The Open Rheumatology Journal




ISSN: 1874-3129 ― Volume 13, 2019
RESEARCH ARTICLE

Tocilizumab in Large Vessel Vasculitis – Different Routes of Administration



Marc Schmalzing*, Ottar Gadeholt, Michael Gernert, Hans-Peter Tony, Eva C Schwaneck
Focus on Rheumatology / Clinical Immunology, Department of Internal Medicine II, University of Würzburg, 97080 Wurzburg, Germany

Abstract

Background:

Tocilizumab is increasingly used in the treatment of large vessel vasculitis with recent approval for giant cell arteritis.

Objective:

To determine the efficacy and safety of tocilizumab in large vessel vasculitis in a real-life setting using different routes of administration.

Methods:

Retrospective analysis of consecutive patients at a tertiary rheumatology department who received tocilizumab for large vessel vasculitis.

Results:

A total of 11 patients were treated with tocilizumab (8 giant cell arteritis, 2 large vessel vasculitis associated with rheumatoid arthritis, 1 Takayasu arteritis) after a median of 2 other steroid-sparing agents (range 1-4). Of these, 9 received tocilizumab as salvage therapy for active vasculitis and 2 due to the toxicity of their former steroid-sparing medication. After a mean follow-up of 23 months 7 patients were in remission as to vasculitis under a mean prednisolone dose of 1.7 ± 1.5 mg; one patient relapsed after long term remission having discontinued tocilizumab for elective surgery; one patient stopped tocilizumab after attributable infectious complications, and two patients died: one due to complications of vascular surgery, probably not attributable to tocilizumab; and the other due to sepsis secondary to sigmoiditis. Only 3 relapses occurred under continuous tocilizumab treatment. In all these 3 cases, renewed remission could be achieved by switching from subcutaneous (162 mg qw) to intravenous tocilizumab (8mg/kg q4w).

Conclusion:

Tocilizumab is efficacious in patients with large vessel vasculitis in a real-life situation. Safety appears to be acceptable, but infectious complications have to be considered. Intravenous tocilizumab may be used in patients who relapse under subcutaneous application.

Keywords: Tocilizumab, Giant cell arteritis, Takayasu arteritis, Route of administration, Infections, Subcutaneous, Intravenous.


Article Information


Identifiers and Pagination:

Year: 2018
Volume: 12
First Page: 152
Last Page: 159
Publisher Id: TORJ-12-152
DOI: 10.2174/1874312901812010152

Article History:

Received Date: 18/5/2018
Revision Received Date: 28/6/2018
Acceptance Date: 16/7/2018
Electronic publication date: 31/08/2018
Collection year: 2018

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© 2018 Schmalzing et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address for correspondence to this author at the Department of Internal Medicine II, University Hospital Würzburg, Rheumatology /Clinical Immunology, Oberdürrbacher Strasse 6, 97080 Würzburg, Germany; Tel: +49 931 201 40100; Fax: +49 0931 201 640100; E-mail: Schmalzing_m@ukw.de




1. INTRODUCTION

Takayasu Arteritis (TAK) and Giant Cell Arteritis (GCA) are the two major variants of Large Vessel Vasculitis (LVV). LVV can also occur in association with other inflammatory rheumatic diseases [1Ernst D, Bearlecken N, Ernst Schmidt R, Witte T. Two subsets of large vessel vasculitis characterized by the absence or presence of spondyloarthritis or its associated diseases. Open Rheumatol J 2016; 10: 101-8.[http://dx.doi.org/10.2174/1874312901610010101] [PMID: 28077977] ].TAK mainly involves the aorta and large arterial branches leading to ischemic complications of limbs and brain, whereas symptoms in GCA are usually caused by the predominant involvement of temporal arteries or other medium-sized extracranial arteries. Both diseases can cause severe morbidity and mortality.

