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Background: Vaccinations represent an easily accessible, safe, and important method for preventing infections. Patients with primary immunodeficiencies (PID) are more susceptible to infections and should receive an extended spectrum of immunizations in many countries., Methods: Between January 2019 and May 2020, vaccination certificates of 70 patients with PID from the regions of Würzburg and Hanover in Germany were evaluated. The patients were additionally surveyed regarding their attitude towards vaccinations and the communication with their physicians. Medical records were analyzed., Results: Of the 70 patients, 54 (77%) suffered from common variable immunodeficiency, 30 (43%) were diagnosed with accompanying autoimmunity, 62 (89%) had an increased susceptibility to infections, and 56 (80%) were on immunoglobulin substitution therapy. Seven patients (10%) had neither a vaccination certificate nor were they able to recollect of their last vaccination. Only 55 (79%) and 43 (61%) patients stated that their rheumatologist or immunologist had recommended an influenza and a pneumococcal vaccination, respectively. When asked about their overall trust in vaccinations on a scale of 0 to 10 (0 = very low, 10 = very high), the mean value was 7.8. The most common vaccination was against tetanus in 63 (90%) patients, 49 (70%) had received vaccination against pneumococci, and 39 (56%) had received an influenza vaccination. Interestingly, 26 patients (37%) were vaccinated against measles, even though this is contraindicated in most PID patients., Conclusion: Our data suggest that vaccination rates in this at-risk population are insufficient. Healthcare providers should emphasize vaccinations routinely when caring for these patients., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Objective: To estimate the effects of Janus kinase inhibitors (JAKi), tumour necrosis factor inhibitors (TNFi), other biologic(b) or conventional synthetic(cs) disease-modifying antirheumatic drugs (DMARDs) on the risk of major adverse cardiovascular events (MACE) in patients with rheumatoid arthritis (RA)., Methods: Cohort study analysing episodes of DMARD-treatment initiated between January 2017 and April 2022 in the biologics register Rheumatoid Arthritis: Observation of Biologic Therapy. Incidence rates (IRs) per 100 patient-years with 95% CIs were calculated for overall patients and those with cardiovascular risk (age ≥50 years and ≥1 cardiovascular risk factor). MACE risk was estimated as HRs by inverse probability of treatment weight-adjusted Andersen-Gill models., Results: A total of 154 MACE occurred among 14 203 treatment episodes (21 218 patient-years). IRs were 0.68 (0.47; 0.95), 0.62 (0.45; 0.83), 0.76 (0.53; 1.06) and 0.95 (0.68; 1.29) for JAKi, TNFi, bDMARDs and csDMARDs, respectively. IRs were higher in cardiovascular risk patients. Adjusted HRs (95% CI) comparing JAKi, bDMARDs and csDMARDs with TNFi were 0.89 (0.52 to 1.52), 0.76 (0.45; to1.27) and 1.36 (0.85 to 2.19) in overall, and 0.74 (0.41 to 1.31), 0.75 (0.45 to 1.27) and 1.21 (0.74 to 1.98) in cardiovascular risk patients. HRs were not increased in patients ≥65 years, with cardiovascular history or smokers, and also not when using csDMARD as reference instead of TNFi. IRs for baricitinib, tofacitinib and upadacitinib were 0.49 (0.25 to 0.85), 0.98 (0.58 to 1.55) and 0.53 (0.15 to 1.36), respectively., Conclusion: In this German observational cohort study, MACE did not occur more frequently with JAKi compared with other DMARDs. However, individual JAKis showed different unadjusted IRs., Competing Interests: Competing interests: YM: Lecture honoraria from Lilly, Pfizer. MS: None. KA: None. JK: None. SZ: Consulting fees from UCB, Astra-Zeneca, Galapagos, Lecture honoraria from Lilly, Jannsen, Abbvie, Biogen, Support for meeting attendance/Travel: Amgen, Leadership/ fiduciary role in other board, society, committee or advocacy group: BDRH e.V. HPT: Consulting fees from Abbvie, Chugai, Janssen, Lilly, Novartis, Galapagos, BMS, Sanofi. AS: Lecture honoraria from AbbVie, Amgen, BMS, Celltrion, MSD, Lilly, Pfizer, Roche, UCB., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction/objectives: The ASCORE study on treatment for rheumatoid arthritis (RA) showed better retention and clinical response rates for abatacept as first-line