bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alemtuzumab as Remission Induction Therapy in Behçet Disease: A 20-year Experience
Authors: Mohammad Aladdin J. , Smith Rona M. , Chow Yok W. , Chaudhry Afzal N. , Jayne David R.W. 
Published: August 2015

Objective.To study the efficacy and safety of anti-CD52 antibody (alemtuzumab) in the treatment of refractory and relapsing Behçet disease (BD).Methods.Thirty-two patients (22 women) with BD received 60 courses of alemtuzumab between 1994 and 2013. Three-dose regimens were used: 134 mg in 21 courses (Group 1), 95 mg in 18 courses (Group 2), and 60 mg in 21 courses (Group 3). Immunosuppressive drugs were stopped at the time of alemtuzumab, and prednisolone was reduced according to clinical response. Treatment response was assessed by clinical status, inflammatory activity, prednisolone dose, and the need for subsequent immunosuppressive drugs and disease relapse.Results.After the first alemtuzumab course, 27 of 32 patients (84%) achieved partial or complete remission (CR). Fifty of 60 courses (83%) resulted in remission (66% CR) without differences in remission rates between dosing regimens. Profound lymphocyte depletion occurred after all courses. Relapse-free survival rates were 83.6% at 6 months and 52.8% at 12 months, and were higher among Group 1 patients (Group 1: 100% and 77.8%, Group 2: 81.3% and 37.5%, and Group 3: 65.0% and 37.1%, p < 0.001). Mild to moderate infusion reactions occurred after 16 courses (27%). Eight patients (25%) developed symptomatic thyroid disease.Conclusion.Alemtuzumab led to remission in the majority of patients with difficult-to-treat BD. Relapse was common and may be associated with lower dosing. Adverse events included infusion reactions and new autoimmunity. Achieving complete lymphocyte depletion did not affect the remission rate or duration.
Longterm Safety of Rituximab: Final Report of the Rheumatoid Arthritis Global Clinical Trial Program over 11 Years
Authors: van Vollenhoven Ronald F. , Fleischmann Roy M. , Furst Daniel E. , Lacey Stuart , Lehane Patricia B. 
Published: August 2015

Objective.Final evaluation of the longterm safety of rituximab (RTX) in rheumatoid arthritis (RA) up to 11 years.Methods.Pooled observed case analysis of data from patients with moderate to severe, active RA in a global clinical trial program.Results.As of September 2012, 3595 patients received a mean of 4 courses (range 1–20) of RTX over 11 years [14,816 patient-years (PY)]. Of these, 1246 patients had > 5 years of followup (8970 PY). A pooled placebo population (n = 818) was included in the analysis. The overall serious infection event (SIE) rate was 3.76/100 PY (2.71/100 PY in patients observed for > 5 yrs) and comparable with rates reported previously at 9.5 years (3.94/100 PY and 3.26/100 PY, respectively). SIE rates continued to be similar before and during/after development of low immunoglobulin levels, and serious opportunistic infections remained rare. Rates of cardiac events remained consistent with previous analysis and with rates in the general RA population. No increased risk of malignancy over time was observed.Conclusion.This final report demonstrates that RTX remains well tolerated over time and multiple courses. No new safety risks were identified and there was no increase in the rate of any types of adverse events with prolonged exposure to RTX during 11 years of observation.
Relation of Autoimmune Cytopenia to Glandular and Systemic Manifestations in Primary Sjögren Syndrome: Analysis of 113 Korean Patients
Authors: Koh Jung Hee , Lee Jennifer , Chung So-Hyang , Kwok Seung-Ki , Park Sung-Hwan 
Published: August 2015

