Key PointsQuestion
What is the association of secukinumab with active tuberculosis (TB) development, TB reactivation, and latent tuberculosis infection (LTBI) activation?
Findings
In this pooled cohort study of 12 319 patients with psoriasis, psoriatic arthritis, or ankylosing spondylitis, spontaneous reporting of new LTBI while undergoing secukinumab treatment was rare. No active cases of TB or LTBI reactivation were reported.
Meaning
The findings of this study provide a broader understanding of the safety of secukinumab and appear to support its long-term use in chronic systemic inflammatory conditions.
Importance
Approximately one-quarter of the global population have latent tuberculosis infection (LTBI), and tuberculosis (TB) is accountable for more than 1.5 million deaths annually. Methotrexate, cyclosporine, and tumor necrosis factor inhibitors may be associated with increased risk of TB and LTBI reactivation, although data are limited on the risks of TB with use of newer biologics.
Objective
To assess the association of secukinumab with reporting of active TB development, TB reactivation, and LTBI activation as an adverse event (AE) in patients with psoriasis, psoriatic arthritis, or ankylosing spondylitis.
Design, Setting, and Participants
This pooled cohort study pooled data from 28 clinical trials of secukinumab used in psoriasis (17 phase 3 or 3b and 2 phase 4 trials), psoriatic arthritis (5 phase 3 trials), and ankylosing spondylitis (4 phase 3 trials). A search of the Novartis Secukinumab Compound Pool Database was conducted for the 28 trials. All trial participants who had received at least 1 approved subcutaneous dose of secukinumab (150 mg or 300 mg) were included. Before randomization in these trials, patients underwent screening for TB. Patients with active TB were excluded, and patients with LTBI were treated according to local guidelines. Data were analyzed from the start of treatment in the individual studies through December 25, 2018.
Main Outcomes and Measures
Reporting of active TB or LTBI as an AE over a 5-year period using exposure-adjusted incidence rates (EAIR; incidence rates per 100 patient-years).
Results
A total of 12 319 patients were included, of whom 8819 patients had psoriasis (71.6%; 5930 men [67.2%]; mean [SD] age, of 44.9 [13.5] years), 2523 had psoriatic arthritis (20.5%; 1323 women [52.4%]; mean [SD] age, 48.8 [12.1] years), and 977 had ankylosing spondylitis (7.3%; 658 men [67.3%]; mean [SD] age, 42.3 [11.9] years). In the total population, 684 patients (5.6%) had tested positive for LTBI at screening. Over 5 years, LTBI as an AE during secukinumab treatment was reported in 13 patients (0.1% of 12 319). Of these 13 patients, 6 had a prior positive LTBI test result, and 7 were newly diagnosed as having LTBI. Four of the 7 patients had psoriasis (EAIR, 0.03; 95% CI, 0.01-0.07), 1 had psoriatic arthritis (EAIR, 0.02; 95% CI, 0.00-0.11), and 2 had ankylosing spondylitis (EAIR, 0.08; 95% CI, 0.01-0.28). No cases of active TB were reported.
Conclusions and Relevance
This study found that LTBI reported as an AE after secukinumab treatment was uncommon and appeared to support the use of secukinumab in chronic systemic inflammatory conditions.
Tuberculosis (TB) caused by Mycobacterium tuberculosis is the leading cause of death from an infectious agent.1 In 2017, there were an estimated 10 million new cases of TB infection worldwide, and more than 1.5 million deaths annually were attributed to this infection.1 Only a small proportion of those with M tuberculosis will develop active TB and show signs and symptoms of infection. Most people with M tuberculosis will have latent TB infection (LTBI) and show no clinical signs or symptoms of disease. Most cases of active TB are associated with the development of LTBI.2 The global burden of LTBI is estimated to be 23%, amounting to approximately 1.7 billion people.3 Therefore, a window of opportunity to detect and treat LTBI in at-risk populations is needed to reduce the global burden of active TB.
