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Abstract
Background To evaluate the efficacy of rituximab in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients not responding to conventional immune therapies.
Methods An open-label, prospective exploratory study was conducted with intravenous rituximab on 17 CIDP patients who had not responded to at least two first-line therapies. The primary endpoint was to determine the proportion of patients who showed improvement 6 months after rituximab therapy. The percentage of responders to rituximab, along with a 95% CI, was reported and compared with the 30% response rate after other immunosuppressive drugs previously documented in the literature.
Results 13 of the 17 treated patients (76.5%) showed improvement at 6 months (95% CI 50.1 to 93.2). Among the 14 patients who completed the 12-month follow-up (2 were lost to follow-up after showing improvement at months 8 and 10, and 1 deteriorated at 6 months), 13 (92.9%) demonstrated improvement at 12 months (95% CI 66.1 to 99.8). Nerve conduction parameters improved by at least 20% in two nerves in 6 out of 15 (40%) patients at 6 months and in 7 out of 13 (53.9%) at 12 months. None of the treated patients withdrew from the study due to side effects. There was a significant reduction of circulating CD19+ cells 15 days, 2, 6 and 12 months after treatment.
Conclusion Rituximab seems to be a safe therapy in most patients with CIDP not responding to conventional immune therapies. The high percentage of patients who improved in this study suggests a possible positive effect of rituximab which is worth investigating in future randomised controlled clinical trials.
Trial registration number NCT05877040.
- NEUROIMMUNOLOGY
- NEUROPATHY
Data availability statement
Data are available on reasonable request. Anonymised data used for this study are available on reasonable request from the corresponding author.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Most chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients show improvement with long-term therapy with steroids, intravenous immunoglobulins or plasma exchange. However, a significant proportion does not respond or becomes resistant to these treatments.
WHAT THIS STUDY ADDS
The majority of patients not responding to conventional immune therapies included in this prospective open-label study improved after therapy with intravenous rituximab and maintained the improvement until the end of the 12- month follow-up. None of the patients suspended the therapy for adverse events.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
This study supports the efficacy of rituximab in patients with CIDP not responding to first line therapies. It also emphasises the importance of conducting randomised controlled trials to validate these results.
Introduction
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic and disabling disorder of the peripheral nervous system with a prevalence ranging from 0.8 to 8.9 cases per 100.000 individuals.1 2 There is a general consensus that CIDP is an immune-mediated disorder1 leading to the use of immune therapies including steroids, plasma exchange, high-dose intravenous immunoglobulin, and, more recently, subcutaneous immunoglobulin. These therapies have demonstrated efficacy in the range of 50%–80% treated patients.3–6 To maintain symptom improvement and prevent worsening after treatment cessation, however, extended durations of therapy are necessary. In patients treated with intravenous immunoglobulin, worsening typically occurs after an average of 4.5 months, while for those treated with steroids, it happens after around 14 months.7 Moreover, up to 80% of patients experience relapses within 3.5 years after discontinuing therapy.7–10 Prolonged treatment periods not only increase the cost associated with intravenous immunoglobulin therapy use but also raise the risk of side effects associated with steroids. There is also a significant proportion of patients who do not experience improvement or become resistant to these therapies.11 As a result, there is an increasing demand to investigate alternative immune therapies for CIDP. Numerous immunomodulatory drugs have undergone testing in randomised clinical trials, yet none have demonstrated efficacy in this disorder.11 12
Rituximab is a chimeric monoclonal antibody that targets the CD-20 surface antigen, found on normal and malignant pre-B and mature B cells until their differentiation into plasma cells.13 In autoimmune diseases, its efficacy is attributed to a reduction in the synthesis of new plasma cells or interference with the role of B cells as antigen-presenting cells. Preliminary evidence regarding the potential efficacy of rituximab in CIDP has been summarised in two recent reviews, both indicating improvement in over 70% of the patients.11 14 Additionally, two series of CIDP patients, refractory to conventional therapies, have shown positive outcomes.15 16 These two studies, however, were either retrospective or employed various treatment strategies, different protocols, variable treatment durations and assessment times. Furthermore, studies on patients with antibodies against proteins at the node/paranode of Ranvier, such as contactin 1 (CNTN1) and neurofascin 155 (NF155), have suggested a potential benefit of rituximab. These patients often displayed a limited response to intravenous immunoglobulin but experienced improvement with rituximab.17–21
We conducted a prospective open-label proof-of-concept study using intravenous rituximab in CIDP patients who showed no improvement after undergoing at least two conventional immune therapies.