Objective.To investigate the characteristics of patients with primary Sjögren syndrome (pSS) who have autoimmune cytopenia.Methods.We analyzed 113 participants from the Korean Initiative of Primary Sjögren Syndrome, a prospective pSS cohort. Autoimmune cytopenia was defined as autoimmune origin neutropenia, anemia, and/or thrombocytopenia without vitamin or iron deficiency, or drug-induced cytopenia. To identify the association between autoimmune cytopenia and the clinical characteristics of pSS, extraglandular manifestations were analyzed according to the European League Against Rheumatism Sjögren’s syndrome disease activity index (ESSDAI) definition. Xerophthalmia was assessed with the Ocular Surface Disease Index, Schirmer I test, ocular stain score (OSS), and tear film breakup time.Results.The median total ESSDAI score was 2 (interquartile range 1–6). About a quarter of patients had no systemic activity. Autoimmune cytopenia was observed in 23.9% of patients (n = 27). Moderate biological features were more frequently observed in patients with autoimmune cytopenia than in patients without [10 (37%) and 11 (12.8%), respectively, p = 0.016]. Articular involvement was exhibited in 1 patient with autoimmune cytopenia, but in 23 patients (27.4%) without autoimmune cytopenia (p = 0.013). Higher OSS (p = 0.002) and lower mean Schirmer I test (p = 0.029) were observed in patients with autoimmune cytopenia than in those without. Neutrophils and lymphocytes negatively correlated with OSS (ρ = −0.204, p = 0.041 and ρ = −0.230, p = 0.020, respectively).Conclusion.Autoimmune cytopenia is closely associated with severe ocular surface damage in pSS. Therefore, assessment of xerophthalmia by ophthalmologists may be mandatory, particularly in patients with pSS with cytopenia, even if patients do not complain of eye dryness.
The Endothelial-mesenchymal Transition in Systemic Sclerosis Is Induced by Endothelin-1 and Transforming Growth Factor-β and May Be Blocked by Macitentan, a Dual Endothelin-1 Receptor Antagonist
Authors: Cipriani Paola , Di Benedetto Paola , Ruscitti Piero , Capece Daria , Zazzeroni Francesca , Liakouli Vasiliki , Pantano Ilenia , Berardicurti Onorina , Carubbi Francesco , Pecetti Gianluca , Turricchia Stefano , Alesse Edoardo , Iglarz Marc , Giacomelli Roberto 
Published: August 2015

Objective.High endothelin-1 (ET-1) and transforming growth factor-β (TGF-β) levels may induce in healthy endothelial cells (EC) an endothelial-to-mesenchymal transition (EndMT). The same cytokines are associated with fibrosis development in systemic sclerosis (SSc). Although EndMT has not been definitively shown in SSc, this process, potentially induced by a stimulatory loop involving these 2 cytokines, overexpressed in this disease might contribute to fibroblast accumulation in affected tissues. Macitentan (MAC), an ET-1 receptor antagonist interfering with this loop, might prevent EndMT and fibroblast accumulation.Methods.EC, isolated from healthy controls (HC) and patients with SSc, were treated with ET-1 and TGF-β and successively analyzed for gene and protein expressions of endothelial and mesenchymal markers, and for Sma- and Mad-related (SMAD) phosphorylation. Further, in the supernatants, we evaluated ET-1 and TGF-β production by ELISA assay. In each assay we evaluated the ability of MAC to inhibit both the TGF-β and ET-1 effects.Results.We showed that both TGF-β and ET-1 treatments induced an activation of the EndMT process in SSc-EC as reported in HC cells. The ELISA assays showed a mutual TGF-β and ET-1 induction in both SSc-EC and HC-EC. A statistically significant increase of SMAD phosphorylation after treatment was observed in SSc-EC. In each assay, MAC inhibited both TGF-β and ET-1 effects.Conclusion.Our work is the first demonstration in literature that SSc-EC, under the synergistic effect of TGF-β and ET-1, may transdifferentiate toward myofibroblasts, thus contributing to fibroblast accumulation. MAC, interfering with this processin vitro, may offer a new potential therapeutic strategy against fibrosis.
The Spirit of OMERACT: Q Methodology Analysis of Conference Characteristics Valued by Delegates
Authors: Flurey Caroline A. , Kirwan John R. , Hadridge Phillip , Richards Pamela , Grosskleg Shawna , Tugwell Peter S. 
Published: August 2015