Glucocorticoids still constitute the mainstay for treatment of LVV, but can cause severe side effects, and are associated with a high relapse rate, when used as monotherapy [2Labarca C, Koster MJ, Crowson CS, et al. Predictors of relapse and treatment outcomes in biopsy-proven giant cell arteritis: A retrospective cohort study. Rheumatology (Oxford) 2016; 55(2): 347-56.[http://dx.doi.org/10.1093/rheumatology/kev348] [PMID: 26385368] ].Therefore, in 2009 the European League against Rheumatism (EULAR) recommended considering upfront immunosuppressive steroid-sparing medication in LVV in addition to glucocorticoid therapy [3Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis 2009; 68(3): 318-23.[http://dx.doi.org/10.1136/ard.2008.088351] [PMID: 18413441] ]. Common drugs to consider in this context would be methotrexate, azathioprine, leflunomide, cyclophosphamide, and more recently biological Disease Modifying Anti-Rheumatic Drugs (DMARDs) like TNF inhibitors, abatacept, ustekinumab, and tocilizumab.

Tocilizumab is a humanized immunoglobulin G1 kappa monoclonal antibody that blocks signalling by binding to the alpha chain of the human interleukin-6 receptor, and was approved for the treatment of rheumatoid arthritis, systemic or polyarticular juvenile idiopathic arthritis, and recently, giant cell arteritis [4Mihara M, Kasutani K, Okazaki M, et al. Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family. Int Immunopharmacol 2005; 5(12): 1731-40.[http://dx.doi.org/10.1016/j.intimp.2005.05.010] [PMID: 16102523] ].

There are several studies which show the efficacy of tocilizumab in GCA regarding remission rate, relapse free survival, and steroid-sparing [5Seitz M, Reichenbach S, Bonel HM, Adler S, Wermelinger F, Villiger PM. Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series. Swiss Med Wkly 2011; 141: w13156.[PMID: 21243547] -15Stone JH, Tuckwell K, Dimonaco S, et al. Trial of Tocilizumab in giant-cell arteritis. N Engl J Med 2017; 377(4): 317-28.[http://dx.doi.org/10.1056/NEJMoa1613849] [PMID: 28745999] ]. In these studies, tocilizumab was exclusively used as an intravenous application, with the exception of the recently published, multicentric, randomized GiACTA trial, which led to approval of subcutaneous tocilizumab in giant cell arteritis. In TAK - being the rarer disease - literature on the efficacy of tocilizumab is less conclusive.

Although there is ample evidence of efficacy of tocilizumab in GCA, many questions as to the efficacy in other forms of LVV, route of administration, or safety remain.

The aim of this retrospective analysis was to evaluate efficacy and safety of tocilizumab in different forms of large vessel vasculitis in a real-life setting. Since some patients received tocilizumab both intravenously (TCZ-IV) and subcutaneously (TCZ-SC), an attempt to compare the efficacy of these different routes of application could be undertaken.

2. MATERIALS AND METHODS

A retrospective review of medical records of consecutive patients with large vessel vasculitis at our center, who received tocilizumab, was conducted. The following data were retrieved from an electronic database: patient characteristics, description of vasculitis (C-Reactive Protein (CRP), Erythrocyte Sedimentation Rate (ESR), disease duration, imaging modality documenting vasculitis, complications) and treatment (pretreatment, glucocorticoid dose, adverse events). Descriptive statistics were reported as mean and Standard Deviation (SD). Further statistical analyses were not undertaken due to low number of patients.

For patients with active disease, the mean glucocorticoid dose prior to tocilizumab and at visits at month 3 and month 6 were assessed. Follow up lasted as long as patients received tocilizumab treatment. Glucocorticoid dose at last follow up was assessed for all patients. Physician-assessed vasculitis relapses were recorded (defined as the presence of unambiguous symptoms of active vasculitis or progression in imaging). Acute phase reactants CRP and ESR were not evaluated as outcome parameters, since tocilizumab led to false negative results as expected. Imaging modalities which were used to monitor disease activity were Color Doppler Ultrasound (CDU), fluorodeoxyglucose - Positron Emission Tomography/Computerised Tomography scan (PETCT) and Magnetic Resonance Imaging (MRI). Efficacy of treatment was defined as achievement of sustained remission, i.e. normalization of vessel imaging, and absence of symptoms.

