Abstract
Background
The potential benefit of methotrexate (MTX) in combination with biologic (b) and targeted synthetic (ts) disease modifying anti-rheumatic drugs (DMARDs) in psoriatic arthritis (PsA) is still a matter of debate.
Objectives
To compare clinical and patient reported characteristics as well as drug retention rates in PsA patients receiving b/tsDMARD monotherapy or in combination with MTX.
Methods
RABBIT-SpA is a prospective longitudinal cohort study including axSpA and PsA patients. In this analysis, PsA patients were stratified into two groups: starting b/tsDMARD as monotherapy or in combination with MTX. Treatment retention was compared by drug survival analysis.
Results
69% of the patients (n=900) started b/tsDMARD as monotherapy while 31% were treated in combination with MTX (n=405). At baseline, clinical domains like skin, nail and joint affection, dactylitis, enthesitis and axial involvement were similar between the groups. Only the patients’ satisfaction concerning tolerability of the previous treatment was significantly better in the combination group at treatment start. Drug retention rates did not differ between the groups (p=0.4). At 6/12 months, 66%/48% of patients in monotherapy and 67%/48% in the combination group were still on their original treatment.
Conclusions
We did not identify any clinical parameters with notable influence on the choice of b/tsDMARD mono or MTX-combination therapy in PsA. Drug retention rates are similar between mono and combination therapy. It seems that the decision to continue MTX at initiation of b/tsDMARDs is mostly based on the subjective tolerability of MTX treatment.
Keywords: Psoriatic Arthritis, Methotrexate, Biological Therapy, Epidemiology
WHAT IS ALREADY KNOWN ON THIS TOPIC
Many psoriatic arthritis (PsA) patients are being treated with biologic and targeted synthetic disease modifying anti-rheumatic drug (DMARD) either as monotherapy or in combination with conventional synthetic DMARDs. The drivers of the decision to use either mono or combination therapy are not well defined.
WHAT THIS STUDY ADDS
The study results suggest that the decision to use combination therapy or monotherapy in PsA is more influenced by patient preference and drug tolerability than specific clinical manifestations of the PsA.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
This study highlights the significant role of patient satisfaction and drug tolerability in treatment decisions for PsA, even though the additive use of methotrexate appears to have little influence on drug retention rates.
Introduction
Psoriatic arthritis (PsA) is a chronic, inflammatory disease that is common among patients with psoriasis and may result in permanent joint damage and disability.1 PsA has a prevalence of approximately 0.25% in the general population and up to 30% of patients with psoriasis may develop PsA over the course of their lifetime.2,4 It is a multifaceted disease with musculoskeletal manifestations including peripheral arthritis (mono-, oligo- or polyarticular), enthesitis, dactylitis, spondylitis and/or sacroiliitis, as well as psoriatic nail disease.5 Associated skin manifestations of PsA include various phenotypes of psoriasis with psoriasis vulgaris or plaque psoriasis being the most common.2 The main diseases associated with PsA are uveitis and inflammatory bowel disease.2 Additionally, patients with PsA suffer from serious comorbidities such as cardiovascular disease, metabolic syndrome, obesity, diabetes, fatty liver, depression and anxiety.6
All these manifestations and comorbidities have to be taken into account in the management of this heterogeneous condition, thus treating patients with PsA can be challenging.7 As there has been a substantial expansion of treatment options and therapeutic approaches the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) and the European Alliance of Associations for Rheumatology (EULAR) developed treatment recommendations for the management of PsA with pharmacological therapies.8 9 Besides non-steroidal anti-inflammatory drugs (NSAIDs), physiotherapy and intra-articular glucocorticoids, an increasing number of disease-modifying anti-rheumatic drugs (DMARDs) are being used for PsA. Besides conventional synthetic (cs) DMARDs such as methotrexate (MTX), sulfasalazine and leflunomide, biological (b) DMARDs targeting different cytokines such as tumour necrosis factor inhibitors (TNFi), interleukin (IL)-12/23i, IL-23i, IL-17Ai and IL-17A/Fi as well as targeted synthetic (ts) DMARDs that inhibit phosphodiesterase-4 (PDE4) or Janus kinases (JAKs) have proven efficacy in PSA. Both the EULAR and GRAPPA recommendations still place csDMARDs as common first-line DMARD therapy, the recent EULAR recommendations favouring the immediate start with csDMARDs especially in patients with polyarthritis or those with monarthritis/oligoarthritis and poor prognostic factors.9 As bDMARDs and tsDMARDs have shown superiority to csDMARDs, regular assessment of clinical response and early escalation of therapy are advised in both recommendations.