Methods
Patients
In this study, we enrolled patients with a documented diagnosis of definite or probable CIDP based on the 2010 European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria22 who had not shown improvement after receiving an adequate dosage of at least two of the following therapies: intravenous immunoglobulin (a minimum of 2 g/kg monthly for at least 2 months), steroids (a minimum of 1 mg/kg daily of oral prednisone or equivalent for at least 2 months) or plasma exchanges (a minimum of four exchanges within 2 weeks). Patients were informed about both the potential benefits and adverse events associated with the therapy and provided informed consent to participate in the study. Additional inclusion criteria were as follows: (1) age 18 years or older; (2) receipt of steroids before the screening visit was allowed under specific circumstances, with a maximum dosage equivalent of 25 mg/day of prednisone or pulsed 600 mg/monthly of methylprednisolone. It was required that the dosage had not been increased by more than 20% in the previous 6 months or during the study, and a measurable response to therapy should not have been achieved; (3) female subjects of childbearing potential were required to have a negative serum pregnancy test and agree to use a highly effective method of birth control during the study and for a period of 12 months after their last dose of the study drug; (4) male subjects with partners of childbearing potential were required to be willing to use a highly effective method of birth control for the same period. Patients who met any of the following criteria were excluded: current diagnosis or history of (1) type 1 or type 2 diabetes mellitus; (2) IgM paraproteinaemia with anti-MAG (myelin-associated glycoprotein) antibody; (3) multifocal motor neuropathy; (4) clinical or known evidence of other medical conditions that might cause neuropathy; (5) pregnant or lactating females; (6) patients with any medical or psychiatric condition that could harm the subject or compromise the ability to participate in the study; (7) patients with congestive heart failure or moderate to severe impairment of cardiac function; (8) patients with renal or liver impairment defined by serology tests and those with leucopenia, lymphopenia or a platelet count less than 100 x10∧5/L/mm3; (9) patients with a history or serological evidence of clinically relevant ongoing chronic or active infections or patients hospitalised for infection within 6 weeks prior to the first dose of rituximab; (10) patients with a family history of primary immunodeficiency; (11) patients with an active neoplastic disease or a history of neoplastic disease within 5 years of study entry, except for definitively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the uterine cervix; (12) patients who had undergone plasma exchange, immune absorption, or intravenous immunoglobulin treatment within 1 month before enrolment; (13) patients who had taken immunosuppressive or chemotherapeutic medications or biological therapy, including rituximab, azathioprine, cyclophosphamide, cyclosporine, mycophenolate, etanercept and methotrexate within 12 months before inclusion; (14) patients who underwent total lymphoid irradiation or haematopoietic stem cell transplantation at any time; (15) patients who had received a live vaccination within 8 weeks before the baseline visit, those who planned to receive a live vaccination during the study, or those intending to receive one within 7 weeks following the final dose of rituximab and (16) patients with a history of hypersensitivity to rituximab.
The study is registered under the EUDRACT number 2018-001347-31 and ClinicalTrials.gov Identifier NCT05877040.
Antibody testing
All the sera were tested before treatment for the presence of anti-nodal-paranodal antibodies by ELISA according to previously reported procedure17 23 using recombinant NF155 protein (OriGene RC228652), or CNTN1 protein (OriGene RC214706), or NF186 protein (TP 329070 Origene) or contactin-associated protein (Caspr) 1 protein (2418-CR R&D). After saturation, wells were incubated in duplicate with sera diluted 1:100 and counterstained with horse-radish peroxidase labelled polyclonal rabbit anti-human IgG/HRP. Reactivity was detected with TMB solution (Biolegend). Optical density was measured at a wavelength of 450 nm by a DSX plate reader (manufactured by Technogetics). Sera with an optical density >0.3 were considered positive. All the sera were subsequently tested by immunocytochemistry on transfected human embryonic kidney (HEK) 293 cells at the Neuromuscular Laboratory of the Neurology Department, Hospital de la Santa Creu, Sant Pau, Barcelona, Spain.17
Rituximab treatment
Patients received two doses of intravenous rituximab (Truxima, Celltrion Healthcare Hungary), with the first dose administered on day 1 and the second on day 15, following the protocol approved in Italy for rheumatoid arthritis. Each dose involved the infusion of 1 g of rituximab, which was diluted in 500 mL of sodium chloride solution and administered over approximately 4 hours. To minimise the risk of infusion-related reactions, patients were premedicated with 1 g of oral paracetamol, 10 mg of chlorphenamine maleate in 100 mL of sodium chloride saline solution and 125 mg of methylprednisolone in 100 mL of sodium chloride solution infused over 20 min. A minimum of 30 min elapsed between the end of the methylprednisolone infusion and the administration of rituximab.
