Patients with vasculitis induced by the hepatitis C virus (HCV) have reduced levels of regulatory T cells (Tregs). Resolution of HCV infection correlates with cure of vasculitis and the recovery of ...Treg levels. We reasoned that interleukin-2, a cytokine that promotes Treg survival and function, could be beneficial for patients with vasculitis that is resistant to HCV therapy.
We investigated the safety and immunologic effects of the administration of low-dose interleukin-2 in a prospective open-label, phase 1-phase 2a study. Ten patients with HCV-induced vasculitis that was refractory to conventional antiviral therapy, rituximab therapy, or both and who were not receiving glucocorticoid or immunosuppressant therapy, received one course of interleukin-2 (1.5 million IU per day) for 5 days, followed by three 5-day courses of 3 million IU per day at weeks 3, 6, and 9. Both the safety of the treatment and its effectiveness were evaluated, the latter by monitoring the Treg response and the clinical signs of HCV vasculitis.
No adverse events reached a level higher than grade 1. The treatment did not induce effector T-cell activation, vasculitis flare, or increased HCV viremia. We observed a reduction in cryoglobulinemia in 9 of 10 patients and improvement of vasculitis in 8 of 10. Administration of low-dose interleukin-2 was followed by an increase in the percentage of CD4+, CD25(high), forkhead box P3 (FOXP3+) Tregs E(max) (maximum value)÷baseline value×100=420% with potent suppressive activity in all subjects and by a concomitantly decreased proportion of marginal-zone B cells. Transcriptome studies of peripheral-blood mononuclear cells revealed that interleukin-2 induced a global attenuation of the signatures for inflammation and oxidative stress mediators.
The trial showed that low-dose interleukin-2 was not associated with adverse effects and led to Treg recovery and concomitant clinical improvement in patients with HCV-induced vasculitis, an autoimmune condition. (Funded by the French Agency for Research on AIDS and Viral Hepatitis ANRS and others; ClinicalTrials.gov number, NCT00574652.).
Programmed Death-1 (PD-1), an inhibitory receptor expressed by activated lymphocytes, is involved in regulating T- and B-cell responses. PD-1 and its ligands are exploited by a variety of cancers to ...facilitate tumor escape through PD-1-mediated functional exhaustion of effector T cells. Here, we report that PD-1 is upregulated on Natural Killer (NK) cells from patients with Kaposi sarcoma (KS). PD-1 was expressed in a sub-population of activated, mature CD56dimCD16pos NK cells with otherwise normal expression of NK surface receptors. PD-1pos NK cells from KS patients were hyporesponsive ex vivo following direct triggering of NKp30, NKp46 or CD16 activating receptors, or short stimulation with NK cell targets. PD-1pos NK cells failed to degranulate and release IFNγ, but exogenous IL-2 or IL-15 restored this defect. That PD-1 contributed to NK cell functional impairment and was not simply a marker of dysfunctional NK cells was confirmed in PD-1-transduced NKL cells. In vitro, PD-1 was induced at the surface of healthy control NK cells upon prolonged contact with cells expressing activating ligands, i.e. a condition mimicking persistent stimulation by tumor cells. Thus, PD-1 appears to plays a critical role in mediating NK cell exhaustion. The existence of this negative checkpoint fine-tuning NK activation highlights the possibility that manipulation of the PD-1 pathway may be a strategy for circumventing tumor escape not only from the T cell-, but also the NK-cell mediated immune surveillance.
Objective
Oral ulcers, the hallmark lesion of Behçet's disease (BD), can be disabling and resistant to conventional treatment, and there is a need for safe and effective treatment. We undertook this ...study to investigate the long‐term safety and efficacy of ustekinumab therapy for BD‐related oral ulcers that are resistant to colchicine.
Methods
This multicenter, prospective, open‐label study included 30 patients who fulfilled the criteria of the International Study Group for BD and who were diagnosed as having active oral ulcers resistant to colchicine. Patients were treated subcutaneously with ustekinumab 90 mg at inclusion, at week 4, and then once every 12 weeks. Each patient was assessed longitudinally for the presence and number of oral ulcers, and median numbers of oral ulcers (with interquartile range IQR) were calculated. The primary efficacy end point was the proportion of patients at week 12 who experienced complete response, defined as having no oral ulcers.
Results
The median number of oral ulcers per patient during ustekinumab therapy was significantly lower at week 12 compared to baseline (0 IQR 0–1 versus 2 IQR 2–3; P < 0.0001). Complete response was achieved in 60.0% and 88.9% of patients at weeks 12 and 24, respectively. The median Behçet's Syndrome Activity Score (in which higher scores indicate more active disease) was significantly lower at weeks 12 and 24 (17.5 IQR 10–42.5 and 10 IQR 8–11, respectively) versus baseline (70 IQR 50–70; P < 0.0001). After a median follow‐up of 12 months (IQR 6–16 months), 26 patients (86.7%) were still receiving ustekinumab treatment. Reasons for ustekinumab discontinuation included BD flare (n = 3) and side effects (n = 1). Seven patients (23.3%) experienced adverse events, including headaches (n = 4) and asthenia (n = 2), with no serious side effects.