versus later-line therapy. This post hoc analysis of ASCORE assessed 2-year retention, efficacy, and safety of subcutaneous (SC) abatacept in Germany, Austria, and Switzerland., Methods: Adults with RA who initiated SC abatacept 125 mg once weekly were assessed. Primary endpoint was abatacept retention rate at 2 years. Secondary endpoints: proportions of patients with low disease activity (LDA)/remission per Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (≤ 3.2), Simplified Disease Activity Index (≤ 11), and Clinical Disease Activity Index (≤ 10). Outcomes were analyzed by treatment line and serostatus., Results: For the pooled cohort, the 2-year abatacept retention rate was 47.6%; retention was highest in biologic-naïve patients (50.5% [95% confidence interval 44.9, 55.9]). Patients seropositive for both anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF; + / +) at baseline had a higher 2-year abatacept retention rate than patients with single seropositivity for either APCA or RF or double-seronegativity (- / -), irrespective of treatment line. At 2 years, a higher proportion of patients who were biologic-naïve were in LDA/remission than patients with one or ≥ two prior biologics., Conclusion: A higher proportion of patients with + / + RA (compared with - / - RA) had abatacept retention after 2 years. Early identification of patients with seropositive RA may facilitate a precision-medicine approach to RA treatment, leading to a higher proportion of patients in LDA/remission., Trial Registration Number: NCT02090556; date registered: March 18, 2014 (retrospectively registered). Key Points • This post hoc analysis of a German-speaking subset of European patients with RA from the global ASCORE study (NCT02090556) showed that retention of SC abatacept within this subset was 47.6%, with good clinical outcomes after 2 years. • Patients with double-seropositive RA (ACPA and RF positive) had higher retention of abatacept than patients with double-seronegative RA (ACPA and RF negative). Retention and clinical responses were highest for patients who were biologic-naïve compared with patients who had one or ≥ two prior biologic treatments. • These real-world data may be useful for clinicians in informing individualized treatment pathways for patients with RA, and fostering superior disease control and clinical outcomes., (© 2023. The Author(s).)

Background: Granulomatous and lymphocytic interstitial lung disease (gl-ILD) is a major cause of morbidity and mortality among patients with common variable immunodeficiency. Corticosteroids are recommended as first-line treatment for gl-ILD, but evidence for their efficacy is lacking., Objectives: This study analyzed the effect of high-dose corticosteroids (≥0.3 mg/kg prednisone equivalent) on gl-ILD, measured by high-resolution computed tomography (HRCT) scans, and pulmonary function test (PFT) results., Methods: Patients who had received high-dose corticosteroids but no other immunosuppressive therapy at the time (n = 56) and who underwent repeated HRCT scanning or PFT (n = 39) during the retrospective and/or prospective phase of the Study of Interstitial Lung Disease in Primary Antibody Deficiency (STILPAD) were included in the analysis. Patients without any immunosuppressive treatment were selected as controls (n = 23). HRCT scans were blinded, randomized, and scored using the Hartman score. Differences between the baseline and follow-up HRCT scans and PFT were analyzed., Results: Treatment with high-dose corticosteroids significantly improved HRCT scores and forced vital capacity. Carbon monoxide diffusion capacity significantly improved in both groups. Of 18 patients, for whom extended follow-up data was available, 13 achieved a long-term, maintenance therapy independent remission. All patients with relapse were retreated with corticosteroids, but only one-fifth of them responded. Two opportunistic infections were found in the corticosteroid treatment group, while overall infection rate was similar between cohorts., Conclusions: Induction therapy with high-dose corticosteroids improved HRCT scans and PFT results of patients with gl-ILD and achieved long-term remission in 42% of patients. It was not associated with major side effects. Low-dose maintenance therapy provided no benefit and efficacy was poor in relapsing disease., (Copyright © 2023. Published by Elsevier Inc.)