Objective.To identify the major features of OMERACT meetings as valued by frequent participants and to explore whether there are groups of participants with different opinions.Methods.Using Q methodology (a qualitative and quantitative approach to grouping people according to subjective opinion), participants (who attended more than 1 OMERACT conference) sorted 66 statements relating to the “spirit of OMERACT” according to level of agreement across a normal distribution grid. Data were examined using Q factor analysis.Results.Of 226 potential participants, 105 responded (46%). All participants highly ranked the focus on global standardization of methods, outcome measures, data-driven research, methodological discussion, and international collaboration. Four factors describing the “spirit of OMERACT” were identified: “Evidence not eminence” (n = 31) valued the data- and evidence-driven research above personality and status; “Collaboration and collegiality” (n = 19) valued the international and cross-stakeholder collaboration, interaction, and collegiality; “Equal voices, equal votes, common goals” (n = 12) valued equality in discussion and voting, with everyone striving toward the same goal; “principles and product, not process” (n = 8) valued the principles of focusing on outcome measures and the product of guiding clinical trials, but were unsure whether the process is necessary to reach this. The factors did not segregate different stakeholder groups.Conclusion.Delegates value different elements of OMERACT, and thus the “spirit of OMERACT” encompasses evidence-based research, collaboration, and equality, although a small group are unsure whether the process is necessary to achieve the end result. Q methodology may prove useful for conference organizers to identify their delegates’ different needs to tailor conference content.
Association Between Infrapatellar Fat Pad Volume and Knee Structural Changes in Patients with Knee Osteoarthritis
Authors: Cai Jingyu , Xu Jianhua , Wang Kang , Zheng Shuang , He Fan , Huan Shuting , Xu Shengqing , Zhang Hui , Laslett Laura , Ding Changhai 
Published: August 2015

Objective.The function of the infrapatellar fat pad (IPFP) in knee osteoarthritis (OA) remains uncertain. This study aimed to examine cross-sectional associations between IPFP volume and knee structures in patients with knee OA.Methods.The study included 174 patients with clinical knee OA (mean age, 55.5 yrs). Fat-suppressed 3-D T1-weighted spoiled gradient recall magnetic resonance imaging (MRI) was used to measure the IPFP and cartilage volume. T2-weighted fast spin echo MRI was used to assess cartilage defects and bone marrow lesions (BML). Radiographic knee osteophytes and joint space narrowing (JSN) were assessed using the Osteoarthritis Research Society International atlas.Results.After adjustment for potential confounders, greater IPFP volume was associated with greater tibial and patellar cartilage volume (all p < 0.05), and fewer cartilage defects at all sites (OR 0.88–0.91, all p < 0.05). IPFP volume was associated with presence of BML at lateral tibial and medial femoral sites (OR 0.88–0.91, all p < 0.05) and osteophytes at lateral tibiofemoral compartment (OR 0.88, p < 0.05). IPFP volume was not significantly associated with JSN.Conclusion.Greater IPFP volume was associated with greater knee cartilage volume and fewer structural abnormalities, suggesting a protective role of IPFP size in knee OA.
Factor H Autoantibodies in Patients with Antiphospholipid Syndrome and Thrombosis
Authors: Foltyn Zadura Anna , Memon Ashfaque A. , Stojanovich Ljudmila , Perricone Carlo , Conti Fabrizio , Valesini Guido , Bogdanovic Gordana , Hillarp Andreas , Shoenfeld Yehuda , Sundquist Jan , Leffler Jonatan , Svensson Peter J. , Trouw Leendert A. , Blom Anna M. 
Published: August 2015

