Correspondence to Dr Frank Behrens; [email protected]
What is already known about this subject?
Several studies have reported sex-based differences in disease characteristics and treatment response in patients with psoriatic arthritis (PsA) and other rheumatologic conditions.
What does this study add?
This study provides the first analysis of differences in outcomes between females and males with PsA during treatment with an interleukin 12/23 inhibitor, both as monotherapy and in combination with methotrexate (MTX).
Although ustekinumab was effective in both females and males, females had numerically lower treatment responses and more adverse events associated with MTX compared with males.
How might this impact on clinical practice or future developments?
Our data provide further insights into the influence of sex on PsA disease presentation and treatment response, and may be valuable in developing individualized treatment strategies for patients with PsA.
Introduction
Biological sex could influence disease manifestations, disease course, treatment response and adverse effect profiles through multiple mechanisms encompassing both biological and social factors.1 2 In patients with rheumatoid arthritis (RA)3 4 or axial spondyloarthritis,5 female sex has been associated with lower rates of response to biological therapies. Less is known about psoriatic arthritis (PsA).6 Available evidence suggests that females often have greater disease activity than males at treatment initiation and show a reduced response to biological therapies.7–16 Furthermore, the response of females and males to biological therapy in combination with methotrexate (MTX) may also vary.10 11 These data suggest that sex may be associated with important differences in disease presentation and treatment response in PsA.
To date, there have been no studies to specifically evaluate the effect of sex on response to interleukin (IL)-12/23 inhibition, with or without MTX, in patients with PsA. In a randomised, placebo-controlled study in patients with active PsA (the Impact of Concomitant Methotrexate on Efficacy, Safety, and Adherence of Ustekinumab Treatment in Patients with Active Psoriatic Arthritis [MUST] trial), we found that ustekinumab plus placebo was non-inferior to ustekinumab plus MTX. This observation was true in both females and males in post hoc analyses, but mean values for Disease Activity Score-28 joints based on erythrocyte sedimentation rate (DAS28-ESR) at week 24, the primary study outcome, were higher in females than in males.17 Because elevated ESR in females18 may have contributed to this finding, we conducted exploratory post hoc analyses to further evaluate data from the MUST trial. The objective of this post hoc study was to gain insights into sex-associated differences in baseline characteristics and treatment and safety outcomes in the MUST trial.
Methods
Patients and study design
The design of the prospective, investigator-initiated, randomised, placebo-controlled, phase IIIb MUST trial (EudraCT number 2015-005777-20; ClinicalTrials.gov NCT03148860) has been previously reported.17 Briefly, ustekinumab-naïve adults with active PsA were enrolled at 22 centres in Germany between 24 January 2017 and 12 April 2021. Patients with prior anti-IL-23 or IL-12/23 treatment were excluded. Enrolled patients were stratified by prior MTX use and randomised 1:1 to blinded MTX (15 mg weekly) or placebo. All patients received open-label subcutaneous ustekinumab at weeks 0, 4 and every 12 weeks up to 52 weeks. The study randomised patients across treatment groups, but not between sexes.
Outcomes
Analyses were based on sex of the patient as reported by the clinician. Efficacy outcomes included minimal disease activity (MDA) criteria,19 Disease Activity in PSoriatic Arthritis (DAPSA) scores, and assessments of joints, psoriasis, enthesitis, dactylitis, health-related quality of life and patient-reported outcomes (PROs)20 (see online supplemental section S1 for details). Safety data were reported as adverse events (AEs) and serious AEs (SAEs) by system organ class (SOC) and preferred term.
Statistical methods
Sample size calculations for the overall study have been described previously.17 Sample size calculations for sex-disaggregated analyses were not conducted.
Descriptive statistics were calculated for all outcomes. Comparisons between male and female subgroups were made using two-sided van Elteren tests (stratified Mann-Whitney test) for interval-scaled endpoints and Cochran-Mantel-Haenszel tests (with Breslow-Day tests) to assess qualitative endpoints by sex stratified by treatment groups (see online supplemental section S2 for additional information). Within group comparisons were performed by two-sided Wilcoxon rank tests. Due to small numbers, statistical evaluations were performed on SOC AEs only. All tests were exploratory and were performed using SAS V.9.4 and a significance level of 5%.
Results
Of 166 patients enrolled in the MUST trial, 69 (41.6%) were female and 97 (58.4%) male.17 The proportions of female patients were comparable in the ustekinumab+MTX and ustekinumab+placebo groups (42.5% vs 40.5%) (table 1).