Due to the observational, retrospective data analysis, approval from the local ethics committee was not required by German law.

3. RESULTS

3.1. Baseline Characteristics

In total, 11 patients received tocilizumab (TCZ-IV 8mg/kg q4w or TCZ-SC 162 mg qw) for the diagnosis of large vessel vasculitis from July 2012 to July 2017 (patient characteristics: Table 1): 8 patients with giant cell arteritis, 2 patients with large vessel vasculitis associated with rheumatoid arthritis, and 1 patient with Takayasu arteritis.

Table 1
Patient characteristics.


In 9 patients tocilizumab was started due to active vasculitis after failure of a median of 2 immunosuppressive agents (range 1-4), including Methotrexate (n=9), leflunomide (n=7), cyclophosphamide (n=5), or azathioprine (n=4). Active vasculitis directly before the start of tocilizumab was properly documented in all patients by CRP (n=6), ESR (n=7), CDU (n=5), MRI (n=4), and PETCT (n=3). The other 2 patients without active vasculitis were started on TCZ-SC due to side effects of their former steroid-sparing medication.

In 7 patients, tocilizumab was started as a subcutaneous application. Of the 4 other patients who started tocilizumab intravenously, one stayed on TCZ-IV (number 6), while three switched from TCZ-IV to TCZ-SC in remission for logistic reasons (two after 8 weeks, and one after 27 months).

3.2. Efficacy

Patients with active vasculitis had a mean CRP of 5.02 +- 5.87 mg/dl and a mean ESR of 58.2 +-45.9 mm/h. As expected, CRP and ESR normalized after the initiation of tocilizumab, and stayed so throughout the whole treatment period in all patients except for one female patient with rheumatoid arthritis, who had an arthritic relapse after 6 months of TCZ-SC (CRP 1.50 mg/dl). The MRI at that time did not show active vasculitis of the aorta.

In addition to serological markers, the disease course of patients with active vasculitis was monitored by clinical parameters (n=9), CDU (n=6), MRI (n=3), and PETCT (n=1).

In the 8 patients with active vasculitis who could be evaluated, mean daily prednisolone dose at the time of flare before steroid pulse and the start of tocilizumab was 11.3 ± 7.7 mg. Mean prednisolone dose of the steroid pulse was 185.8 ± 336.1 mg (range 5 - 1000 mg). Mean prednisolone dose was 10.2 ± 5.9 mg after 3 months of tocilizumab, and 9.2 ± 8.6 mg after 6 months, respectively. One patient (number 5) with active vasculitis refused to reduce his prednisolone dose below 75 mg daily for fear of blindness and was excluded from the analysis.

After a mean follow up of 23 months (range 4-60) 8 of 11 patients were still under tocilizumab treatment (4 TCZ-IV, 4 TCZ-SC), with a mean prednisolone dose of 4,0 mg (± 6.6 mg). Excluding the patient (number 9) who relapsed probably because of perioperative termination of TCZ, last mean prednisolone dose was 1.7 ± 1.5 mg in the 7 patients in remission as to vasculitis. Reasons for discontinuation of TCZ in the other 3 patients are described below (safety chapter).

Of the 9 patients with active vasculitis before initiating TCZ 3 relapsed with vasculitis (all under TCZ-SC, number 9-11). In all 3 patients, TCZ-SC was switched to TCZ-IV, which led to a marked response in all patients. Since this response may speak in favor of a superior efficacy of TCZ-IV, we present these three cases in more detail.