While the combination therapy with MTX and b/tsDMARDs is common standard in rheumatoid arthritis,10 this combination is still a matter of debate in PsA. The EULAR recommendations favour to continue combination therapy with a csDMARD versus monotherapy and to continue MTX with a bDMARD in patients already taking this drug and tolerating it well.9 In contrast, GRAPPA concludes that a combination of csDMARDs with bDMARDs might not be necessary to achieve short-term response.8 However, both recommendations conclude that the potential benefit of concomitant therapy with csDMARDs with all bDMARDs is incompletely defined.8 9 Moreover, it is still unclear, if there is a subset of patients who may benefit from combination therapy and if the combination therapy with MTX may have benefits on drug adherence. Furthermore, for the use of MTX monotherapy clarity is missing in the various domains of PsA due to the absence of placebo-controlled trials. GRAPPA recommends MTX monotherapy for peripheral arthritis and skin involvement but indicates potential superiority of b/tsDMARDs. Based on limited evidence, MTX received only a conditional recommendation for enthesitis and dactylitis. However, GRAPPA does not recommend MTX for axial and nail manifestations.8
Under the principle of shared decision-making, physicians collaborate with patients both engaging in the decision-making process and reaching consensus on treatment choices. However, in PsA, when initiating b/tsDMARDs, it remains uncertain whether specific variables influence the decision-making process regarding continuation or discontinuation of MTX. The aim of this study was to compare clinical and patient reported baseline parameters of PsA patients starting b/tsDMARD monotherapy with those starting such treatment in combination with MTX as well as to assess the drug retention rates in the two groups. Our hypothesis was that the treatment decision relies on clinical parameters, especially the different disease domains, including skin involvement, joint manifestations, dactylitis, enthesitis, nail psoriasis and axial involvement.
Methods
Description of registry and patient population
The German disease register RABBIT-SpA is a prospective longitudinal observational multi-centre cohort study in Germany, which started in 2017. The main aim of this cohort study is to examine long-term safety and effectiveness of b/tsDMARDs in patients with a diagnosis of either axSpA or PsA. Adult patients diagnosed by the treating rheumatologist either with axSpA or PsA initiating a new treatment with a bDMARD, tsDMARD or a conventional treatment (csDMARDs and/or NSAIDs) can be included in the register. After enrolment, data are collected at 3 and 6 months, and then every 6 months covering physician-reported and patient-reported parameters. A more detailed description of the study can be found elsewhere.11 12
For this analysis, PsA patients at the start of observation were stratified into two groups: b/tsDMARD monotherapy (mono group) and b/tsDMARD in combination with MTX (combi group). All patients fulfilling inclusion criteria (start of b/tsDMARD treatment alone or in combination with MTX) were included in this longitudinal analysis and followed for 12 months. In a secondary analysis, patients who received their b/tsDMARD as first-line therapy were selected. In addition, subgroup analyses for TNFi and IL-17i/12/23i were done.
Variables
Disease activity was measured with Disease Activity in PsA score (DAPSA). DAPSA is a sum score of the tender joint count (TJC) (0–68), swollen joint count (SJC) (0–66), C reactive protein (mg/L), patients global disease activity (Numeric Rating Scale (NRS) 0–10) and patient pain (NRS 0–10). Functional impairment was measured by the Health Assessment Questionnaire (HAQ). The score ranges from 0 (no capacity) to 3 (full capacity) and a score <0.5 is considered normal whereas a score above 1.5 indicates severe disability. Body surface area (physician-reported, 0%–100%) was used to measure the extent of skin involvement and the patient reported Dermatology Life Quality Index (0–30) to measure the impact of skin involvement on quality of life. The patient questionnaire contains a question on the satisfaction about the effectiveness and the tolerability of the previous drug using a 4-point Likert scale. The reasons for stopping treatment were categorised into adverse events, ineffectiveness, remission or others.