Background: The treatment of giant cell arteritis with glucocorticoid-sparing agents is an unmet medical need. We evaluated the efficacy and safety of secukinumab, an anti-interleukin-17A monoclonal antibody, in patients with giant cell arteritis., Methods: We conducted a Bayesian randomised, parallel-group, double-blind, placebo-controlled, multicentre, phase 2 study at 11 clinics or hospitals in Germany. Patients aged 50 years or older with new-onset or relapsing giant cell arteritis who were naive to biological therapy and already receiving glucocorticoids with a prednisolone equivalent dose of 25-60 mg/day were eligible for inclusion. Participants were assigned (1:1) to receive 300 mg secukinumab or placebo subcutaneously once a week up to week 4 and every 4 weeks thereafter. In both treatment groups, prednisolone dose was tapered down to 0 mg over a 26-week period. Patients, investigator staff, and clinical trial team were masked to the treatment assignment. The primary endpoint was the median proportion (Bayesian analysis) of patients with sustained remission until week 28 in the full analysis set (ie, all patients who received at least one dose of assigned treatment, analysed according to treatment assigned at randomisation). Sustained remission rate of the placebo group from a previous trial of tocilizumab in patients with giant cell arteritis was used to derive the prior distribution of placebo sustained remission rate for the primary endpoint. The safety of secukinumab was assessed in the safety set (ie, all patients who received at least one dose of study treatment, analysed according to study treatment received). This trial is completed and is registered with ClinicalTrials.gov, NCT03765788., Findings: Of the 65 patients who were assessed for eligibility, 52 patients (median age 75 years [IQR 69-79]; 35 [67%] female and 17 [33%] male, 52 [100%] White) were enrolled between Jan 30, 2019 and March 30, 2020 and were randomly assigned to receive secukinumab (n=27) or placebo (n=25). Four of 27 patients in the secukinumab group and eight of 25 patients in the placebo group discontinued treatment by week 28 of the study. On the basis of the Bayesian analysis, the median proportion of patients in sustained remission until week 28 was 70% (95% credibility interval 52-85) in the secukinumab group versus 20% (12-30) in the placebo group. The incidence of adverse events was similar in the secukinumab (27 [100%] of 27 patients had any adverse event) and placebo groups (24 [96%] of 25 patients had any adverse event); the most common adverse events were hypertension (six [22%] of 27 patients in the secukinumab group and eight [32%] of 25 patients in the placebo group) and nasopharyngitis (five [19%] of 27 patients in the secukinumab group and five [20%] of 25 patients in the placebo group). Two patients (one in each group) died during the study, neither of which was considered to be related to study treatment., Interpretation: Patients with active giant cell arteritis had a higher sustained remission rate in the secukinumab group than in the placebo group at week 28, in combination with glucocorticoid taper regimen. Secukinumab was tolerated well with no new safety concerns. This proof-of-concept phase 2 study further supports the development of secukinumab as a treatment option for people with giant cell arteritis., Funding: Novartis Pharma., Competing Interests: Declaration of interests NV declares speaker honorarium from AbbVie, AstraZeneca, Novartis, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Roche, UCB, GlaxoSmithKline, and Vifor; being an advisory board member for AbbVie, Chugai, Novartis, UCB, and Vifor; consulting fees from Novartis, AbbVie, Chugai, and Vifor; research grants from Bristol Myers Squibb and Novartis; meeting or travel grants from Bristol Myers Squibb, Novartis, AbbVie, and Vifor; and expert testimony for Novartis, Vifor, and AbbVie. WAS is part of speaker bureaus for AbbVie, Chugai, Medac, Novartis, Roche, and Sanofi; is an advisory board member for AbbVie, Chugai, GlaxoSmithKline, Novartis, Roche, and Sanofi; and received research grants from AbbVie, GlaxoSmithKline, Novartis, and Sanofi. RB is part of speaker bureaus for AbbVie, Bristol Myers Squibb, Chugai, Novartis, Roche, Galapagos, and Glaxo Smith Kline; is an advisory board member for Galapagos, GlaxoSmithKline, and Vifor; received research grants from Vifor; and is an unpaid board member for Commission für student education—German Rheumatology Society. JR is part of speaker bureaus