Assessments
Patients underwent evaluation at several time points: at enrolment, within 1 month before the first rituximab infusion, and then at months 2, 4, 6, 8, 10 and 12. These assessments were conducted by the treating neurologist, who also monitored potential side effects and concomitant diseases or disorders throughout the treatment period and verified the results of laboratory tests. These assessments were consistently conducted by the respective treating neurologist assigned to each patient, ensuring consistency within the same centre. At each visit, muscle strength was evaluated in 12 muscles using the Medical Research Council (MRC) sum score, with a range of 0–60 (from most impaired to healthy).24 Disability was assessed using the Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale, which ranges from 0 to 10 (from most impaired to healthy)25 and using the Inflammatory-Rasch Overall Built Disability Scale (I-RODS), which ranges from 0 to 48 (from most impaired to healthy).26 Quality of life was assessed using the 36-Item Short Form Health Survey questionnaire (SF-36) at enrolment and at 6 and 12 months after treatment.27 A complete electroneurographical evaluation was performed at enrolment and repeated at 6 and 12 months after therapy on the four most affected motor and two sensory nerves. Haematology, chemistry and infectious disease blood tests were conducted at enrolment, between the first and the second rituximab infusion, and at 2, 4, 6 and 12 months after therapy. Blood lymphocyte subpopulation counts, including CD19, were assessed within 30 days before the initiation of treatment and at 2, 6 and 12 months thereafter. Serum samples for antinerve antibodies were collected before treatment and at 6 and 12 months after therapy. ECGs, chest X-rays, and testing for HIV-1, HIV-2, and pregnancy were conducted within 30 days before the treatment commencement.
Objectives of the study
The primary endpoint of the study was defined as the proportion of CIDP patients who demonstrated improvement 6 months after rituximab therapy, meeting at least one of the following criteria: a 1-point improvement on the INCAT scale, a 2-point improvement on the MRC sum score or a 4-centile-point improvement on the RODS scale. Additionally, in accordance with recent 2021 European Academy of Neurology/PNS (EAN/PNS) guidelines on treatment response,28 data were also calculated considering a 4-point improvement in the MRC sum score and 1 point in the adjusted INCAT scale.
Secondary endpoints were as follows: (1) the proportion of patients showing improvement 12 months after rituximab therapy, using the same criteria as mentioned above; (2) the proportion of patients demonstrating improvement in electrophysiological parameters at 6 and 12 months post-therapy, arbitrarily defined as at least a 20% improvement in conduction velocity or distal latency or distal and proximal CMAP amplitude in at least two motor nerves; (3) the proportion of patients discontinuing treatment due to side effects, voluntary withdrawal or those who developed such side effects within 12 months after treatment; (4) the probability of worsening after having achieved an improvement and the duration of improvement within the last follow-up at 12 months, following rituximab therapy; (5) the mean change in the physical component of quality of life, as assessed by the SF-36 scale, at 6 and 12 months after initiating treatment compared with baseline; (6) the difference in the proportion of patients showing improvement at 6 and 12 months between subgroups with and without antibody reactivities and (7) the difference in the proportion of patients showing improvement at 6 and 12 months between subgroups with typical CIDP and atypical CIDP variants.
Statistical analysis
Sample size calculation
Among CIDP patients not responsive to first-line therapies, the percentage of responders to immunosuppressive drugs was reported to be 25%–30%.29 The inclusion of a total of 20 patients with CIDP not responding to conventional immune therapies provides an 80% statistical power to detect a 30% absolute difference in favour of rituximab (60% of responders) compared with an historical assumed response rate of 30%. This analysis was conducted with a significance level of 5% using a single proportion exact binomial test.
Statistical analysis plan
The proportion of patients who experienced improvement was reported along with its corresponding 95% binomial CI (Clopper-Pearson). This was then compared with an assumed response rate of 30% previously reported for other immunosuppressive and immunomodulatory agents.29 The cumulative probability of improvement over the study period was depicted using a Kaplan-Meier curve, where improvement served as the event variable, and the time variable was the duration from study entry to the first visit where improvement was observed. Additionally, the cumulative probability of worsening after improvement was assessed in participants who achieved improvement. For this analysis, the event variable was worsening, and the time variable represented the duration between the first visit showing improvement and the first visit at which worsening was observed.