Statistical analysis
Patient characteristics and clinical parameters at the start of observation were presented using descriptive analysis. Clinical parameters of the two groups (b/tsDMARD monotherapy vs b/tsDMARD in combination with MTX) were compared using Student’s t-test for continuous variables, Mann-Whitney test for categorical variables or χ2 for dichotomous variables. Treatment retention for the two groups was compared by drug survival analysis using a Cox-model approach adjusted by being bionaive or non-bionaive. In a secondary analysis of first-line patients, treatment retention rates were presented without adjustment as Kaplan-Meier curves and compared using log-rank test. Patients who discontinued prior to the end of the 12-month observation period were censored. P values <0.05 are considered statistically significant. Calculations were carried out with SAS V.8.3. Database closure was 1 March 2023.
Results
Description of the cohort
Out of 1642 PsA patients in the register 1305 were included in this analysis, of whom 900 were treated with b/tsDMARD monotherapy (mono group) and 405 with b/tsDMARD in combination with MTX (combination group). The different b/tsDMARDs used as mono or combination treatment are shown in figure 1. 337 patients were excluded from this analysis because they received csDMARD mono treatment (n=296) or b/tsDMARDS in combination with another csDMARD than MTX (n=41).
Figure 1. Treatment used as monotherapy or in combination with MTX. bDMARDs, biologic disease modifying anti-rheumatic drugs; IL, interleukin; MTX, methotrexate; TNFi, tumour necrosis factor inhibitors; tsDMARDs, targeted synthetic disease modifying anti-rheumatic drugs.
Demographic characteristics at baseline are shown in table 1. While age and sex distribution were very similar, the disease duration was slightly shorter in the combination group and a higher percentage of these patients were bionaive (table 1). In both groups, similar percentages of patients were treated in specialised hospital-based outpatient care (combination group 26%, mono group 30%) compared with specialised private practices.
Table 1. Baseline characteristics of patients stratified by treatment group.
| b/tsDMARD mono n=900 | b/tsDMARD+MTX n=405 | |||
| Missing (%) | Value | Missing (%) | Value | |
| Age (years), mean (SD) | 0 | 51.7 (12.6) | 0 | 52.4 (12.0) |
| Female sex, n (%) | 0 | 536 (59) | 0 | 240 (59) |
| BMI, mean (SD) | 2 | 29.2 (6.1) | 2 | 28.8 (6.0) |
| Disease duration (years), mean (SD) | 11 | 7.0 (7.7) | 10 | 6.0 (7.3) |
| Bionaive, n (%) | 0 | 437 (49) | 0 | 255 (63) |
| Hospital-based outpatient care, n (%) | 0 | 272 (30) | 0 | 106 (27) |
| Comorbidities, mean (SD) | 0 | 2.3 (2.4) | 0 | 2.1 (2.2) |
| No comorbidities, n (%) | 0 | 238 (27) | 0 | 114 (28) |
| 1–2 comorbidities, n (%) | 0 | 344 (38) | 0 | 150 (37) |
| ≥3 comorbidities, n (%) | 0 | 318 (35) | 0 | 141 (35) |
bDMARDbiologic disease modifying anti-rheumatic drugBMIbody mass indexMTXmethotrexatetsDMARDtargeted synthetic disease modifying anti-rheumatic drug
With respect to PsA activity at baseline no significant differences were found between the mono and the combination group (table 2). Thus, TJC, SJC, number of involved entheseal sites (SPARCC-Index) and percentage of patients with dactylitis or axial involvement were similar between the two groups. In addition, the extent of skin disease was not significantly different. The mean DAPSA score was also similar with 22.7 and 22.1 in the mono versus the combination group. Also, patient-reported parameters like patient global disease activity, pain and function measured by HAQ were similar.
Table 2. Clinical characteristics at baseline stratified by treatment group.