Psoriasis, psoriatic arthritis, and ankylosing spondylitis are chronic immunological conditions that require long-term immunomodulatory therapies, which are associated with increased risk of infection. Methotrexate sodium, cyclosporine, and tumor necrosis factor (TNF) inhibitors have been associated with increased risk of TB and LTBI activation.4,5 Because of this increased risk, guidelines have been developed for the management of TB infection in patients who are starting anti-TNF therapy.6-10 Clinical treatment with biologics targeting other pathways, such as interleukin (IL)-12/23 or IL-17, appears to have a lower risk of active TB and/or LTBI activation11-13; however, data on their long-term use are limited.
This pooled cohort study assesses the association of secukinumab, a monoclonal antibody that directly inhibits IL-17A, with reporting of active TB development, TB reactivation, and LTBI activation as an adverse event (AE) in patients with psoriasis, psoriatic arthritis, or ankylosing spondylitis. This ad hoc analysis includes 5-year data from 28 phase 3 and 4 clinical trials of secukinumab across the 3 indications.
Each clinical trial sought and received institutional review board approval. Additional institutional review board approval was not necessary for the present study because it analyzed already acquired data.
The data set was pooled from 28 clinical trials of secukinumab in psoriasis (5 phase 3, 12 phase 3b, and 2 phase 4 trials), psoriatic arthritis (5 phase 3 trials), and ankylosing spondylitis (4 phase 3 trials) with up to 5-year follow-up data. A search of the Novartis Secukinumab Compound Pool Database was conducted for the 28 trials. The following preferred terms were used to retrieve cases: tuberculosis, latent tuberculosis, tuberculin test positive, pulmonary tuberculosis, mycobacterium test positive, joint tuberculosis, and mycobacterium tuberculosis complex test positive.
All trial participants who had received at least 1 approved subcutaneous dose of secukinumab, 150 mg or 300 mg, were included. This study population included patients who did not respond to placebo and were randomized again to secukinumab at the end of the placebo-controlled blinded period (12-24 weeks).
Table 1 lists details of the clinical trials selected for this analysis.14-39 Eligible patients 18 years or older with moderate-to-severe plaque psoriasis or active psoriatic arthritis or ankylosing spondylitis were enrolled in the trials according to prespecified inclusion criteria. A history of TB or LTBI was not an exclusion criterion for enrollment in the trials. Prior to enrollment, all patients underwent screening for TB according to local guidelines. As per the study protocols, repeated screening for TB or LTBI was not required after randomization. Patients were tested for TB using 1 of 3 methods outlined in the individual clinical study protocol: QuantiFERON-TB Gold In-Tube test (Qiagen), T-SPOT TB test (Oxford Immunotec International), both of which are interferon (IFN)-γ release assays, or purified protein derivative (PPD) test and tuberculin skin test (TST). For all psoriatic arthritis and ankylosing spondylitis clinical trials, either a QuantiFERON or a PPD test could be used at screening. For 17 of the 19 psoriasis clinical trials, the QuantiFERON was used for TB testing at screening. The 2 exceptions were the CARIMA trial (Evaluation of Cardiovascular Risk Markers in Psoriasis Patients Treated with Secukinumab),27 which used a combination of both the QuantiFERON and PPD tests, and the AJP01 trial (Open-Label Study of Subcutaneous Secukinumab to Evaluate Efficacy and Safety in Patients With Plaque Psoriasis Who Had Inadequate Response to Cyclosporine A),26 which used the T-SPOT TB test (Table 1).
In addition to laboratory analysis, all patients underwent chest imaging at screening (or ≤12 weeks prior to screening) in all trials, with the exception of the PRIME study (Study of Secukinumab Compared to Fumaderm in Adults With Moderate to Severe Psoriasis),30 which did not require chest imaging before study initiation. Repeat chest imaging was not mandated by the clinical study protocol after screening.
If a patient had a positive screening test result for TB, an evaluation for active TB was completed according to local guidelines. Any patient with a diagnosis of active TB at screening was excluded from study enrollment. Patients with LTBI at screening (defined as a positive QuantiFERON, PPD, or T-SPOT test result with no clinical signs or symptoms of active infection) were eligible for study enrollment once treatment was initiated and maintained according to local country guidelines (≥4 weeks prior to randomization).
Frequency and demographic data of patients with a positive LTBI test result at screening (as evaluated by QuantiFERON, T-SPOT, or PPD test) were reported. The Medical Dictionary for Regulatory Activities, or MedDRA, volume 20.0 (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use), was used to analyze the frequency of AEs.