Objective.Autoantibodies to complement factor H (FH) are associated with atypical hemolytic uremic syndrome, but can also be detected in patients with rheumatoid arthritis and in patients positive for lupus anticoagulants and thus potentially antiphospholipid syndrome (APS). To our knowledge, no data are available on the association between the presence of FH autoantibodies in APS and clinical manifestations.Methods.We determined FH autoantibody levels using ELISA in 2 cohorts of patients with primary (PAPS) and secondary APS (SAPS) from Serbia and Italy, and an additional cohort including patients with venous thromboembolism (VTE) from Sweden.Results.FH autoantibodies were detected in 13.7% of patients (n = 73) with PAPS and 30.3% of patients (n = 33) with SAPS in the Serbian cohort. FH autoantibody frequency in the Italian cohort was 33.3% (n = 15) and 36% (n = 25) in PAPS and SAPS, respectively. Both FH autoantibody levels and frequencies observed in both APS cohorts were significantly higher than in matched healthy controls (5%). Further, patients with PAPS with venous thrombosis in the Serbian cohort had significantly higher levels of FH autoantibodies. Therefore, we analyzed a dedicated Swedish thrombosis cohort and found that patients with FH autoantibody positivity had higher risk of VTE recurrence (HR 2.0, 95% CI 1.2–3.3, p = 0.011) compared with the reference group of FH autoantibody–negative patients.Conclusion.Overall, the data indicate that in patients with APS and recurrent venous thrombosis, there are increased levels of FH autoantibodies, a finding associated with poor clinical outcome.
Hydrogel Inlay for Presbyopia: Objective and Subjective Visual Outcomes
Authors: Yoo Aeri , Kim Jae Yong , Kim Myoung Joon , Tchah Hungwon 
Published: August 2015

PURPOSE:
To evaluate changes in visual performance and ocular optical quality after implantation of a corneal hydrogel inlay as a treatment for presbyopia.

METHODS:
A Raindrop Near Vision Inlay (ReVision Optics, Lake Forest, CA) was implanted monocularly on the stromal bed of a femtosecond laser-assisted generated corneal flap of non-dominant eyes of 22 patients with emmetropic presbyopia (preoperative spherical equivalent range: −0.50 to 1.00 diopters). Efficacy was determined by measuring near and distance visual acuities and ocular aberrations, and satisfaction was assessed by a patient questionnaire.

RESULTS:

The preoperative monocular uncorrected near visual acuity of the inlay inserted eye was 20/129 ± 1 Snellen (range: 20/135 to 20/61 Snellen) and improved to 20/35 ± 2 Snellen (range: 20/61 to 20/20 Snellen) (
P
< .01) at 6 months postoperatively. The monocular uncorrected distance visual acuity of the eye receiving the inlay was 20/25 ± 2 Snellen (range: 20/50 to 20/20 Snellen) preoperatively and 20/25 ± 1 Snellen (range: 20/50 to 20/20 Snellen) at 6 months postoperatively (
P
=.257). According to the questionnaire responses, 82% of patients were satisfied. This was despite near glasses needs remaining in 13.6% of the cohort and the presence of glare and a decrease in night vision in approximately 40% of patients. The primary spherical aberration coefficient Z
4
0
changed from positive to negative values in all patients (
P
< .01). However, the point spread function showed no significant change.

CONCLUSIONS:
Hydrogel corneal inlays improve uncorrected near visual acuity in patients with presbyopia with only moderate effect on visual quality. However, the satisfaction with this therapy was relatively lower in these Korean patients than that reported previously in Western patients.

[
J Refract Surg.
2015;31(7):454–460.]
A Modified Glued Transscleral Intraocular Lens Implantation: Suture-Assisted Sutureless Technique
Authors: Kara Necip 
Published: August 2015

PURPOSE:
To report a modified surgical technique as an alternative procedure for sutureless fibrin glue-assisted transscleral intraocular lens (IOL) fixation.