3.2.1. Patient 9

In a 71-year-old, female patient with GCA, MRI showed vasculitis of the abdominal aorta and both common iliac arteries. Response to methotrexate alone or combined with leflunomide, and cyclophosphamide was inadequate, upon which TCZ-IV was commenced. After two initial intravenous applications, TCZ was switched to TCZ-SC. Prednisolone was tapered to 5 mg within 4 months without symptoms indicating relapse. The patient relapsed after seven months, with cervical tenderness, signs of aortitis on MRI and vessel wall thickening of the carotid arteries (daily prednisolone dose at relapse: 5 mg). TCZ-SC was switched back to TCZ-IV, and prednisolone dose was increased to 30 mg with consecutive tapering. 3 months later, under 10 mg of prednisolone, wall thickening of the carotid arteries and of the aorta markedly decreased in CDU, and MRI respectively. The patient was free of clinical symptoms and remained in remission for 9 months (prednisolone dose 5 mg), until tocilizumab was stopped in preparation of valve surgery for progressive aortic regurgitation. 4 weeks after surgery, tocilizumab was restarted and prednisolone dose increased to 20 mg due to relapse (aortic histology, CRP).

3.2.2. Patient 10

In a 47-year-old, female patient with GCA and anterior ischemic optical neuropathy, MRI and CDU showed halo and increased wall thickness of both ACC. Steroid-sparing treatment with methotrexate, leflunomide, and azathioprine had to be stopped due to toxicity. Intravenous cyclophosphamide (cumulative dose: 8000 mg) was ineffective. Therefore, TCZ-SC was started. Within 6 months prednisolone could be reduced to 5 mg, and CDU aspect became normal. After 10 months of TCZ-SC treatment, the patient relapsed with severe cervical tenderness responsive to prednisolone (daily prednisolone dose before pulse 5 mg). Therefore, TCZ-SC was switched to TCZ-IV. After a further follow up of 24 months, the patient is still in remission after tapering prednisolone to 3 mg with normal CDU.

3.2.3. Patient 11

In a 21-year-old, female patient with TAK, CDU showed vessel wall thickening of both ACC, occluding the right one, of both internal and external carotid arteries, the left subclavian artery with occlusion, and the left vertebral artery with occlusion. She relapsed after 2 months of treatment with methotrexate and prednisolone, wherefore TCZ-SC was added and prednisolone increased from 15 to 100 mg. While tapering prednisolone in the following 4 months, the patient suffered two minor and one major relapse (severe cervical tenderness and progressive wall thickening in CDU), treated by prednisolone pulses. Prednisolone was increased from 15 mg to 100 mg and TCZ-SC was switched to TCZ-IV. Since the switch, no further relapse occurred during follow up of 20 months, and prednisolone could be tapered to 4 mg.

3.3. Safety

Three patients suffered infectious complications under TCZ treatment:

One patient (number 3) had to stop tocilizumab after 4 months due to Campylobacter-induced colitis and oropharyngeal candidiasis under a concomitant prednisolone dose of 10 mg.

The second patient (number 4) developed cellulitis of her right foot after one application of TCZ-SC under 5 mg prednisolone daily. After antibiotic therapy tocilizumab could be restarted, which she received for one more year. TCZ-SC was then stopped in preparation for vascular surgery of progressive aortic aneurysm. TCZ could not be restarted due to severe complications after surgery, of which she died 7 months later.

The third patient (number 5) died from sepsis shortly after surgery for a pertrochanteric fracture after 4 months of TCZ treatment. Escherichia coli was found in several blood cultures, and wall thickening of the sigma was detected in CT scan. This was the aforementioned patient who did not lower his prednisolone dose below 75 mg due to fear of blindness.

No other side effects could be attributed to tocilizumab in all patients.

4. DISCUSSION

In this retrospective analysis, we confirm the efficacy and safety of tocilizumab in different forms of large vessel vasculitis, either given intravenously or subcutaneously, even in a heavily pretreated patient population. Seven out of eleven patients still showed good disease control with low prednisolone dose under continuous tocilizumab, at last, follow up (mean follow up of about 23 months, range 4-60 months).