The rate of an AE of LTBI was calculated using the exposure-adjusted incidence rate (EAIR; patient incidence rates per 100 patient-years). For patients reporting an AE of LTBI, individual patient-level data were assessed to ascertain the duration and severity of the AE, concomitant medication type and duration, and action taken (eg, study drug interrupted or discontinued).
Data were analyzed from the start of treatment in the individual studies through December 25, 2018. For all analyses, SAS, version 9.4 (SAS Institute, Inc) was used. All clinical trial data are stored and pooled in the Global Programming System.
In total, 12 319 patients treated with secukinumab who were pooled from 28 clinical trials were included in this study. This sample comprised 8819 patients with psoriasis (71.6%) and a cumulative secukinumab exposure of 15062.7 patient-years, 2523 patients with psoriatic arthritis (20.5%) and a cumulative secukinumab exposure of 4943.5 patient-years, and 977 patients with ankylosing spondylitis (7.3%) and a cumulative secukinumab exposure of 2542.1 patient-years. The mean (SD) follow-up period was 1.7 (1.6) years for patients with psoriasis, 2.0 (1.4) years for patients with psoriatic arthritis, and 2.6 (1.4) years for patients with ankylosing spondylitis.
The psoriasis cohort was composed of 5930 men (67.2%) and 2889 women (32.8%) with a mean (SD) age of 44.9 (13.5) years. The psoriatic arthritis cohort was composed of 1200 men (47.6%) and 1323 women (52.4%) with a mean (SD) age of 48.8 (12.1) years. The ankylosing spondylitis cohort was composed of 658 men (67.3%) and 319 women (32.7%) with a mean (SD) age of 42.3 (11.9) years. These frequencies are consistent with those in epidemiological studies that have reported a male preponderance in both psoriasis and ankylosing spondylitis cohorts.40,41 For all indications, 85% or more of patients were White (Table 2). Geographically, approximately 70% of the total population across indications were from the World Health Organization (WHO) region of Europe and 20% were from the WHO region of the Americas. According to the WHO Global Tuberculosis Report 2019, the TB incidence rates were 28 cases per 100 000 people in Europe and 29 cases per 100 000 people in the Americas.1 Approximately 7% of the total population across indications were from the WHO Western Pacific region (with TB incidence rates of 96 cases per 100 000 people1), and approximately 2% were from the WHO region of Southeast Asia (with TB incidence rates of 220 cases per 100 000 people1).
Within the total population, 684 patients (5.6%) had a positive LTBI test result at screening. Patients with ankylosing spondylitis had a higher percentage of positive LTBI test results (15.3% [n = 149]) compared with those with either psoriasis (4.3% [n = 383]) or psoriatic arthritis (6.0% [n = 152]) at screening. Baseline characteristics of the total population and patients with a positive LTBI result at screening were generally comparable (Table 2). For example, Table 2 shows the mean (SD) weight of patients across the 3 indications in the total population vs the subpopulation with positive LTBI test result (psoriasis: 86.6 [21.3] kg vs 85.2 [18.9] kg; psoriatic arthritis: 84.3 [19.6] kg vs 81.5 [17.1] kg; and ankylosing spondylitis: 79.9 [17.7] kg vs 80.6 [15.3] kg).
In the total population, 70 patients with psoriasis (0.8%) and 15 patients with psoriatic arthritis (0.6%), or less than 1%, reported a medical history of active TB before study inclusion compared with 100 patients with ankylosing spondylitis (10.2%). More than two-thirds of patients with ankylosing spondylitis and a positive LTBI test result at screening (n = 100 [67.1%]) had a medical history of active TB disease.
A greater percentage of Asian patients with psoriasis and psoriatic arthritis were observed in the subpopulation of patients with positive LTBI result at screening than in the total population (psoriasis: 14.6% [n = 56] vs 8.3% [n = 735]; psoriatic arthritis: 17.1% [n = 26] vs 9.1% [n = 229]) (Table 2).