METHODS:
Description of the modified surgical technique with an accompanying video.

RESULTS:
In the standard glued IOL fixation technique, the leading haptic is externalized using a forceps through the sclerotomy and an assistant holds the haptic while the second IOL haptic is bimanually externalized, using the handshake technique, through the other sclerotomy site. In the author’s technique, called the suture-assisted sutureless technique, IOL haptics were tied with a looped 9-0 polypropylene suture with an attached curved needle. The suture needle was fastened to the haptic, passed through the sclerotomy site, and pulled out to externalize the haptic through the sclerotomy site.

CONCLUSIONS:
This technique is an easy, feasible, and assistant-free procedure for glued IOL implantation in aphakic eyes.

[
J Refract Surg.
2015;31(7):488–491.]
IRF4 Is a Critical Gene in Retinoic Acid–Mediated Plasma Cell Formation and Is Deregulated in Common Variable Immunodeficiency–Derived B Cells
Authors: Indrevær Randi L. , Moskaug Jan Ø. , Paur Ingvild , Bøhn Siv K. , Jørgensen Silje F. , Blomhoff Rune , Aukrust Pål , Fevang Børre , Blomhoff Heidi K. 
Published: August 2015

Abstract
In the present study, we aimed at identifying the mechanisms whereby the vitamin A metabolite all-trans retinoic acid (RA) promotes the formation of plasma cells upon stimulation of B cells via the innate immunity receptors TLR9 and RP105. Most often, differentiation of B cells involves the sequential events of class switch recombination and somatic hypermutations characteristic of germinal center reactions, followed by plasma cell formation. By studying the regulatory networks known to drive these reactions, we revealed that RA enhances the expression of the plasma cell–generating transcription factors IFN regulatory factor (IRF)4 and Blimp1, and paradoxically also activation-induced deaminase (AID) involved in somatic hypermutations/class switch recombination, in primary human B cells. IRF4 was identified as a particularly important protein involved in the RA-mediated production of IgG in TLR9/RP105-stimulated B cells. Based on kinetic studies, we present a model suggesting that the initial induction of IRF4 by RA favors AID expression. According to this model, the higher level of IRF4 that eventually arises results in sustained elevated levels of Blimp1. Regarded as a master regulator of plasma cell development, Blimp1 will in turn suppress AID expression and drive the formation of IgG-secreting plasma cells. Notably, we demonstrated IRF4 to be deregulated in B cells from common variable immunodeficiency patients, contributing to the observed aberrant expression of AID in these patients. Taken together, the present study both provides new insight into the mechanisms whereby RA induces differentiation of B cells and identifies IRF4 as a key to understand the defective functions of B cells in common variable immunodeficiency patients.
1,25(OH)2D3 Promotes the Efficacy of CD28 Costimulation Blockade by Abatacept
Authors: Gardner David H. , Jeffery Louisa E. , Soskic Blagoje , Briggs Zoe , Hou Tie Zheng , Raza Karim , Sansom David M. 
Published: August 2015

Abstract
Inhibition of the CD28:CD80/CD86 T cell costimulatory pathway has emerged as an effective strategy for the treatment of T cell–mediated inflammatory diseases. However, patient responses to CD28-ligand blockade by abatacept (CTLA-4-Ig) in conditions such as rheumatoid arthritis are variable and often suboptimal. In this study, we show that the extent to which abatacept suppresses T cell activation is influenced by the strength of TCR stimulation, with high-strength TCR stimulation being associated with relative abatacept insensitivity. Accordingly, cyclosporin A, an inhibitor of T cell stimulation via the TCR, synergized with abatacept to inhibit T cell activation. We also observed that 1,25-dihydroxyvitamin D3 enhanced the inhibition of T cell activation by abatacept, strongly inhibiting T cell activation driven by cross-linked anti-CD3, but with no effect upon anti-CD28 driven stimulation. Thus, like cyclosporin A, 1,25-dihydroxyvitamin D3 inhibits TCR-driven activation, thereby promoting abatacept sensitivity. Vitamin D3 supplementation may therefore be a useful adjunct for the treatment of conditions such as rheumatoid arthritis in combination with abatacept to promote the efficacy of treatment.
Cutting Edge: miR-17-92 Is Required for Both CD4 Th1 and T Follicular Helper Cell Responses during Viral Infection
Authors: Wu Tuoqi , Wieland Andreas , Lee Judong , Hale J. Scott , Han Jin-Hwan , Xu Xiaojin , Ahmed Rafi 
Published: August 2015