Table 1Baseline characteristics by sex*
| Characteristic | UST+MTX (n=87) | UST+PBO (n=79) | All patients (n=166) | |||
| Female (n=37) | Male (n=50) | Female (n=32) | Male (n=47) | Female (n=69) | Male (n=97) | |
| Age, years (SD) | 47.6 (15.2) | 45.7 (13.9) | 52.7 (11.7) | 48.0 (13.5) | 50.5 (13.4) | 46.6 (13.7) |
| Time since PsA diagnosis, median years (IQR) | 1.1 (0.1–4.5) | 0.3 (0.1–1.8) | 3.1 (1.3–6.6) | 1.9 (0.8–5.6) | 2.8 (0.7–6.2) | 0.8 (0.2–4.9) |
| Baseline MTX therapy, n (%) | 23 (62.2) | 20 (40.0) | 17 (53.1) | 20 (42.6) | 40 (58.0) | 40 (41.2) |
| BMI, kg/m2 (SD) | 28.1 (4.8) | 29.6 (5.0) | 30.3 (6.9) | 28.1 (4.0) | 29.4 (6.2) | 29.0 (4.6) |
| CRP, median (IQR) | 5.5 (2.7–14.0) | 6.5 (1.9–14.5) | 3.7 (2.3–7.8) | 4.8 (0.8–12.8) | 4.7 (2.3–11.7) | 5.5 (1.6–13.4) |
| ESR, median (IQR) | 20.0 (10.0–38.0) | 12.0 (8.0–26.0) | 17.5 (11.5–26.5) | 12.0 (4.0–22.0) | 19.0 (11.0–30.0) | 12.0 (6.0–25.0) |
| HAQ-DI, median (IQR) | 1.0 (0.5–1.4) | 0.6 (0.3–1.5) | 1.3 (0.3–1.6) | 0.8 (0.4–1.3) | 1.0 (0.6–1.5) | 0.6 (0.3–1.3) |
| DAS28-ESR, mean (SD) | 5.1 (1.0) | 4.7 (1.2) | 5.0 (0.9) | 4.3 (1.0) | 5.1 (0.9) | 4.5 (1.1) |
| Presence of dactylitis, n patients with dactylitis count>0 (%) | 4 (10.8) | 17 (34.0) | 4 (12.5) | 11 (23.4) | 8 (11.6) | 28 (28.9) |
| Nail involvement, n patients with mtNAPSI>0 (%) | 18 (48.6) | 33 (66.0) | 12 (37.5) | 32 (68.1) | 30 (43.5) | 65 (67.0) |
| PASI, median (SD) | 3.2 (0.6–6.4) | 2.2 (0.9–7.1) | 1.2 (0.2–3.5) | 3.2 (0.6–7.7) | 2.4 (0.3–5.3) | 2.9 (0.8–7.6) |
| DAPSA, mean (SD) | 37.1 (15.4) | 36.6 (16.6) | 37.0 (11.7) | 33.5 (13.9) | 37.1 (13.7) | 35.1 (15.3) |
| Presence of enthesitis (LEI>0), n (%) | 20 (54.1) | 24 (48.0) | 20 (62.5) | 20 (42.6) | 40 (58.0) | 44 (45.4) |
| PhGA, mean (SD) | 56.1 (20.2) | 62.3 (15.8) | 58.7 (19.3) | 58.4 (19.2) | 57.3 (19.7) | 60.4 (17.5) |
| PtGA, mean (SD) | 53.5 (22.1) | 58.5 (21.6) | 64.9 (16.8) | 56.7 (21.6) | 58.8 (20.5) | 57.6 (21.5) |
| Pain, mean (SD) | 53.9 (23.5) | 56.0 (20.9) | 62.9 (17.4) | 55.5 (20.1) | 58.2 (21.2) | 55.8 (20.4) |
| TJC68, median (IQR) | 14.0 (8.0–22.0) | 11.0 (7.0–16.0) | 13.0 (9.5–17.0) | 11.0 (8.0–17.0) | 13.0 (9.0–19.0) | 11.0 (8.0–16.0) |
| SJC66, median (IQR) | 8.0 (6.0–10.0) | 7.0 (6.0–11.0) | 7.5 (6.0–10.5) | 8.0 (5.0–10.0) | 8.0 (6.0–10.0) | 7.0 (5.0–10.0) |
| BSA, median % (IQR) | 3.7 (0.8–7.0) | 2.4 (1.0–7.7) | 1.0 (0.6–4.0) | 1.3 (0.7–5.4) | 2.0 (0.6–7.0) | 2.0 (1.0–7.0) |
| DLQI, median (IQR) | 7.0 (2.0–14.0) | 7.0 (3.0–14.0) | 4.5 (1.0–8.5) | 6.0 (1.0–12.0) | 5.0 (1.0–11.0) | 6.0 (2.0–13.0) |
Data are presented as n (%), mean (SD) or median (IQR) for values that were not normally distributed.
