1,624 research outputs found
MonitorNet: studio italiano osservazionale multicentrico per la valutazione del profilo rischio-beneficio dei farmaci biologici nella pratica clinica reumatologica
Over the last decade, several new biologic agents have become available for the treatment of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS) and psoriasis (Ps). In contrast to conventional disease modifying anti-rheumatic drugs (DMARDs), these biological agents have rapid onset of action and pronounced disease reducing activity when administered as monotherapy or in combination with MTX. Pre-registration randomised clinical trials have compared biological agents against placebo over a limited time span (1-3). Wider use of biologics has resulted in reports of a wide range of adverse events (4), including evidence of reactivation of latent tuberculosis, increased incidence..
Differences in pharmacology of tumor necrosis factor (TNF) antagonists
The commercially available inhibitors of TNF are constituted by two classes of molecules: the soluble receptors (Etanercept: Amgen Inc. Wyeth) and the monoclonal antibodies (Adalimumab: Abbott Laboratories and Infliximab: Centocor, Inc.). The differences in their molecular structure, mechanism of action, pharmacokinetics (PK) and pharmacodynamics (PD) are discussed, along with the differences concerning dose, administration regimens, drug concentrations and pharmacological interactions. In order to explain the clinical differences observed when these agents are used in the "real world", which can arise from the respective PK characteristics (kinetics, route and frequency of administration, type of TNF binding, effects on cytokines) and PD responses and peculiar mechanisms of action, with distinctive immune function (LFTa inactivation; apoptosis induction, TNF immunoprecipitation, C1q binding and CDC induction; Fcg cross-linking and ADCC induction), the dynamics of interaction of the two classes of neutralizing molecules with TNF, and the ability in restoring TNF homeostasis, are outlined
Development and performance of the Clinical Trials ESSDAI (ClinTrialsESSDAI), consisting of frequently active clinical domains, in two randomised controlled trials in primary Sjogren's syndrome
Objective. To develop and evaluate the Clinical Trials EULAR Sjogren's Syndrome Disease Activity Index (ClinTrialsESSDAI), consisting of frequently active clinical domains of the ESSDAI, using two randomised controlled trials in primary Sjogren's syndrome (pSS). Methods. The ASAP-III trial in abatacept (80 pSS patients) and TRACTISS trial in rituximab (133 pSS patients) were analysed. The most frequently active clinical domains were selected, and ClinTrialsESSDAI total score was calculated using existing weightings of the ClinESSDAI (which also excludes the biological domain). Performance of the ClinTrialsESSDAI was compared to ClinESSDAI and ESSDAI. Responsiveness was assessed using standardised response mean (SRM), and discrimination was assessed using adjusted mean difference. Results. Besides the biological domain, the most frequently active domains were glandular, articular, haematological, constitutional, lymphadenopathy and cutaneous. These domains were selected for the ClinTrialsESSDAI. At primary endpoint visits, SRM values of ClinTrialsESSDAI, ClinESSDAI and ESSDAI were respectively -0.65/-0.59, -0.63/-0.59 and - 0.64/-0.61 for abatacept/placebo and -0.33/-0.13, -0.34/0.12 and -0.41/-0.16 for rituximab/placebo. Adjusted mean differences between active treatment and placebo groups were respectively -1.7, -1.4 and -1.1 for ASAP-III and -1.1, -1.1 and -1.2 for TRACTISS. Conclusion. The ClinTrialsESSDAI, consisting of six frequently active clinical domains of the ESSDAI, shows closely similar responsiveness and discrimination between treatment groups compared to the ClinESSDAI and ESSDAI. Therefore, this ClinTrialsESSDAI is not preferable to ClinESSDAI and ESSDAI for use as primary endpoint. A composite endpoint combining response at multiple clinically relevant items seems more suitable as primary study endpoint in pSS
Neuropsychiatric Questionnaires in Systemic Lupus Erythematosus
Patients with systemic lupus erythematosus
(SLE) can be affected by a multitude
of neurologic and psychiatric symptoms with a wide range of prevalence and severity. Irrespectively from attribution to SLE or other causes, neuropsychiatric
(NP) symptoms strongly impact short-term and long-term outcomes,thus NP evaluation during routine clinical practice in SLE should be undertaken regularly.
The assessment of NP involvement in
SLE patients is challenging and the
available diagnostic tools fail to guarantee optimal diagnostic accuracy, sensitivity to changes as well as feasibility in routine clinical care.
Standardised questionnaires (both physician-administered and self-reported)
can offer valuable help to the treating
physician to capture all possible NP
syndromes; few SLE-specific NP questionnaire have been developed but validation in large cohort or cross-cultural adaptations are still pending. On the other hand, general instruments have
been largely applied to SLE patients.
Both kinds of questionnaires can address
all possible NP manifestations either globally or, more frequently, focus
on specific NP symptoms. These latter have been mainly used in SLE to detect and classify mild and subtle symptoms, more likely to be overlooked during routine clinical assessment such as headache, cognitive impairment and psychiatric manifestations.