| b/tsDMARD monon=900 | b/tsDMARD+MTXn=405 | P value | |||
| Missing (%) | Value | Missing (%) | Value | ||
| Tender joint count (0–68), mean (SD) | 1 | 7.1 (8.5) | 0 | 6.7 (7.4) | 0.441 |
| Swollen joint count (0–66), mean (SD) | 1 | 3.5 (5.2) | 0 | 2.7 (3.7) | 0.302 |
| SPARCC Enthesitis (0–16), mean (SD) | 1 | 0.6 (1.6) | 1 | 0.7 (1.8) | 0.762 |
| Dactylitis, n (%) | 1 | 175 (19) | 0 | 65 (16) | 0.128 |
| Axial disease, n (%) | 1 | 201 (22) | 0 | 87 (22) | 0.689 |
| Body surface area (%), mean (SD) | 3 | 8.6 (15.7) | 3 | 7.7 (12.8) | 0.55 |
| CRP mg/L, mean (SD) | 4 | 7 (11.2) | 6 | 7.4 (13.2) | 0.627 |
| CRP (≥5 mg/L), n (%) | 359 (41.7) | 152 (39.9) | 0.976 | ||
| Physician global (NRS 0–10), mean (SD) | 3 | 5.1 (1.9) | 3 | 5.3 (1.8) | 0.087 |
| DAPSA (units), mean (SD) | 15 | 22.8 (14.2) | 14 | 22.1 (12.5) | 0.424 |
| DAPSA >28 (high disease activity), n (%) | 208 (27.1) | 77 (22.1) | 0.859 | ||
| DAS28-CRP (units), mean (SD) | 15 | 3.5 (1.2) | 14 | 3.6 (1.1) | 0.786 |
| DAS28-CRP >5.1, n (%) | 74 (10) | 32 (9) | 0.534 | ||
| Patient global (NRS 0–10), mean (SD) | 10 | 5.7 (2.4) | 8 | 5.8 (2.4) | 0.756 |
| Patient pain (NRS 0–10), mean (SD) | 10 | 5.5 (2.4) | 8 | 5.6 (2.4) | 0.562 |
| HAQ (0–3), mean (SD) | 12 | 1.0 (0.7) | 10 | 0.9 (0.7) | 0.658 |
| Satisfaction with the effectiveness of previous treatment, n (%) | 27 | 288 (44) | 21 | 163 (51) | 0.037 |
| Satisfaction with the tolerability of previous treatment, n (%) | 29 | 380 (59) | 22 | 239 (76) | <0.005 |
bDMARDbiologic disease modifying anti-rheumatic drugCRPC reactive proteinDAPSADisease Activity in PsAHAQHealth Assessment QuestionnaireMTXmethotrexateNRSNumeric Rating ScaletsDMARDtargeted synthetic disease modifying anti-rheumatic drug
There was a significant difference regarding satisfaction with the previous treatment: While in the combination group, 51% of patients were satisfied with the efficacy and 76% with the tolerability of their previous treatment; numbers were significantly lower in the monotherapy group (44% and 59%, respectively).
Drug retention
The mean drug duration was 14.4 and 15.2 months in the mono versus combination group. After 6 months, 66% in the mono group and 67% in the combination group were still on the b/tsDMARD treatment. After 12 months, 48% of patients in each group were still on the b/tsDMARDs treatment. The adjusted treatment retention rates of the two groups were similar with no significant difference (p=0.4, figure 2).
Figure 2. Drug retention, adjusted for the patient being bionaive versus not bionaive. bDMARDs, biologic disease modifying anti-rheumatic drugs; MTX, methotrexate; tsDMARDs, targeted synthetic disease modifying anti-rheumatic drugs.
Of those who discontinued the treatment the reasons for stopping treatment were also similar in the two groups. Due to adverse events treatment was discontinued in 36% in the monotherapy and in 32% in the combination group. Treatment stop due to ineffectiveness was 61% in the monotherapy and 57% in the combination group. A similar percentage of patients experienced at least one adverse event (45% in the combination group and 42% in the monotherapy group). Furthermore, 10% of the patients in the combination group experienced at least one severe adverse event and 14% in the monotherapy group.
Secondary analyses
The secondary analysis included 692 patients who were treated with their first-line b/tsDMARD, of whom 437 were treated with first-line b/tsDMARD monotherapy and 255 patients with first-line b/tsDMARD+MTX combination therapy. The results were similar to the entire cohort with no significant differences in baseline clinical characteristics including TJC, SJC, entheseal sites, dactylitis, axial involvement and skin manifestation or disease activity parameters between the two groups.
When comparing only first-line patients in the mono versus combi group, there were no differences between the treatment groups (first line: mono group vs combination group 14.4 vs 14.9 months, p=0.48). Drug retention is shown in figure 3.
Figure 3. First line treatment only: drug retention of b/tsDMARD mono compared with b/tsDMARD+MTX. bDMARDs, biologic disease modifying anti-rheumatic drugs; MTX, methotrexate; tsDMARDs, targeted synthetic disease modifying anti-rheumatic drugs.
The results were similar when analysing first-line TNFi mono versus first-line TNFi combination therapy and other modes of action (IL-17i, IL-12/23i and IL-23i) as mono versus combination therapy (figure 4).