Grey shading indicates statistically significant differences (p≤0.05) for females versus males.
*P values were determined by van Elteren tests (stratified rank test with stratum treatment group) except for enthesitis, dactylitis, baseline MTX treatment and nail involvement, which used Cochran-Mantel-Haenszel tests (stratum treatment group).
BMI, body mass index; BSA, body surface area; CRP, C reactive protein; DAPSA, Disease Activity in Psoriatic Arthritis; DAS28, Disease Activity Score-28 joints; DLQI, Dermatology Life Quality Index; ESR, erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire-Disability Index; LEI, Leeds Enthesitis Index; mtNAPSI, modified target nail psoriasis severity index; MTX, methotrexate; PASI, Psoriasis Area and Severity Index; PBO, placebo; PhGA, physician’s global assessment of disease activity; PtGA, patient’s global assessment of disease activity; SJC, swollen joint count; TJC, tender joint count; UST, ustekinumab; VAS, Visual Analogue Scale.
Thirty patients discontinued before week 52 (17 (56.7%) female and 13 (43.3%) male). Discontinuation rates were higher for females than for males in the ustekinumab+MTX (32.4% vs 18.0%) and ustekinumab+placebo (15.6% vs 8.5%) groups.
Baseline characteristics stratified by sex
Females and males were generally well matched within treatment groups with respect to key measures of disease including joint counts, body surface area affected by psoriasis and patient global disease activity (PtGA). Females had a significantly longer time since PsA diagnosis, higher rates of baseline MTX use and significantly higher Health Assessment Questionnaire-Disability Index (HAQ-DI) scores (table 1). DAS28-ESR values were also significantly higher. Dactylitis and nail involvement were significantly less common in females versus males. Within treatment groups, differences between sexes generally showed the same trends as the full patient cohort but did not always achieve statistical significance (table 1).
Outcomes stratified by sex
As previously reported, the primary study outcome, mean DAS28-ESR at week 24, was non-inferior in the ustekinumab+placebo arm versus the ustekinumab+MTX arm, both in the overall cohort (mean DAS28-ESR of 2.9 vs 3.1) and in subgroups of females (3.5 vs 3.6) and males (2.5 vs 2.8). Values in females were numerically higher than in males.17
Because DAS28-ESR and ACR response assessments can be influenced by elevated ESR levels in females, we focused on other outcomes as more reliable indicators of sex-associated differences. At week 24, females had significantly higher HAQ-DI values than males in both treatment groups (figure 1A), similar to the differences observed at baseline. Changes from baseline to week 24 in HAQ-DI, joint counts and most other outcomes were not significantly different between females and males (figure 1B,C), but females generally had lower levels of change from baseline in disease activity scores (DAPSA and Psoriasis Area and Severity Index (PASI)) and PROs (PtGA and pain) in both treatment arms (figure 1C) and achieved MDA and PASI75 responses at lower rates than males (online supplemental table 1). Similar results were observed in other secondary outcomes at weeks 24 and 52 (online supplemental tables 1 and 2).
Enlarge this image.Figure 1. Efficacy outcomes by sex for (A) median HAQ-DI and joint counts at week 24; (B) change from baseline to week 24 in HAQ-DI and joint counts; (C) change from baseline to week 24 in DAPSA, PASI, PhGA, PtGA and pain; (D) proportion of patients with enthesitis. The ustekinumab+MTX subgroup included 37 females and 50 males. The ustekinumab+placebo subgroup included 32 females and 47 males. The exact numbers of patients for outcomes with missing values are shown in online supplemental tables S1 and S2 . Bars indicate SD (for mean values) or IQR (for median values). P values within treatment groups were determined by the Wilcoxon test. DAPSA, Disease Activity in Psoriatic Arthritis; HAQ-DI, Health Assessment Questionnaire-Disability Index; LEI, Leeds Enthesitis Index; MDA, minimal disease activity; MTX, methotrexate; PASI, Psoriasis Area and Severity Index; PhGA, physician global assessment of disease activity; PtGA, patient global assessment of disease activity; SJC, swollen joint count; TJC, tender joint count.