Although there was good disease control in our study with tocilizumab treatment, the mean steroid-sparing effect in the first 6 months was only marginal. In the majority of patients, prednisolone could be reduced to an acceptable level according to EULAR guidelines only after longer follow-up [16Strehl C, Bijlsma JW, de Wit M, et al. Defining conditions where long-term glucocorticoid treatment has an acceptably low level of harm to facilitate implementation of existing recommendations: Viewpoints from an EULAR task force. Ann Rheum Dis 2016; 75(6): 952-7.[http://dx.doi.org/10.1136/annrheumdis-2015-208916] [PMID: 26933146] ]. The fact that 56% of patients in the tocilizumab arms in the GiACTA trial had sustained remission in week 52 with a prednisone tapering regimen of merely 26 weeks, would suggest a very strong steroid-sparing effect with a high rate of prednisone discontinuation. This was not necessarily the case in our heavily pretreated population arguing in favor of an important role of a glucocorticoid maintenance therapy in combination with tocilizumab.

So far, there is no evidence that intravenous application of tocilizumab shows superior efficacy compared to subcutaneous application in large vessel vasculitis. However, in our cohort three patients, who relapsed under TCZ-SC, showed good disease control after switching to TCZ-IV, although prednisolone was then tapered to an even lower dose than under TCZ-SC. The disease course of these three patients may speak in favor of a better efficacy of TCZ-IV compared to TCZ-SC.

This postulated superiority of TCZ-IV could be explained by different pharmacokinetics. Studies in RA show comparable serum trough levels for both TCZ-IV and TCZ-SC [17Ogata A, Tanimura K, Sugimoto T, et al. Phase III study of the efficacy and safety of subcutaneous versus intravenous tocilizumab monotherapy in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken) 2014; 66(3): 344-54.[http://dx.doi.org/10.1002/acr.22110] [PMID: 23983039] ], but a higher area under the curve (AUC) for TCZ-IV [18Burmester GR, Rubbert-Roth A, Cantagrel A, et al. A randomised, double-blind, parallel-group study of the safety and efficacy of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with moderate to severe rheumatoid arthritis (SUMMACTA study). Ann Rheum Dis 2014; 73(1): 69-74.[http://dx.doi.org/10.1136/annrheumdis-2013-203523] [PMID: 23904473] ]. Furthermore, it was shown that the efficacy of TCZ-SC could be worse in patients with high body weight [19Iwamoto N, Fukui S, Umeda M, et al. Evaluation of switching from intravenous to subcutaneous formulation of tocilizumab in patients with rheumatoid arthritis. Mod Rheumatol 2016; 26(5): 662-6.[http://dx.doi.org/10.3109/14397595.2015.1129692] [PMID: 26708444] ]. Only one of the three patients, who relapsed in our study under TCZ-SC, was obese with a body weight of 100 kg, the two other patients weighed only 61 and 57.5 kg respectively. Thus, obesity cannot explain the inferior efficacy of TCZ-SC in our patients.

Another explanation for the different efficacy of TCZ-IV and TCZ-SC could be disease-related. Response to interleukin-6-receptor-inhibition by tocilizumab with respect to elevation of interleukin-6 or soluble-interleukin-6-receptor in patients sera can depend on the disease entity. This was shown in a study of rheumatoid arthritis and Castleman’s disease, respectively [20Nishimoto N, Terao K, Mima T, Nakahara H, Takagi N, Kakehi T. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood 2008; 112(10): 3959-64.[http://dx.doi.org/10.1182/blood-2008-05-155846] [PMID: 18784373] ]. So far, there are no similar observations concerning large vessel vasculitis.

The inferior disease control under TCZ-SC, which the three patients applied themselves, may in principle be due to worse adherence. Nevertheless, the patients in question did not show any signs of lower adherence, they requested their tocilizumab prescriptions in time, ESR and CRP were always suppressed as expected, they had no difficulty with subcutaneous application, and they all showed a credible positive attitude towards tocilizumab due to fear of ischemic complications. Even in the unlikely case of better disease control under intravenous tocilizumab being caused by adherence issues, our experience would argue in favor of using the more reliable intravenous application in patients with active vasculitis prone to ischemic complications.