Figure 4. First-line treatment only: (A) drug retention of TNFi mono compared with TNFi+MTX; (B) drug retention of IL-17/12/23i mono compared with IL-17/12/23i+MTX. IL, interleukin; MTX, methotrexate; TNFi, tumour necrosis factor inhibitors.
Discussion
The aim of our analysis was to compare demographic and disease-specific parameters in PsA patients initiating b/tsDMARD therapy as monotherapy or in combination with MTX using data from the RABBIT-SpA registry. We also examined drug retention rates in both treatment groups. Our results revealed that in a substantial proportion of PsA patients (31%), b/tsDMARD therapy was used in combination with MTX, while the majority (69%) was treated with monotherapy. This reflects the complexity of treatment decisions in everyday clinical practice. There was no difference in the number of patients receiving additional MTX when comparing patients being treated in specialised hospital outpatient clinics or by rheumatologists in ambulatory practice.
Domain-specific treatment is recommended in commonly used treatment recommendations.8 9 For example, in axial disease there is a strong recommendation against the use of csDMARDs. Therefore, our hypothesis was that the treatment decision relies on clinical parameters, especially the different disease domains, including skin involvement, joint manifestations, dactylitis, enthesitis, nail psoriasis and axial involvement. Surprisingly, we found no significant differences in the distribution of these clinical parameters between the two treatment groups. Furthermore, there were no significant differences between the groups in disease activity, physical function or psoriasis severity at baseline. Similar results were seen in our subgroup analysis in patients receiving first-line ts/bDMARDs therapy.
Our results suggest that clinical manifestations may not have a large impact on the decision to continue or discontinue MTX alongside b/tsDMARDs. Instead, the choice seemed to be largely driven by the subjective tolerability of ongoing MTX treatment. Patients starting combination therapy reported greater satisfaction with the tolerability of their previous treatment, emphasising the importance of subjective patient experiences in treatment selection. In the combination therapy group, a higher percentage of patients were satisfied with both the effectiveness and tolerability of their previous treatments, compared with the monotherapy group. Hence, a key finding of our study is that clinical parameters have limited influence on the decision to continue MTX when initiating b/tsDMARD therapy in patients with PsA.
The growing number of approved therapies and the heterogeneity of PsA necessitates personalised treatment decisions. However, real-world data on treatment decisions and the impact of patient and clinician factors remain limited.13 A recent multicentre study identified the physician’s assessment of disease activity as the primary driver of treatment changes, alongside variables such as swollen joint count, previous medications, quality of life and disease duration.13 Differences in physicians and patients perceptions of disease activity and symptom severity may lead to divergent treatment expectations and decisions, potentially resulting in suboptimal treatment outcomes.14,16 Moreover, many patients lack a comprehensive understanding of the systemic nature of their disease and consequently play a limited role in treatment decisions, leading to dissatisfaction with their current treatment regimen and inadequate awareness of long-term disease management strategies.14
In this cohort, almost one-third of the patients received combination therapy. This highlights a notable discrepancy between current treatment recommendations, evidence from clinical trials and real-world clinical practice. The evidence supporting the adjunctive use of MTX in conjunction with b/tsDMARDs is not robust. Studies involving TNFi,17,20 IL-12/23i,21 IL-23i,22 IL-17i23 24 and JAKi25 have failed to demonstrate significant benefit with the addition of MTX. Notably, there is only one controlled, randomised study to date that has investigated the coadministration of MTX (randomised and blinded for MTX) with the IL-12/23 inhibitor ustekinumab.21 This study revealed no additional benefit for patients, neither in terms of therapeutic efficacy nor drug retention.21 26 Furthermore, there was no discernible difference in the formation of antidrug antibodies between the two treatment groups in this study.27
When looking at efficacy data from registries and cohorts, there are inconsistent results. In line with our results, data from the National Register for Biologic Treatment in Finland (ROB-FIN) indicate that co-therapy with csDMARDs did not affect the effectiveness of TNFi therapy.28 29 Similar results were reported from the British Society for Rheumatology Biologics Registry, the Norwegian Disease Modifying Anti-Rheumatic Drug and the Danish registry (DANBIO) with no association of higher effectiveness of TNFi therapy when concomitant MTX was used.30,32 While a large observational study based on prospectively collected data from 13 rheumatology registers in Europe, aggregated through the EuroSpA collaboration showed that combination was associated with better remission rates for adalimumab and infliximab but not for etanercept.33