Conclusion
Ustekinumab seems to be effective in treating BD‐related oral ulcers that are resistant to treatment with colchicine.
Objective
To analyze the factors associated with response to anti–tumor necrosis factor (anti‐TNF) treatment and compare the efficacy and safety of infliximab (IFX) and adalimumab (ADA) in patients ...with refractory noninfectious uveitis.
Methods
This was a multicenter observational study of 160 patients (39% men and 61% women; median age 31 years interquartile range 21–42) with uveitis that had been refractory to other therapies, who were treated with anti‐TNF (IFX 5 mg/kg at weeks 0, 2, 6, and then every 5–6 weeks n = 98 or ADA 40 mg every 2 weeks n = 62). Factors associated with complete response were assessed by multivariate analysis. Efficacy and safety of IFX versus ADA were compared using a propensity score approach with baseline characteristics taken into account. Subdistribution hazard ratios (SHRs) and 95% confidence intervals (95% CIs) were calculated.
Results
The main etiologies of uveitis included Behçet's disease (BD) (36%), juvenile idiopathic arthritis (22%), spondyloarthropathy (10%), and sarcoidosis (6%). The overall response rate at 6 and 12 months was 87% (26% with complete response) and 93% (28% with complete response), respectively. The median time to complete response was 2 months. In multivariate analysis, BD and occurrence of >5 uveitis flares before anti‐TNF initiation were associated with complete response to anti‐TNF (SHR 2.52 95% CI 1.35–4.71, P = 0.004 and SHR 1.97 95% CI 1.02–3.84, P = 0.045, respectively). Side effects were reported in 28% of patients, including serious adverse events in 13%. IFX and ADA did not differ significantly in terms of occurrence of complete response (SHR 0.65 95% CI 0.25–1.71, P = 0.39), serious side effects (SHR 0.22 95% CI 0.04–1.25, P = 0.089), or event‐free survival (SHR 0.55 95% CI 0.28–1.08, P = 0.083).
Conclusion
Anti‐TNF treatment is highly effective in refractory inflammatory uveitis. BD is associated with increased odds of response. IFX and ADA appear to be equivalent in terms of efficacy.
To analyze the factors associated with response (control of ocular inflammation and corticosteroid-sparing effect) to biologics (anti-tumor necrosis factor TNF-α agents and tocilizumab) in patients ...with refractory uveitic macular edema (ME).
Multicenter, retrospective, observational study.
Adult patients with uveitic ME refractory to systemic corticosteroids, disease-modifying antirheumatic drugs, or both.
Patients received anti-TNF-α agents (infliximab 5 mg/kg at week 0, 2, 6, and every 4-6 weeks n = 69 and adalimumab 40 mg/2 weeks n = 80) and tocilizumab (8 mg/kg every 4 weeks intravenously n = 39 and 162 mg/week subcutaneously n = 16).
Analysis of complete and partial response rates, relapse rate, low vision (visual acuity in at least 1 eye of ≥ 1 logarithm of the minimum angle of resolution), corticosteroid-sparing effect, and adverse events at 6 months.
Two hundred four patients (median age, 40 years interquartile range, 28-58 years; 42.2% men) were included. Main causes of uveitis included Behçet's disease (17.2%), birdshot chorioretinopathy (11.3%), and sarcoidosis (7.4%). The overall response rate at 6 months was 46.2% (21.8% of complete response) with anti-TNF-α agents and 58.5% (35.8% of complete response) with tocilizumab. In multivariate analysis, treatment with tocilizumab (odds ratio, 2.10; 95% confidence interval CI, 1.06-4.06; P = 0.03) was associated independently with complete response of uveitic ME compared with anti-TNF-α agents. Anti-TNF-α agents and tocilizumab did not differ significantly in terms of relapse rate (hazard ratio, 1.00; 95% CI, 0.31-3.18; P = 0.99) or occurrence of low vision (odds ratio, 1.02; 95% CI, 0.51-2.07; P = 0.95) or corticosteroid-sparing effect (P = 0.29). Adverse events were reported in 20.6% of patients, including serious adverse events reported in 10.8% of patients.
Tocilizumab seems to improve complete response of uveitic ME compared with anti-TNF-α agents.
Objective
Relapsing polychondritis (RP) is a rare condition characterized by recurrent inflammation of cartilaginous tissue and systemic manifestations. Data on this disease remain scarce. This study ...was undertaken to describe patient characteristics and disease evolution, identify prognostic factors, and define different clinical phenotypes of RP.
Methods
We performed a retrospective study of 142 patients with RP who were seen between 2000 and 2012 in a single center.