No cases of active TB were reported as an AE for any indication throughout the observation period. In total, LTBI was identified as an AE in 13 (0.1%) of 12 319 patients (8 with psoriasis, 3 with psoriatic arthritis, and 2 with ankylosing spondylitis), 7 of which were considered new LTBI. Among the remaining 6 patients in which LTBI was not considered new, 5 had a positive LTBI test result at screening (4 with psoriasis, and 1 with psoriatic arthritis). The sixth patient (with psoriatic arthritis) reported a history of LTBI, which was diagnosed 2 months before study inclusion. Although this patient did not have a positive LTBI test result at screening, the person was receiving isoniazid (INH) treatment at the time of study drug initiation. The patient was tested later during the trial because of a potential TB exposure. The LTBI test result was positive, and INH was reinitiated. Therefore, these 6 cases were not considered new LTBI. The reason for LTBI retesting in these patients was not specified in their respective case report forms; however, it was reported that patients did not have any sign of active TB disease.
Each of the 7 patients with an AE of LTBI that was considered new did not have a positive LTBI test result at the time of screening visits. Four of these patients had psoriasis (EAIR, 0.03; 95% CI, 0.01-0.07), 1 patient had psoriatic arthritis (EAIR, 0.02; 95% CI, 0.00-0.11), and 2 patients had ankylosing spondylitis (EAIR, 0.08; 95% CI, 0.01-0.28). Details of these cases are described in Table 3.
All 7 patients with new LTBI AEs were men with a mean age of 51 years, and 6 were White participants. The method of diagnosing LTBI included both the QuantiFERON test (used in 1 patient with psoriasis, and 1 patient with psoriatic arthritis) and TST (used in 3 patients with psoriasis, and 2 patients with ankylosing spondylitis). In addition, INH therapy was reported for 4 of 7 cases, and the information on LTBI therapy was missing in 2 cases. One patient reported no treatment for LTBI.
Trial participation of 2 patients with psoriasis was permanently discontinued. In 1 case, the investigator made the decision to withdraw the patient because of lack of patient compliance. In the other case, INH was initiated while secukinumab was temporarily discontinued. After beginning INH, the patient reported abnormal results on the liver function tests (recorded as an AE) and was subsequently treated with L-ornithine L-aspartate (HepaMerz). Shortly after, participation by the patient was permanently discontinued, but the definitive reason for discontinuation was not recorded.
This pooled cohort study examined the reported active TB and LTBI in 12 319 patients with psoriasis, psoriatic arthritis, or ankylosing spondylitis who were treated with secukinumab for up to 5 years. No active cases of TB were reported as an AE for any indication, which is consistent with findings in previous pooled analyses of patients with psoriasis who were treated with secukinumab.12,42
It is well established that TNF-α plays a vital role in clearing TB infection through recruiting immune cells to the site of the infection, stimulating the production of cytokines and inducing macrophage phagocytosis to kill mycobacteria.43 For this reason, blocking TNF-α with TNF inhibitors has been associated with active TB and activation of LTBI.44,45 The role of IL-17 in the pathogenesis of TB, however, has been somewhat controversial, leading to safety concerns and uncertainty regarding opportunistic infections such as TB or LTBI. Although some studies have suggested that IL-17 has a protective role in M. tuberculosis infection, IL-17 seems to act as a regulator of inflammation.46 In a murine model of IL-123 p19-deficient mice, the number of IFN-γ–producing antigen-specific CD 4 T cells was not decreased, even in the presence of an almost-total loss of IL-17-producing antigen-specific CD4 T cells.47 These data support the theory that depletion of IL-17–producing T cells has no association with the progression of M. tuberculosis. Supporting these mechanistic data, clinical studies that used biologics to target the IL-12/23 and IL-17 pathways have reported few cases of active TB and/or LTBI reactivation,11-13 and expert opinions have deemed anti-IL-17 therapy safe to use in patients with psoriasis and LTBI.48
Among 3177 patients treated with ustekinumab, 1 patient had active TB and experienced reactivation of LTBI.11 No active cases were found in patients with baseline LTBI who were receiving concomitant INH.11 Similarly, data from 10 phase 2 to 3 clinical trials of secukinumab in psoriasis (n = 3993) indicated no active cases of TB or LTBI reactivation.12,42 A recent systematic review of IL-17 inhibitors (including secukinumab, ixekizumab, and brodalimumab) in psoriasis concluded that no active cases of TB were reported in patients with psoriasis who were being treated with anti-IL-17 therapy and suggested that IL-17 inhibitors were safe to use in patients with psoriasis and LTBI who were receiving appropriate LTBI treatment.49
In this study, we found that 10.2% of patients with ankylosing spondylitis had a medical history of active TB vs less than 1% of patients with either psoriasis or psoriatic arthritis. A previous study demonstrated that a low body mass index was an independent risk factor for TB in patients with ankylosing spondylitis.50 Consistent with this finding, baseline demographic data in the present study showed that the mean weight of patients with ankylosing spondylitis (79.9 kg) was lower by approximately 5 kg than that of patients with either psoriasis (86.6 kg) or psoriatic arthritis (84.3 kg). Furthermore, ankylosing spondylitis complications (such as Andersson lesions) can be misdiagnosed in clinical practice as TB of the spine,51 and non-TB pulmonary fibrosis in ankylosing spondylitis is often confused with pulmonary TB.52,53 Low body weight or TB misdiagnosis may account for the higher TB rates in the ankylosing spondylitis population in the present study, but this is speculative and further studies are warranted.