Our study revealed that treatment retention rates did not significantly differ between the two treatment groups. After 6 months, approximately 67% of patients in the combination therapy group and 65% in the monotherapy group remained on the respective treatment. The results from other registries and previous observational studies regarding the impact of combination therapy on drug survival demonstrates inconsistent results. Some studies, in line with our results, indicate no difference between combination therapy and monotherapy28 34 35; other findings propose that bDMARD persistence is slightly improved in combination with csDMARDs.3236,38 Recently, a cohort study from the Spanish BIOBADASER III registry demonstrated that combination therapy is associated with lower persistence compared with monotherapy PsA.39 Furthermore, a recent investigation of cohorts from five different European countries presented inconsistent results of the potential beneficial use of MTX.40 While a retrospective observational study using data from the US administrative database showed that the therapy with TNFi in combination with MTX was associated with increased persistence of the TNFi.41
While there was no difference in the safety profile between the mono and combination therapy in our study, data from the Spanish registry showed that the addition of a csDMARD to a b/tsDMARD was associated with a significantly worse safety profile than b/tsDMARD monotherapy with infections being the adverse events with the highest increase.39
Our results need to be interpreted within the context of the limitations of our study design. RABBIT-SpA is an observational study, thus confounding by indication cannot be ruled out completely. Furthermore, we do not have any data on antidrug antibodies that have been described in the context of bDMARD treatment, as this is not a common laboratory test used in routine care. The choice of treatment, whether combination therapy or monotherapy, was made by patients and their treating physicians based on clinical considerations and preferences. It has been shown that not all potential treatment outcomes that are important to patients are measured in routine care.42 For example, it is possible that mild adverse events like mild nausea have occurred, which have not been documented. This could lead to potential unknown confounders. Understanding the underlying motivations for choosing combination therapy or monotherapy could provide deeper insights.
In conclusion, our study contributes to the understanding of treatment decision-making in PsA. The choice between b/tsDMARD monotherapy and combination with MTX is mainly based on patient preference and drug tolerability. This highlights the role of patient satisfaction in determining treatment choices.
supplementary material
Acknowledgements
The authors acknowledge the invaluable contributions of all participating consultant rheumatologists and their patients. In particular, we would like to thank those rheumatologists who enrolled the highest numbers of patients: Kaufmann J, Schwarze I, Bohl-Bühler M, Feuchtenberger M, Eisterhus C, Kellner H, Klopsch T, Zinke S, Spengler L, Karberg K, Krüger K, Wernitzsch H, Marycz T, Liebhaber A, Stille C, Krause A, Müller B, Fricke-Wagner H, Kühne C, Dahmen G, Tony H-P, Burmester G, Baumann C, and Häckel B. We also acknowledge the significant contributions of Xenofon Baraliakos, Herne, Frank Behrens, Frankfurt and Denis Poddubnyy, Berlin, as members of the advisory board. Parts of this analysis have been presented at the EULAR congress 2023 as an oral abstract presentation.43
Footnotes
Funding: RABBIT-SpA is supported by a joint, unconditional grant from AbbVie, Amgen, Biogen, Celltrion, Hexal, Janssen-Cilag, Lilly, MSD, Novartis, Pfizer, UCB and Viatris.
Patient consent for publication: Consent obtained directly from patient(s)
Ethics approval: This study involves human participants and was approved by Charité-Universitätsmedizin Berlin, #EA1/246/16. Prior to enrolment into RABBIT-SpA, all patients gave their informed consent.
Provenance and peer review: Not commissioned; externally peer reviewed.
Correction notice: This article has been corrected since it was first published online. The authors ACR and DK contributed equally to this paper. This has now been stated.
Contributor Information
Anne Constanze Regierer, Email: Anne.Regierer@drfz.de.
David Kiefer, Email: David.Kiefer@elisabethgruppe.de.
Georg Schett, Email: georg.schett@uk-erlangen.de.
Andreas Krause, Email: andreas.krause@immanuelalbertinen.de.
Anja Weiß, Email: weiss@drfz.de.
Philipp Sewerin, Email: philipp.sewerin@elisabethgruppe.de.
Anja Strangfeld, Email: strangfeld@drfz.de.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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Data Availability Statement
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