In the primary trial analysis, there were no significant differences in the proportions of patients with enthesitis between the ustekinumab+MTX and ustekinumab+placebo groups at weeks 24 or 52.17 However, our sex-disaggregated analyses suggested that males with enthesitis had a better response to ustekinumab+MTX than to ustekinumab+placebo at week 24, whereas females showed similar improvements with both treatments (figure 1D). Differences in enthesitis responses in males did not persist at week 52.
AEs stratified by sex
Overall AE and SAE rates were comparable between female and male subgroups (table 2), but females reported more general disorders and administration site condition AEs (20% vs 9%) and fewer investigations (7% vs 19%). In the ustekinumab+MTX treatment group, higher rates of gastrointestinal disorders occurred in females versus males (38% vs 18%).
Table 2Adverse events and serious adverse events by sex*
| Characteristic | UST+MTX (n=87) | UST+PBO (n=79) | All patients (n=166) | |||
| Female (n=37) | Male (n=50) | Female (n=32) | Male (n=47) | Female (n=69) | Male (n=97) | |
| Patients with ≥1 serious adverse event (no of events) | 3 (8%) (4) | 5 (10%) (5) | 3 (9%) (4) | 4 (9%)(6) | 6 (9%) (8) | 9 (9%) (11) |
| Patients with ≥1 adverse event (no of events) | 33 (89%) (179) | 43 (86%) (184) | 30 (94%) (135) | 41 (87%) (155) | 63 (91%) (314) | 84 (87%) (339) |
| Adverse events by SOC and PT | ||||||
| Infections and infestations | 22 (59%) | 25 (50%) | 22 (69%) | 29 (62%) | 44 (64%) | 54 (56%) |
| Gastroenteritis | 2 (5%) | 5 (10%) | 3 (9%) | 2 (4%) | 5 (7%) | 7 (7%) |
| Nasopharyngitis | 7 (19%) | 11 (22%) | 8 (25%) | 13 (28%) | 15 (22%) | 24 (25%) |
| Oral herpes | 5 (14%) | 2 (4%) | 2 (6%) | 2 (4%) | 7 (10%) | 4 (4%) |
| Upper respiratory tract infection | 3 (8%) | 4 (8%) | 4 (13%) | 7 (15%) | 7 (10%) | 11 (11%) |
| Musculoskeletal and connective tissue disorders | 15 (41%) | 16 (32%) | 16 (50%) | 15 (32%) | 31 (45%) | 31 (32%) |
| Psoriatic arthopathy | 7 (19%) | 6 (12%) | 6 (19%) | 5 (11%) | 13 (19%) | 11 (11%) |
| Gastrointestinal disorders | 14 (38%) | 9 (18%) | 7 (22%) | 14 (30%) | 21 (30%) | 23 (24%) |
| Diarrhoea | 5 (14%) | 5 (10%) | 0 | 4 (9%) | 5 (7%) | 9 (9%) |
| Vomiting | 4 (11%) | 2 (4%) | 3 (9%) | 1 (2%) | 7 (10%) | 3 (3%) |
| General disorders and administration site conditions | 9 (24%) | 3 (6%) | 5 (16%) | 6 (13%) | 14 (20%) | 9 (9%) |
| Pain | 4 (11%) | 0 | 1 (3%) | 0 | 5 (7%) | 0 |
| Skin and subcutaneous tissue disorders | 7 (19%) | 6 (12%) | 7 (22%) | 8 (17%) | 14 (20%) | 14 (14%) |
| Psoriasis | 4 (11%) | 1 (2%) | 4 (13%) | 1 (2%) | 8 (12%) | 2 (2%) |
| Nervous system disorders | 7 (19%) | 5 (10%) | 4 (13%) | 3 (6%) | 11 (16%) | 8 (8%) |
| Injury, poisoning and procedural complications | 6 (16%) | 13 (26%) | 4 (13%) | 4 (9%) | 10 (14%) | 17 (18%) |
| Procedural nausea | 5 (14%) | 7 (14%) | 2 (6%) | 1 (2%) | 7 (10%) | 8 (8%) |
| Respiratory, thoracic and mediastinal disorders | 4 (11%) | 6 (12%) | 2 (6%) | 3 (6%) | 6 (9%) | 9 (9%) |
| Investigations | 4 (11%) | 10 (20%) | 1 (3%) | 8 (17%) | 5 (7%) | 18 (19%) |
| Psychiatric disorders | 4 (11%) | 5 (10%) | 1 (3%) | 4 (9%) | 5 (7%) | 9 (9%) |
Adverse events occurring at a rate of 10% or higher in any subgroup are reported by SOC and PT. Grey shading indicates statistically significant differences (p≤0.05) for females versus males. Due to small numbers only SOCs were evaluated for statistical significance.