Within-group differences in SF-36 scores and haematological findings at months 6 and 12 compared with baseline were assessed with the paired t-test or the Wilcoxon signed-rank test. The proportion of responders to rituximab at 6 and 12 months was compared between patients with and without antibody reactivity and between typical CIDP and variants using the χ2 or the Fisher’s exact test.
Results
20 patients were enrolled in the study. Three patients were excluded after the screening assessment: one withdrew consent before treatment for COVID-19 concern, and two had nerve conduction studies inconsistent with the 2010 EFNS/PNS diagnostic criteria for CIDP (figure 1). This resulted in a total of 17 included patients. Of these, two were lost to follow-up, one at month 8 and another after the visit at month 10, due to their relocation abroad. One patient deteriorated at the visit of month 6 and voluntarily withdrew from the study. All these three patients were evaluated at month 6.
Flow diagram of the study.
Table 1 summarises the demographic and clinical characteristics of the 17 treated patients. Mean age at study entry was 56.0 years (range 49–70). Median disease duration was 9.5 years (range 1–44). Four patients had symptom duration before enrolment of less than 5 years, five between 5 and 10 years and eight over 10 years. Mean dose of rituximab per patient was 541.4 mg/m2 (range 427.4–689.7). Only two patients had a CIDP variant (one pure motor CIDP and one distal CIDP). One patient tested positive for NF-155 antibodies by cell-based immunoassay but not ELISA. All patients had received a minimum of three intravenous immunoglobulin infusions at a dosage of 2 g/kg and had undergone at least 2 months of treatment with prednisone at a dose of 1 mg/kg, or alternatively, three cycles of monthly intravenous methylprednisolone. Five patients were on treatment with oral prednisone before inclusion, prescribed at daily doses of 2.5 mg, 5 mg, 7.5 mg (one patient each) and 12.5 mg (two patients). These patients continued the same or lower dosage during the study.
Demographic and clinical features of the treated patients
Table 2 summarises the treatment response results 6 months after rituximab therapy (primary endpoint) and the response to treatment at 6 months for each scale. Based on the defined criteria for improvement, 76.5% (95% CI 50.1% to 93.2%) of the treated patients exhibited improvement at month 6. Even with a large variability in the estimated proportion of improvement, the CI was above the historical 30% of improvement29 observed for other immunosuppressive drugs. When the analysis was repeated considering 4-point increase as the threshold for improvement on the MRC sum score,28 the observed improvement proportion was 58.8% (95% CI 32.9% to 81.6%), therefore with a 95% CI that remained above the historical 30% observed for other immunosuppressive drugs. No differences were detected when the data were calculated using the adjusted INCAT scale. A clinical improvement confirmed by at least two measured scales was obtained by 7 (41.1%) patients (95% CI 18.4% to 67.1%). The proportion of patients who clinically improved at 6 months was similar for those with symptom duration before inclusion of less than 10 years (7/9; 78%) and more than 10 years (6/8; 75%) (p=1.00, Fisher’s exact test). Nerve conduction studies were not conducted for two patients at 6 months. In the remaining patients, nerve conduction studies revealed improvement in 40% of patients based on our arbitrary cut-off and in 73.3% based on the published minimum clinical important difference (MCID) thresholds.30
Response to rituximab treatment at 6 months (primary endpoint)
Table 3 summarises treatment response 12 months after rituximab therapy (secondary endpoint), along with the response in each scale. Based on the defined criteria for improvement, 92.9% (95% CI 66.1% to 99.8%) of the treated patients improved. A less frequent improvement was observed when considering a 4-point difference in the MRC sum score,28 (71.4%; 95% CI 41.9% to 91.6%). In both cases, the 95% CI was above the historical 30% of improvement observed for other immunosuppressive drugs.29 No differences were detected when the data were calculated using the adjusted INCAT scale. Clinical improvement was confirmed by at least two outcome measures in 6 (35.3%) patients (95% CI 14.2% to 61.7%). A sensitivity analysis was also conducted, which involved including the three patients who were lost to follow-up before the 12-month visit. Among these patients, two showed improvements at their last available visits (at month 8 and month 10, respectively) and were imputed as improved, while one patient who experienced significant worsening at month 6 was imputed as not improved (table 3). The proportion of patients who clinically improved at 12 months was comparable for those with a symptom duration before inclusion of less than 10 years (5/6, 83%) and more than 10 years (8/8, 100%) (p=0.43, Fisher’s exact test). This trend persisted at 12 months, even when including missing data (7/9 (78%) improved with less than 10 years and 8/8 (100%) improved with more than 10 years; p=0.51, Fisher’s exact test). Nerve conduction studies were not conducted for two patients at 12 months. In the remaining patients, nerve conduction studies revealed improvement in 53.9% of patients based on both our arbitrary cut-off and the published MCID thresholds.30
Response to rituximab treatment at 12 months (secondary endpoint)
The cumulative probability of improvement over the study period is depicted in figure 2, which shows that half of the patients achieved improvement after 4 months from the start of rituximab treatment. Considering all improved participants, the improvement was sustained until the end of the 12-month follow-up in all but one patient.