In this analysis, 5.6% (n = 684) of patients had LTBI at screening and received prophylactic treatment according to local guidelines. In a recent case series of patients with psoriasis and LTBI who were receiving secukinumab without previous prophylaxis, no signs of TB reactivation up to 52 weeks were observed.54 The authors of that study concluded that secukinumab could be used in patients with psoriasis who cannot receive TB prophylaxis.54
Only 7 patients (<1%) of the total 12 319 developed LTBI while receiving secukinumab treatment, demonstrating that the occurrence of LTBI as an AE was uncommon in the studied indications. The predominant method for LTBI identification in clinical trials included in this analysis was the QuantiFERON test. Although the TST and QuantiFERON test are the current criterion standard methods used to detect LTBI, both have technical limitations.55 Both tests do not have the ability to distinguish between recent and remote infection; thus, LTBI cases may likely be reported as an AE because of the failure rate of the tests to detect the disease at baseline.
Discontinuation of secukinumab because of an identified AE of LTBI was uncommon. Only 2 patients diagnosed with LTBI throughout the treatment period were permanently removed from their respective clinical trials, and the reason for 1 of these discontinuations was patient noncompliance.
This study has some limitations. First, the retesting for LTBI in asymptomatic patients who were using biologics was not standardized in these trials, and the identification of LTBI relied on AE reporting. In addition, dropout rates for each individual trial were not considered. Therefore, we may have underestimated the rate of incident LTBI and cannot report LTBI seroconversion rates. Second, we acknowledge the presence of reporting bias given the post hoc nature of this study and the differences in methodologies used in the clinical trials and across their multiple sites. However, in the absence of guidelines recommending serial retesting in patients who were treated with biologics, we believe that this study reflects what is occurring in real-world clinical practice. For example, several previous studies have addressed the seroconversion rates of patients with psoriasis in a high-burden area after serial QuantiFERON tests identified the differences between biologics.56-58 Of those patients with psoriasis who originally had negative QuantiFERON test results at baseline, 14.3% who received anti-TNF therapy,56 7.3% who were treated with ustekinumab,57 and 1.3% who had anti–IL-17A therapy (either secukinumab or ixekizumab)58 seroconverted after a period of 11 months or more. Furthermore, the conduct of clinical trials is protocol-specified, which may not fully reflect real-world clinical experience. Some trials included in the analysis differed in terms of baseline selection criteria, patient characteristics, and treatment regimens. Third, we did not perform a long-term placebo comparison because of ethical considerations.
In this large, pooled cohort study involving 12 319 patients with psoriasis, psoriatic arthritis, or ankylosing spondylitis, spontaneously reported new LTBI during secukinumab treatment was rare. No cases of active TB or LTBI activation were reported. Findings of this analysis are consistent with those of other studies, demonstrating that secukinumab is not associated with an increased risk of active TB or TB reactivation in patients with a history of LTBI. We believe this study provides a broader understanding of the safety of secukinumab and supports its long-term use in chronic systemic inflammatory conditions.
Accepted for Publication: July 2, 2020.