Whether TCZ-IV is more effective in large vessel vasculitis than TCZ-SC, should be a matter of future research.

With regard to safety, there were three severe infections in our eleven patients. One patient had to stop tocilizumab due to infectious colitis, whereas another patient could restart tocilizumab after antibiotic treatment. One patient died from sepsis, but took a high concomitant prednisolone dose. Of note, the most likely source for sepsis of the deceased patient was sigmoiditis. At least in RA patients a higher risk of lower intestinal tract perforations of tocilizumab compared to other biological DMARDs was found in studies [21Strangfeld A, Richter A, Siegmund B, et al. Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs. Ann Rheum Dis 2017; 76(3): 504-10.[http://dx.doi.org/10.1136/annrheumdis-2016-209773] [PMID: 27405509] ]. This finding was not confirmed in the GiACTA trial. Nevertheless, this signal would call for large prospective studies in a non-interventional real life setting to evaluate safety in a population which is highly problematic as to infectious risk. Our patient population was mainly elderly, had a high cumulative dose of prednisolone, and suffered from multiple comorbidities (diabetes, osteoporosis, heart failure, renal failure, pulmonary arterial hypertension, diverticulosis), which would account for the relatively high rate of severe infections.

Our study has several weaknesses. The patient number is low and patients suffered from different forms of large vessel vasculitis, which renders the study population heterogeneous. Nevertheless, the excellent response in almost all patients, and the disease control of three patients after switching from TCZ-SC to TCZ-IV could be a basis for further studies comparing efficacy of TCZ-SC versus TCZ-IV in GCA and TAK, respectively.

CONCLUSION

In summary, tocilizumab constitutes an efficacious treatment option even for heavily pretreated patients with large vessel vasculitis in a real-life situation. Safety seems to be acceptable, but infectious complications have to be considered. This report suggests that switching from subcutaneous to intravenous tocilizumab may achieve better disease control.

LIST OF ABBREVIATIONS

ACC = Common carotid artery/arteries
CDU = Color Doppler Ultrasound
CRP = C-Reactive Protein
CT = Computerised Tomography scan
ESR = Erythrocyte Sedimentation Rate
EULAR = European League Against Rheumatism
DMARDs = Disease Modifying Anti-Rheumatic Drugs
GCA = Giant Cell Arteritis
LVV = Large Vessel Vasculitis
MRI = Magnetic Resonance Imaging
PETCT = Positron Emission Tomography/Computerised Tomography scan
PMR = Polymyalgia Rheumatica
RA = Rheumatoid Arthritis
SD = Standard Deviation
TAK = Takayasu Arteritis
TCZ = Tocilizumab
TCZ-IV = Intravenous Tocilizumab
TCZ-SC = Subcutaneous Tocilizumab

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Due to the observational, retrospective data analysis, approval from the local ethics committee was not required by German law.

HUMAN AND ANIMAL RIGHTS

No Animals were used in this research. All human research procedures followed were in accordance with the ethical standards of the committee responsible for human experimentation (institutional and national), and with the Helsinki Declaration of 1975, as revised in 2013.

CONSENT FOR PUBLICATION

Due to the retrospective design patients’ consent was not required. The three patients described in more detail gave their consent for publication.

CONFLICT OF INTEREST

Marc Schmalzing, Hans-Peter Tony and Eva C. Schwaneck received speaker’s fees, travel expenses, a research grant, or compensation for consultation from Roche and Chugai.

ACKNOWLEDGEMENTS

Declared none.

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[19] Iwamoto N, Fukui S, Umeda M, et al. Evaluation of switching from intravenous to subcutaneous formulation of tocilizumab in patients with rheumatoid arthritis. Mod Rheumatol 2016; 26(5): 662-6.[http://dx.doi.org/10.3109/14397595.2015.1129692] [PMID: 26708444]
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Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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