Kaplan-Meier curve on cumulative probability of improvement after treatment with rituximab.
In terms of health-related quality of life, a slight but not statistically significant improvement in physical activity at 6 and 12 months compared with baseline was observed. The mean increase was 5 points both at 6 months (IQR −5 to 20, p=0.10) and 12 months (IQR 0–20, p=0.11). Additionally, there was a slight improvement on the standardised physical component scale at 12 months compared with baseline, with a mean increase of 6 points (IQR 0–8; p=0.05).
Comparison related to antibody reactivity could not be conducted as only one patient had antibodies to NF-155 by cell-based immunoassay. This patient improved at months 6 and 12. Similarly, due to the limited number of patients with a CIDP variant, a comparison with typical CIDP was not possible.
The changes in haematological parameters after rituximab treatment are presented in online supplemental table 1. A significant reduction in CD19+cells was observed at months 2, 6 and 12, with only two patients showing a moderate reduction (16%) or normalisation at month 12. Lymphocyte reduction was significant at day 15, months 2 and 6, but not at month 12. No significant reduction was observed in the number of red blood cells, leucocytes and platelets throughout the treatment.
Supplemental material
Only two (12%) patients reported undesired side effects during the treatment period. Specifically, one patient disclosed, prior to the second rituximab infusion, that a medical examination by their physician had revealed mild hepatic steatosis accompanied by fibrosis, conditions not previously detected in blood tests conducted at the time of enrolment and during subsequent follow-up, and to which the patient had been previously unaware. The other patient experienced a single episode of epistaxis, which completely resolved and was considered unrelated to the treatment. Additionally, he had one episode of cough and dysuria, both of which resolved within a few days and were considered to have a possible relation to the study drug.
Discussion
In this open-label prospective study involving patients with CIDP not responding to adequate dose of conventional immune therapies, intravenous therapy with rituximab resulted in a clinical improvement in most patients at both 6 months (76.5%) and 12 months (88.2%) after treatment. These improvement proportions were higher than previously reported in a retrospective analysis of the efficacy of other immunosuppressive therapies in CIDP (30%).29 The improvement observed in our study was also greater than that reported in the patients with CIDP included in the Italian CIDP database who were treated with other immunosuppressive therapies (28%), excluding rituximab.31 These findings were confirmed when considering the more restrictive MCID threshold for MRC sum score recommended by the 2021 EAN/PNS guidelines.28 The clinical improvement observed in our patients was further supported by improvements in nerve conduction studies, as assessed based on our arbitrary criteria and on the published MCID cut-offs,30 both at 6 months and at 12 months. The persistent reduction of CD19+cells at month 12 could potentially explain the prolonged efficacy of rituximab in the majority of patients in our cohort.
Rituximab was well tolerated, with only one patient discontinuing treatment due to clinical worsening at 6 months, and one patient experiencing minor side effects (cough and dysuria) possibly related to the therapy.
Our results confirm the numerous case reports and two retrospective case series reporting the efficacy of rituximab in idiopathic CIDP.11 15 16 32–34 In most of these cases, patients had no antinodal and paranodal protein antibodies, reported no side effects after rituximab therapy and presented clinical improvement within 6 months of the infusion. In one of these studies, improvement in nerve conduction study parameters after rituximab therapy was reported.16 A similar positive response to rituximab was reported in patients with antibodies targeting nodal and paranodal proteins, primarily anti-CNTN-1 or anti-NF-155.19–21 These findings suggest that B cells may play a crucial role in the pathogenesis not only of nodo-paranodopathies but also in idiopathic CIDP, and targeting them with rituximab could result in significant clinical improvement.