Published Online: September 30, 2020. doi:10.1001/jamadermatol.2020.3257
Correction: This article was corrected on December 23, 2020, to change the study type from qualitative study to pooled cohort study, to eliminate the statement about the SRQR reporting guideline, and to list SAS (SAS Institute, Inc) as the statistical software used for all analyses.
Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2020 Elewski BE et al. JAMA Dermatology.
Corresponding Author: Boni E. Elewski, MD, University of Alabama at Birmingham, Department of Dermatology, Eye Foundation Hospital, 1720 University Blvd, Room 414, Birmingham, AL 35294 (beelewski@gmail.com).
Author Contributions: Dr Elewski had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Elewski, Magrey, Soriano, Soung, Marfo, Patekar, Sharma, Lebwohl.
Acquisition, analysis, or interpretation of data: Elewski, Baddley, Deodhar, Magrey, Rich, Soriano, Soung, Bao, Keininger, Patekar, Sharma, Shete.
Drafting of the manuscript: Baddley, Soung, Bao, Marfo, Patekar, Shete.
Critical revision of the manuscript for important intellectual content: Elewski, Baddley, Deodhar, Magrey, Rich, Soriano, Soung, Keininger, Patekar, Sharma, Lebwohl.
Statistical analysis: Bao, Shete.
Administrative, technical, or material support: Baddley, Marfo, Patekar, Sharma, Shete.
Supervision: Soung, Keininger, Patekar, Sharma.
Conflict of Interest Disclosures: Dr Elewski reported receiving grants and personal fees from Novartis Pharma during the conduct of the study; grants from Pfizer, Eli Lilly, Merck, AbbVie, and Sun; and grants and personal fees from Amgen, Janssen, and Ortho Dermatologics outside the submitted work, and serving as a consultant to Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Leo, Eli Lilly, Menlo, Novartis Pharma, Pfizer, Sun, Valeant, Verrica, Ortho Dermatologics, and Arcutis. Dr. Baddley reported serving as a consultant (DSMB adjudication committee) for Pfizer, Eli Lilly, R-Pharm, and Viela Bio. Dr Deodhar reported receiving grants, personal fees, and nonfinancial support from Novartis Pharma during the conduct of the study, Amgen, Eli Lilly, GSK, Pfizer, and UCB outside the submitted work; personal fees from Celgene; and personal fees and nonfinancial support from Boeheringer Ingelheim, Gilead, and Janssen. Dr Magrey reported receiving personal fees from Novartis Pharma, Eli Lilly, Janssen, Pfizer, and UCB outside the submitted work, and involvement in clinical trials with AbbVie and Amgen. Dr Rich reported receiving grants from Novartis Pharma, Boehringer Ingelheim, Eli Lilly, Janssen-Ortho, Sun Pharma, UCB, Bristol Myers Squibb, and Pfizer during the conduct of the study and grants from Galderma, Moberg, and Kadmon outside the submitted work. Dr Soriano reported receiving grants and personal fees from AbbVie, Janssen, Novartis Pharma, Pfizer, Roche, and UCB outside the submitted work, and personal fees from Eli Lilly, Amgen, Bristol Myers Squibb, and Sanofi. Dr Soung reported receiving nonfinancial support from Novartis Pharma during the conduct of the study; personal fees from Celgene, Amgen, National Psoriasis Foundation, and Regeneron; grants and personal fees from Eli Lilly, AbbVie, Actelion, Leo Pharma, Dermira, UCB, Janssen, and Novartis Pharma outside the submitted work; grants from Pfizer, Galderma, and Cassiopeia; grants, personal fees, and nonfinancial support from Ortho Dermatologics and Dermavant; and grants and nonfinancial support from Boeringher Ingelheim. Mr Bao reported that his wife is an employee of and has stock in Novartis Pharma outside the submitted work. Ms Keininger reported being an employee and holding stock in Novartis Pharma. Drs Marfo, Patekar, and Sharma reported being employees of Novartis Pharma. Dr Shete reported being an employee and holding stock in Novartis Pharma.
Funding/Support: This study was funded by Novartis Pharma AG.
Role of the Funder/Sponsor: The funder had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: Trudy McGarry, PhD, Novartis Ireland Ltd, provided medical writing and editorial support, which was funded by Novartis Pharma AG, in accordance with Good Publication Practice guidelines.
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