for AbbVie, Biogen, Bristol Myers Squibb, Chugai, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Roche, Sanofi, Sobi, and UCB and received consulting fees from AbbVie, Biogen, Bristol Myers Squibb, Chugai, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Roche, Sanofi, Sobi, and UCB. LU received payments for speeches and seminar presentations from Novartis. H-PT is an advisory board member for AbbVie, Bristol Myers Squibb, Chugai, Gilead, Lilly, Novartis, Roche, and Sanofi. SF received consulting fees from Amgen and Novartis; speaker honorarium from AbbVie, Amgen, Galapagos, Novartis, and UCB; and meeting or travel grants from Novartis, UCB, Galapagos, and Sobi. IA received consulting fees from Amgen, Boehringer Ingelheim, Chugai, Galapagos, Lilly, Novartis, Pfizer, Sobi, Takeda, and UCB; is part of speaker bureaus for AbbVie, Chugai, Gilead, Lilly, MSD, Novartis, Pfizer, Sobi, and UCB; received payments for other services (receipt of equipment, materials, drugs, medical writing, and gifts) from Novartis; and received research grants from Lilly. SMW is an advisory board member for Novartis; received speaker honorarium from AbbVie, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi-Sankyo, MSD, Novartis, Otsuka, Pfizer, and Roche; received meeting or travel grants from Abbvie, Amgen, Bristol Myers Squibb, Otsuka, Pfizer, and UCB; and is an unpaid board member for Saarländisch-Pfälzische Internistengesellschaft and Arbeitskreis Nephrologie Saar-Pfalz Mosel. PL received speaker honorarium from Bristol Myers Squibb, GlaxoSmithKline, Janssen, UCB, and Vifor; is an advisory board member for GlaxoSmithKline and Vifor; and received research grants from Bundesministerium für Bildung und Forschung, Deutsche Forschungsgemeinschaft, John Grube Foundation, and Vifor. HS-K is part of speaker bureaus for AbbVie, Bristol Myers Squibb, Chugai, GlaxoSmithKline, Janssen, Medac, Novartis, Pfizer, Roche, Sanofi, and UCB; is an advisory board member for AbbVie, Bristol Myers Squibb, Chugai, Janssen, Medac, Pfizer, Novartis, Roche, Sanofi, and UCB; and received research grants from AbbVie and Novartis. CA is an employee of Novartis Pharma. EP is an employee of Novartis Pharma and owns Novartis stock. MHM is an employee and shareholder of Novartis Pharmaceuticals and is named on the patent for secukinumab in the treatment of giant cell arteritis, as an employee of Novartis, the funder. CS is an employee of Novartis Pharma and has Novartis stock options. MM is an employee of Novartis Pharma. JT declares speaker honorarium from Novartis, GlaxoSmithKline, Bristol Myers Squibb, Roche, AstraZeneca, and Vifor; is an advisory board member for Novartis; received consulting fees from Novartis, Janssen, and GlaxoSmithKline; and received research grants from Bristol Myers Squibb and Novartis. DMK declares no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Several studies have shown that tapering or stopping disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients in sustained remission is feasible. However, tapering/stopping bears the risk of decline in physical function as some patients may relapse and face increased disease activity. Here, we analyzed the impact of tapering or stopping DMARD treatment on the physical function of RA patients. The study was a post hoc analysis of physical functional worsening for 282 patients with RA in sustained remission tapering and stopping DMARD treatment in the prospective randomized RETRO study. HAQ and DAS-28 scores were determined in baseline samples of patients continuing DMARD (arm 1), tapering their dose by 50% (arm 2), or stopping after tapering (arm 3). Patients were followed over 1 year, and HAQ and DAS-28 scores were evaluated every 3 months. The effect of treatment reduction strategy on functional worsening was assessed in a recurrent-event Cox regression model with a study-group (control, taper, and taper/stop) as the predictor. Two-hundred and eighty-two patients were analyzed. In 58 patients, functional worsening was observed. The incidences suggest a higher probability of functional worsening in patients tapering and/or stopping DMARDs, which is likely due to higher relapse rates in these individuals. At the end of the study, however, functional worsening was similar among the groups. Point estimates and survival curves show that the decline in functionality according to HAQ after tapering or discontinuation of DMARDs in RA patients with stable remission is associated with recurrence, but not with an overall functional decline.