*P values were determined Cochran-Mantel-Haenszel tests (stratum treatment group) to confirm that statistical significance was not affected by the treatment group assignment.
MTX, methotrexate; PBO, placebo; PT, preferred term; SOC, system organ class; UST, ustekinumab.
Discussion
In post hoc exploratory evaluations of the MUST study, differences between sexes were observed in baseline characteristics, treatment response and AEs. These data extend recent observations concerning sex-based differences in patients with PsA.7–16 and provide insights into treatment outcomes in females and males during ustekinumab therapy, alone or in combination with MTX.
At baseline, females had a longer time since PsA diagnosis and a higher rate of MTX therapy, while males had more dactylitis and nail involvement. Disease activity measures were fairly well matched between females and males, and observed differences, such as DAS28-ESR, were likely driven by higher ESR values in females. In evaluations of ESR-independent treatment outcomes, some significant elevations were observed in mean or median values in females compared with males, perhaps reflecting baseline differences. Changes from baseline to week 24 were generally reduced in females versus males, but differences did not achieve statistical significance. Our exploratory analyses thus suggest that both sexes had similar treatment responses to ustekinumab with or without MTX.
As reported previously, the addition of MTX to ustekinumab did not result in overall benefits in efficacy outcomes.17 The sex-disaggregated data reported here confirm this finding, with the potential exception of enthesitis at week 24 in males. It is possible that combination therapy accelerates the enthesitis treatment response in males. However, these findings are exploratory and should be considered as hypothesis-generating.
Overall AE rates were generally comparable in females and males, but females in the ustekinumab+MTX subgroup had higher rates of gastrointestinal disorders, consistent with a study of MTX-treated patients with RA.21
The major limitation of our study was the low number of patients and lack of statistical power for analyses stratified by sex. In addition, randomisation balanced baseline characteristics across treatment subgroups but not between sexes. The open-label administration of ustekinumab may have influenced patient expectations and responses to PROs. Data on patient-reported gender were not collected; these data would be a valuable addition to future studies and may provide insights into the different influences of societal versus biological factors in PsA disease characteristics and outcomes.
In conclusion, our analyses confirm the efficacy of ustekinumab in both females and males. With the possible exception of enthesitis in males, the addition of MTX to ustekinumab did not appear to influence outcomes in either sex and was associated with high rates of gastrointestinal disorders in females. Our data support additional studies on sex-associated differences in treatment response in patients with PsA, with the goal of optimising therapy and refining individualised treatment strategies.
We would like to thank the participating patients and study centre personnel in the MUST trial. We also wish to thank Sharon L Cross, Ph.D., who provided medical writing services on behalf of Fraunhofer Institute for Translational Medicine & Pharmacology ITMP, Frankfurt am Main, Germany.
Ethics statements
Patient consent for publication
Not applicable.
Ethics approval
This study follows the Declaration of Helsinki. The study protocol was approved by the ethics committee of Goethe University (Ethikkommission des Fachbereichs Medizin der Goethe Universität; reference number 323/16) and by each local ethics committee at participating sites. Participants gave informed consent to participate in the study before taking part.
Collaborators The MUST Investigator Group: Rieke HE Alten (Berlin), Frank Behrens (Frankfurt am Main), Karolina Benesova (Heidelberg), Raoul Bergner (Ludwigshafen), Gerd R Burmester (Berlin), Jan Brandt-Jürgens (Berlin), Jürgen Braun (Heme), Winfried Demary (Hildesheim), Stephanie Finzel (Freiburg), Peter Kästner (Erfurt), Herbert Kellner (München-Nymphenburg), Arnd Kleye (Erlangen), David Kofler (Köln), Klaus Krüger (München), Gabriele Lorenz (Chemnitz), Regina Max (Heidelberg), Denis Poddubnyy (Berlin), Jürgen Rech (Erlangen), Andrea Rubbert-Roth (Köln), Holger Schwenke (Dresden), Maren Sieburg (Magdeburg), Diamant Thaci (Lübeck), Astrid Thiele (Wuppertal), Reinhard E Voll (Freiburg), Ulrich von Hinüber (Hildesheim), Jochen Walter (Rendsburg), Siegfried Wassenberg (Ratingen).