In conclusion, this literature review
highlights a clear case for validation
studies in this area and the wider implementation of questionnaires to assess
NP involvement is still warranted. The
broader use of such instruments could
have important consequences; first of
all, by standardising symptom assessment,
a better definition of the prevalence
of NP manifestation across different
centres could be achieved. Secondly,
prospective studies could allow for
the evaluation of clinical significance
of mild symptoms and their impact on
the patient’s function and quality of life
Intestinal pseudo-obstruction in inactive systemic lupus erythematosus: An unusual finding
Abstract
Chronic intestinal pseudo-obstruction (CIP) is an infrequent complication of an active systemic lupus erythematosus (SLE). We illustrate a case of SLE inactive-related CIP. A 51-year old female with inactive SLE (ECLAM score 2) was hospitalized with postprandial fullness, vomiting, abdominal bloating and abdominal pain. She had had no bowel movements for five days. Plain abdominal X-ray revealed multiple fluid levels and dilated small and large bowel loops with air-fluid levels. Intestinal contrast radiology detected dilated loops. CIP was diagnosed. The patient was treated with prokinetics, octreotide, claritromycin, rifaximin, azathioprine and tegaserod without any clinical improvement. Then methylprednisolone (500 mg iv daily) was started. After the first administration, the patient showed peristaltic movements. A bowel movement was reported after the second administration. A plain abdominal X-ray revealed no air-fluid levels. Steroid therapy was slowly reduced with complete resolution of the symptoms. The patient is still in a good clinical condition. SLE-related CIP is generally reported as a complication of an active disease. In our case, CIP was the only clinical demonstration of the SL
Blocking T cell co-stimulation in primary Sjögren's syndrome:rationale, clinical efficacy and modulation of peripheral and salivary gland biomarkers
There is accumulating evidence that patients with primary Sjögren's syndrome (pSS) display aberrant CD4+ T cell responses, both in the peripheral compartment and in the inflamed salivary glands. CD4+ T cell abnormalities are also critically associated with B cell hyper activation, one of the hallmarks of disease, which is linked with disease severity and evolution to lymphoma. T cell activation and the cross-talk between T and B cells are tightly regulated by the balance between co-stimulatory pathways, such as the interactions between CD80/CD86:CD28, CD40:CD40L and ICOS:ICOSL, and co-inhibitory signals, including the immunoregulatory CTLA-4 protein. Evidence from patients with pSS as well as data from animal models of the disease suggests that these pathways play a critical role in pSS pathogenesis and their targeting could be exploited for therapeutic purposes. In this review, we first summarise the evidence implicating aberrant T cell co-stimulation and co-inhibition in driving the disease before focusing on the results of recent randomised controlled trials (RCTs) with compounds able to block T cell co-stimulation and enhance T cell co-inhibition. Despite a clear biological effect on downstream B cell activation has been observed in patients treated with CTLA-4-Ig (abatacept) and with monoclonal antibodies targeting CD40 and ICOSL, the clinical efficacy of this approach has so far yielded mixed results; while the anti-CD40 monoclonal antibody iscalimab showed significant improvement in systemic disease activity compared to placebo, two large RCTs with abatacept and a phase IIa RCT with an anti-ICOSL monoclonal antibody (prezalumab) failed to reach their primary endpoints. Although the discrepancies between biological and clinical efficacy of targeting T cell co-stimulation on pSS remain unresolved, several factors including drug bioavailability and receptor occupancy, patient stratification based on T-cell related biomarkers and the choice of study outcome are likely to play an important role and form the basis for further work towards the quest for a disease-modifying biologic therapy in pSS
Blocking T cell co-stimulation in primary Sjögren's syndrome:rationale, clinical efficacy and modulation of peripheral and salivary gland biomarkers
There is accumulating evidence that patients with primary Sjögren's syndrome (pSS) display aberrant CD4+ T cell responses, both in the peripheral compartment and in the inflamed salivary glands. CD4+ T cell abnormalities are also critically associated with B cell hyper activation, one of the hallmarks of disease, which is linked with disease severity and evolution to lymphoma. T cell activation and the cross-talk between T and B cells are tightly regulated by the balance between co-stimulatory pathways, such as the interactions between CD80/CD86:CD28, CD40:CD40L and ICOS:ICOSL, and co-inhibitory signals, including the immunoregulatory CTLA-4 protein. Evidence from patients with pSS as well as data from animal models of the disease suggests that these pathways play a critical role in pSS pathogenesis and their targeting could be exploited for therapeutic purposes. In this review, we first summarise the evidence implicating aberrant T cell co-stimulation and co-inhibition in driving the disease before focusing on the results of recent randomised controlled trials (RCTs) with compounds able to block T cell co-stimulation and enhance T cell co-inhibition. Despite a clear biological effect on downstream B cell activation has been observed in patients treated with CTLA-4-Ig (abatacept) and with monoclonal antibodies targeting CD40 and ICOSL, the clinical efficacy of this approach has so far yielded mixed results; while the anti-CD40 monoclonal antibody iscalimab showed significant improvement in systemic disease activity compared to placebo, two large RCTs with abatacept and a phase IIa RCT with an anti-ICOSL monoclonal antibody (prezalumab) failed to reach their primary endpoints. Although the discrepancies between biological and clinical efficacy of targeting T cell co-stimulation on pSS remain unresolved, several factors including drug bioavailability and receptor occupancy, patient stratification based on T-cell related biomarkers and the choice of study outcome are likely to play an important role and form the basis for further work towards the quest for a disease-modifying biologic therapy in pSS
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