Our study does not permit to clarify whether rituximab might be effective also in patients with CIDP improved after therapy with intravenous immunoglobulin, steroids or plasma exchange. The two ongoing randomised controlled study testing rituximab in CIDP patients responsive to conventional immune therapies will clarify this aspect.
The main limitation of our prospective open-label proof-of-concept study is the absence of an active parallel control group. We partially addressed this limitation by comparing our results with those of a retrospective Italian study on refractory CIDP patients who received immune suppressive or immune modulatory therapies other than steroids, intravenous immunoglobulin or plasma exchange. Nevertheless, we acknowledge the possibility that the assessment of improvement with the Rankin scale used in this retrospective study may have yielded a lower efficacy assessment compared with our prospective study. In addition, the estimated proportion of improvement observed in the historical control group was obtained from a study with a limited sample size and was, therefore, very variable by itself. We calculated the sample size of the present study based on a comparison with this historical control group and this is a further limitation. The estimated sample size was too small to obtain an adequate level of precision for the estimates of improvement. This is, however, an exploratory study, and the high proportion of improvement still gives some suggestions on a possible positive effect of rituximab, independently from the comparison with previously reported data. It is worth noting, that the improvement in electrodiagnostic parameters, which occurred in most patients after therapy with rituximab, is an objective, unbiased element supporting the effectiveness of the drug. It is also possible that the minimal 2 months interval that we used to define unresponsiveness to conventional immune therapies might have included patients who may have had a late response to either intravenous immunoglobulin35 or steroids,36 even if this is probably the mostly used criteria in clinical practice. Furthermore, while the majority of patients had received prior treatment at the participating centres, where the absence of their response to treatment was objectively assessed, information on the lack of response to past therapies relied on reported non-responses from both the treating physician and the patient. Due to these considerations, we preferred to avoid the term ‘refractory’ for our non-responding patients. Another limitation was the open-label design of the study, which may have introduced potential bias. A randomised controlled trial is, therefore, necessary to confirm our findings.
Despite all these limitations, we think that the results of this small open-label study suggest that rituximab seems to be an effective and safe therapy for CIDP patients not improving after conventional immune therapies.
Data availability statement
Data are available on reasonable request. Anonymised data used for this study are available on reasonable request from the corresponding author.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and the study was approved by the Ethical Committee of IRCCS Humanitas Clinical Institute (ID: DM 8/2/13 -307/18) and each participating centre. Participants gave informed consent to participate in the study before taking part.
Acknowledgments
We deeply thank Antonietta Scarale for the enormous support in reviewing and completing the case report forms (CRF) of the study. We also thank Daniela Gussetti and Marta Massi Mauri from Evidence Health srl for reviewing the CRF.
References
Footnotes
X @f.germano
Contributors PED contributed to the conception, organisation and execution of the study and reviewed the results and contributed to the final report. DC, RF and LB contributed to the conception, organisation and execution of the study and reviewed the results and the final report. EP, GL YMF, FGermano, FGallia, CG and CL contributed to the organisation and execution of the study and reviewed the results and the final report of the study. EB performed the statistical analysis of the study and contributed to the final report of the study. EN-O contributed to the conception and organisation of the study, wrote the protocol, reviewed the results of the study and wrote the final report.EN-O accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
Funding The study was supported by Italian Ministry of Health, Ricerca Finalizzata, Grant RF-2016- 02361887.
Disclaimer The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests PED received travel grants to attend scientific meetings from CSL Behring—Italy and Kedrion—Italy. DC received honoraria for lecturing from CSL Behring—Italy, Kedrion—Italy and Shire/Takeda—Italy and received travel grants to attend scientific meetings from CSL Behring—Italy, Kedrion—Italy and Shire/Takeda. RF has served on scientific advisory boards for CSL Behring—Italy and received travel grants to attend scientific meetings from CSL Behring—Italy and Kedrion—Italy. EP has received travel grants to attend scientific meetings from CSL Behring—Italy. GL has received travel grants to attend scientific meetings from CSL Behring—Italy and Kedrion—Italy. EN-O reports personal fees for Advisory or Scientific Board from ArgenX—Belgium, CSL-Behring—USA, Dianthus—USA; Janssen—USA, Kedrion—Italy, LFB—France, Longboard Pharma—USA, Roche—Switzerland, Sanofi—USA and received travel grants to attend scientific meetings from CSL Behring—Italy and Kedrion—Italy. The other authors declare no conflict of interest.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
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