was 15%. We conclude that the toxicity of this regimen has not been high, with the liver being the most seriously affected organ. A longer follow-up is necessary to assess long-term consequences.

Interleukin-11 stimulates the proliferation of human hematopoietic CD34+ and CD34+CD33-DR- cells and synergizes with stem cell factor, interleukin-3, and granulocyte-macrophage colony-stimulating factor.

We have studied the effects of recombinant human interleukin-11 (rhIL-11), alone and combined with stem cell factor (SCF or c-kit ligand), IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) on the proliferation of highly enriched human hematopoietic CD34+ and CD34+CD33-DR- progenitor cells. CD34+ cells were purified using the avidin-biotin immunoabsorption technique and CD33+DR+ cells were subsequently removed by immuno-magnetic separation. The colony assays were performed in the presence and absence of exogenous serum. IL-11, as a single agent, induced the growth of a small number of colony-forming units-granulocyte/macrophage (CFU-GM) derived from purified CD34+ cells and failed to support the colony growth of CD34+CD33-DR- cells. The addition of erythropoietin (Epo) to IL-11 induced the growth of erythroid progenitors (BFU-E) derived from CD34+ cells but not from the same population depleted of CD33+DR+ cells. The combination of IL-11 with SCF, IL-3, or GM-CSF, in the presence of Epo, resulted in a synergistic or additive increase in the number of CFU cells (CFU-C) derived from both cell fractions. Moreover, the addition of SCF to IL-11 stimulated the development of macroscopic erythroid and multilineage colonies (CFU-GEMM) containing more than 10(4) cells. A combination of three factors (IL-11, SCF, and IL-3) resulted in the increase of the number of colonies arising from CD34+ and CD34+CD33-DR- cells (but not of their size) compared to the cultures treated with IL-11 plus SCF or IL-11 plus IL-3. The pattern of proliferative response of primitive hematopoietic progenitor cells to IL-11 in serum-free conditions was very similar to the cultures grown in serum-containing medium. It is noteworthy that IL-11 and SCF yielded colony formation that was comparable to that observed in the presence of serum. The effects of IL-11 on CD34+CD33-DR- cells were also studied in a short-term suspension culture system, which was shown to be specific for evaluating the proliferation of pluripotent hematopoietic precursors (Delta assay). In this system, IL-11 had a minimal effect on its own, whereas IL-11 plus SCF acted synergistically and their proliferative activity was improved by the addition of GM-CSF. These experiments indicate that IL-11 may be considered a "permissive" cytokine, capable of initiating the proliferation of very primitive human hematopoietic cells, which are then able to respond to late-acting CSFs.(ABSTRACT TRUNCATED AT 400 WORDS)

Donor origin of hematopoiesis after a case of allogeneic transplantation with cryopreserved marrow.

In allogeneic marrow transplantation (BMT), fresh donor marrow is generally given like a simple transfusion immediately after collection. Cryopreservation, on the other hand, is extensively used in autologous marrow transplantation (ABMT). However, there could be a few instances in which donor marrow should be cryopreserved for later reinfusion mainly because of the donor's inability, for logistic or medical reasons, to undergo marrow harvesting immediately prior to transplantation. We wish to describe a case of ALL transplanted with donor harvested earlier and cryopreserved. The bone marrow was cryopreserved with 10% DMSO in a controlled rate freezer and stored for 1 month in liquid nitrogen. The VNTR (variation number tandem repeat) technique was used to demonstrate the donor origin of blood cells. Hematological reconstitution was rapidly achieved and we demonstrated the allogeneic origin of the recipient's blood cells. We confirm the possibility of using cryopreserved marrow stem cells for BMT. Cryopreservation of stem cells from other origin may also find a useful application in BMT.

GM-CSF production in human adenocarcinoma cell lines.

We describe the production of human granulocyte-macrophage colony-stimulating factor (hGM-CSF), by cell lines established from patients with different stages of breast, lung and colon adenocarcinoma. GM-CSF expression has been identified by immunocytochemistry determination, quantified on conditioned medium with specific ELISA procedure and evaluated by means of proliferation and differentiation of normal human monocytic and granulocytic progenitors. The growth of cell lines after incubation with exogenous GM-CSF and antibody-antiGM-CSF was not modified. To better understand the patho-physiologic role of hGM-CSF in vivo we also estimated its serum levels at diagnosis in 75 patients with breast lung and colon adenocarcinoma and in 69 healthy person. Only two patients showed detectable GM-CSF levels. The lack of growth modulation observed in vitro with exogenous GM-CSF and antibody anti-GM-CSF suggests a non autocrine secretion by adenocarcinoma cells. The serum investigation evidences that the leukocytosis observed in adenocarcinoma patients is unrelated to a GM-CSF constitutive tumor production in vivo.