Abstract
Viral infections induce the differentiation of naive CD4 T cells into two distinct lineages, Th1 cells and T follicular helper (TFH) cells. Two recent studies demonstrated that the microRNA cluster miR-17-92 selectively promotes CD4 TFH responses. However, we show in this study that miR-17-92 expression is required for the clonal expansion of both virus-specific Th1 and TFH cells. Upon viral infection, miR-17-92–deficient CD4 T cells showed impaired clonal expansion and subsequent memory formation. Although miR-17-92 deficiency impaired the clonal expansion of both Th1 and TFH cells, the expansion of Th1 cells was more affected. Overexpression of miR-17-92 in CD4 T cells resulted in increased expansion of both virus-specific Th1 and TFH cells but selectively enhanced the Th1 response. Taken together, our data suggest that miR-17-92 is necessary for both Th1 and TFH cells to respond efficiently to viral infections and that the Th1 response is more sensitive to the level of miR-17-92 expression.
Priming of Human Resting NK Cells by Autologous M1 Macrophages via the Engagement of IL-1β, IFN-β, and IL-15 Pathways
Authors: Mattiola Irene , Pesant Matthieu , Tentorio Paolo F. , Molgora Martina , Marcenaro Emanuela , Lugli Enrico , Locati Massimo , Mavilio Domenico 
Published: August 2015

Abstract
The cross talk between NK cells and macrophages is emerging as a major line of defense against microbial infections and tumors. This study reveals a complex network of soluble mediators and cell-to-cell interactions allowing human classically activated (M1) macrophages, but not resting (M0) or alternatively activated (M2) macrophages, to prime resting autologous NK cells. In this article, we show that M1 increase NK cell cytotoxicity by IL-23 and IFN-β–dependent upregulation of NKG2D, IL-1β–dependent upregulation of NKp44, and trans-presentation of IL-15. Moreover, both IFN-β–dependent cis-presentation of IL-15 on NK cells and engagement of the 2B4-CD48 pathway are used by M1 to trigger NK cell production of IFN-γ. The disclosure of these synergic cellular mechanisms regulating the M1–NK cell cross talk provides novel insights to better understand the role of innate immune responses in the physiopathology of tumor biology and microbial infections.
Cutting Edge: AhR Is a Molecular Target of Calcitriol in Human T Cells
Authors: Takami Mariko , Fujimaki Kotaro , Nishimura Michael I. , Iwashima Makio 
Published: August 2015

Abstract
The immunoregulatory functions of vitamin D have been well documented in various immunological disorders, including multiple sclerosis, arthritis, and asthma. IL-10 is considered a chief effector molecule that promotes the vitamin D–induced immunosuppressive states of T cells and accessory cells. In this article, we demonstrate that the active form of vitamin D, 1,25-dihydroxyvitamin D3 (calcitriol), has a profound inhibitory effect on the development of human Th9, a CD4 T cell subset that is highly associated with asthma, in an IL-10–independent manner. Our data show that calcitriol represses the expression of BATF, a transcription factor essential for Th9, via suppressing the expression of aryl hydrocarbon receptor, without an increase in IL-10. The data show a novel link between vitamin D and two key transcription factors involved in T cell differentiation.