Contributors MK, ACF and FB conceptualised the study, MK wrote the first draft of the study protocol. The protocol was reviewed by MK, ACF, TR and FB prior to submission to the Goethe University ethics committee and the Paul-Ehrlich-Institut. FB was the principal investigator of the study. Recruitment and screening of study participants was performed by MK, HK, UK, GRB, DMK, JB, SF, RB, MS and FB. Data were interpreted by MK, ACF, HK, UK, GRB, DMK and JB. Statistics were performed by ACF. The manuscript was prepared by MK, ACF, TR and FB with medical writing support provided by Sharon L. Cross (funded by Fraunhofer-Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany). All authors reviewed and revised the manuscript, and all authors approved the final manuscript. MK and FB had full access to all data in the study and had final responsibility for the decision to submit the manuscript for publication.
Funding The study was supported by a grant from Janssen Cilag who in addition provided study medication; they had no influence on the design, conduct or analysis of the trial. Medical writing services were supported by Fraunhofer Institute for Translational Medicine & Pharmacology ITMP, Frankfurt am Main, Germany, a non-profit organisation. The clinical research group Frankfurt is supported by the Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD) and the LOEWE Zentrum Translational Medicine and Pharmacology.
Competing interests MK received consulting fees or honoraria from Amgen, Janssen-Cilag, Lilly, Novartis and UCB and received travel support from UCB. UK received grant and research support and consultancy fees from AbbVie, Amgen, Biocad, Biogen, BMS, Chugai, Eli Lilly, Fresenius, Gilead, Grünenthal, GSK, Hexal, Janssen, MSD, Novartis, onkowissen.de, Pfizer, Roche, UCB and Viatris and participated on a data safety monitoring or advisory board for the COPAGO trial, conducted by the German Ministry of Health. GRB received fees or honoraria for serving as a speaker and/or consultant from Abbvie, Galapagos, Janssen, Lilly, Novartis and UCB, meeting or travel support from Abbvie and Lilly and is the editor-in-chief of RMD Open. DMK received honoraria for serving as a speaker for Sanofi-Aventis. SF received scientific grants from Novartis, honoraria or fees for serving as a speaker and/or consultant from Abbvie, AstraZeneca, Chugai, Galapagos, Novartis, NovoNordisc and UCB, and travel or meeting support from Abbvie, Galapagos, Janssen Cilag, Novartis, SOBI and UCB. RB received honoraria or fees for serving as a speaker and/or consultant from Abbvie, BMS, Chugai, GSK, Galapagos, Novartis, Roche and Vifor and meeting or travel support from Chugai and Galapagos. MS received research support from Charité. FB received research support for this study from Janssen Cilag, consulting fees or honoraria from Abbvie, Acelyrin, Amgen, Janssen Cilag, Lily, Novartis, Pfizer and UCB, and meeting or travel support from Abbvie and UCB. ACF, TR, HK and JB have no competing interests to declare.
Provenance and peer review Not commissioned; externally peer reviewed.
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Details
; Foldenauer, Ann C 2
; Rossmanith, Tanja 2 ; Kellner, Herbert 3 ; Kiltz, Uta 4
; Burmester, Gerd R 5
; Kofler, David M 6
; Brandt, Jan 7 ; Finzel, Stephanie 8
; Bergner, Raoul 9
; Sieburg, Maren 10 ; Behrens, Frank 1
1 Division of Rheumatology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany; Fraunhofer Cluster of Excellence for Immune-Mediated Diseases CIMD, Frankfurt am Main, Germany
2 Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany; Fraunhofer Cluster of Excellence for Immune-Mediated Diseases CIMD, Frankfurt am Main, Germany
3 Schwerpunktpraxis für Rheumatologie und Gastroenterologie und Ärztlicher Leiter, Abteilung Rheumatologie, Krankenhaus Neuwittelsbach, Munchen, Germany
4 Rheumazentrum Ruhrgebiet, Herne, Germany; Ruhr University Bochum, Bochum, Germany
5 Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
6 Clinical Immunology and Rheumatology, Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany
7 Rheumatologische Schwerpunktpraxis, Berlin, Germany
8 Rheumatology and Clinical Immunology, University of Freiburg Medical Center, Freiburg, Germany
9 Medizinische Klinik A, Klinikum Ludwigshafen, Ludwigshafen, Germany
10 Rheumatologische Facharztpraxis, Magdeburg, Germany