Results
Of the 142 patients, 86 (61%) were women. The mean ± SD age at first symptoms was 43.5 ± 15 years. Patients had the following chondritis types: auricular (89%; n = 127), nasal (63%; n = 89), laryngeal (43%; n = 61), tracheobronchial (22%; n = 32), and/orcostochondritis (40%; n = 57). The main other manifestations were articular (69%; n = 98), ophthalmologic (56%; n = 80), audiovestibular (34%; n = 48), cardiac (27%; n = 38), and cutaneous (28%; n = 40). At a mean ± SD followup of 13 ± 9 years, the 5‐ and 10‐year survival rates were 95 ± 2% and 91 ± 3%, respectively. Factors associated with death on multivariable analysis were male sex (P = 0.01), cardiac abnormalities (P = 0.03), and concomitant myelodysplastic syndrome (MDS) (P = 0.004) or another hematologic malignancy (P = 0.01). Cluster analysis revealed that separating patients into 3 groups was clinically relevant, thereby separating patients with associated MDS, those with tracheobronchial involvement, and those without the 2 features in terms of clinical characteristics, therapeutic management, and prognosis.
Conclusion
This large series of patients with definite RP revealed an improvement in survival as compared with previous studies. Factors associated with death were male sex, cardiac involvement, and concomitant hematologic malignancy. We identified 3 distinct phenotypes.
Diagnosis of uveitis is difficult. Etiologic investigations should take into account the epidemiology of uveitis and should focus on the most severe forms of the disease and those which can be ...treated. This study was undertaken to establish recommendations for the diagnosis of uveitis.
Recommendations were developed by a multidisciplinary panel of 14 experts, including internists, ophthalmologists, and rheumatologists, and are based on a review of the literature and the results of the ULISSE study, which was the first prospective study to assess the efficacy of a standardized strategy for the etiologic diagnosis of uveitis. The following groups of patients are not included in these recommendations: children, immunocompromised patients, patients with severe retinal vasculitis, and those with specific eye diseases diagnosed by ophthalmologic examination only.
Diagnosis should be guided by the medical history of the patient and physical examination. Serologic screening for syphilis is appropriate in all forms of uveitis. If uveitis is not diagnosed at this stage, investigations oriented by the anatomic characteristics of uveitis are proposed. These consist of assays for HLA-B27 (in unilateral acute anterior non-granulomatous uveitis), serum angiotensin-converting enzyme, interferon-gamma release, chest computed tomography (chronic uveitis), cerebral magnetic resonance imaging and anterior chamber tap with interleukin-10 analysis (intermediate or posterior uveitis in patients >40years-old). Other investigations prescribed in the absence of orientation are usually unhelpful.
A strategy is proposed for the etiologic diagnosis of uveitis. The benefit of more invasive investigations remains to be determined.
•Etiologic diagnosis of uveitis should be guided by anatomic localization.•Syphilis serology is useful in all types of uveitis.•HLA-B27 typing is helpful in acute anterior non-granulomatous uveitis.•Measurement of ACE, IFN-γ release, and chest CT scans are useful in chronic uveitis.•Cerebral MRI and ACT with IL-10 analysis help in intermediate or posterior uveitis.
BACKGROUND
Clinical presentation and risk factors of death in COVID‐19 in oldest adults have not been well characterized.
OBJECTIVES
To describe clinical features and outcome of COVID‐19 in patients ...older than 85 years and study risk factors for mortality.
DESIGN
Prospective cohort.
PARTICIPANTS AND SETTING
Patients aged 85 years and older, admitted in noncritical care units at the University Hospital Lariboisière Fernand‐Widal (Paris, France) for confirmed severe acute respiratory syndrome coronavirus 2 infection were included and followed up for 21 days.
MEASUREMENTS
Clinical and laboratory findings were collected. Cox survival analysis was performed to explore factors associated with death.
RESULTS
From March 14 to April 11, 2020, 76 patients (median age = 90 (86–92) years; women = 55.3%) were admitted for confirmed COVID‐19. Of the patients, 64.5% presented with three or more comorbidities. Most common symptoms were asthenia (76.3%), fever (75.0%) and confusion and delirium (71.1%). An initial fall was reported in 25.0% of cases, and digestive symptoms were reported in 22.4% of cases. COVID‐19 was severe in 51.3% of cases, moderate in 32.9%, and mild in 15.8%. Complications included acute respiratory syndrome (28.9%), cardiac decompensation (14.5%), and hypotensive shock (9.0%). Fatality at 21 days was 28.9%, after a median course of disease of 13 (8–17) days. Males were overrepresented in nonsurvivors (68.2%). In survivors, median length of stay was 12 (9–19.5) days. Independent predictive factors of death were C‐reactive protein level at admission and lymphocyte count at nadir.
CONCLUSION
Specific clinical features, multiorgan injury, and high case fatality rate are observed in older adults with COVID‐19. However, rapid diagnosis, appropriate care, and monitoring seem to improve prognosis.
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