Background: Digital health applications/apps (DiGA) are entering many medical disciplines and have the potential to revolutionize patient care. In rheumatology, the use for axial spondyloarthritis (axSpA) would be conceivable in the form of an exercise app. Therefore, a representative survey among axSpA patients was conducted to determine the need for an axSpA exercise app., Materials and Methods: An anonymous online survey among axSpA patients of the German Bechterew's Disease Association was conducted using a questionnaire; data were analysed using Excel, and GraphPad Prism., Results: Four hundred and thirty-five axSpA patients participated in the survey. Eighty-four percent of the participants responded that there is a need to develop an axSpA-specific exercise app, and the same proportion want to use it. Patients under 60 years, patients under 60 years on biologics or Janus kinase inhibitor therapy, and patients with frequent back pain reported a greater need than their respective control subgroups (p < 0.001 in each case)., Conclusion: The development of an exercise app for axSpA is considered necessary by a large proportion of the patients; younger and more intensively treated patients appear to have a greater need., (© 2021. The Author(s).)

Background: The optimal dose of rituximab in combination with leflunomide in patients with rheumatoid arthritis (RA) is not known., Methods: In Part 1 (previously reported) of the investigator-initiated AMARA study (EudraCT 2009-015950-39; ClinicalTrials.gov NCT01244958), improvements at week (W)24 were observed in patients randomized to rituximab + leflunomide compared with placebo + leflunomide. In the study reported here (Part 2), Part 1 responders received rituximab 500 or 1000 mg at W24/26 plus ongoing leflunomide. Patients were randomized at baseline to their eventual W24 treatment group. The Part 2 primary outcome was the mean Disease Activity Score-28 joints (DAS28) at W52, based on the last observation carried forward (LOCF) analyses and a two-sided analysis of variance. Patient-reported outcomes (PROs) and adverse events were evaluated., Results: Eighty-three patients received rituximab at W24/26 (31 rituximab→rituximab 1000 mg; 29 rituximab→rituximab 500 mg; 10 placebo→rituximab 1000 mg; 13 placebo→rituximab 500 mg). At W52, there were no significant differences in DAS28 between rituximab doses in patients originally treated with rituximab or those originally treated with placebo. In the Part 1 placebo group, the higher rituximab dose was associated with greater improvements in ACR response rates and some PROs. Adverse events were similar regardless of rituximab dose., Conclusions: Retreatment with rituximab 500 mg and 1000 mg showed comparable efficacy, whereas an initial dose of rituximab 500 mg was associated with lower response rates versus 1000 mg. Reduced treatment response with the lower dose in patients initially treated with placebo may have been influenced by small numbers and baseline disease activity.

Objectives: 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) PET/CT can be utilized in patients with giant cell arteritis (GCA), but pretest probability of established laboratory marker such as C-reactive protein (CRP) and white blood cell count (WBC) has not been defined yet. We aimed to elucidate the clinical utility of CRP and WBC for scheduling an [ 18 F]FDG scan., Methods: 18 treatment-naïve GCA patients and 14 GCA subjects with anti-inflammatory treatment (glucocorticoids or comparable drugs), who underwent [ 18 F]FDG PET/CT and who had no other inflammatory disease at time of scan, were identified. A semi-quantitative analysis in 11 vessel segments was conducted, with averaged jugular vein, healthy liver and lung tissue (Target-to-background ratio [TBR] VJ/liver/lung ) serving as background. Derived TBR were then correlated with CRP and WBC at time of PET using Spearman's correlation., Results: For all treatment-naïve patients, TBR VJ was 2.3±1.1 (95%CI, 2.2-2.5), TBR liver was 1.0±0.5 (95%CI, 0.9-1.0) and average TBR lung was 6.3±3.6 (95%CI, 5.8-6.8). No significant correlation was noted for either CRP (TBR VJ : R=-0.19; TBR liver : R=-0.03; TBR lung : R=-0.17; each P ≥ 0.44) or for WBC (TBR VJ : R=-0.40; TBR liver : R=-0.32; TBR lung : R=-0.37; each P ≥ 0.10). Similar results were recorded for patients under treatment at time of PET. Again, no significant correlation was reached for either CRP (TBR VJ : R=-0.17; TBR liver : R=-0.28; TBR lung : R=-0.09; each P ≥ 0.32) or WBC (TBR VJ : R=-0.06; TBR liver : R=-0.13; TBR lung : R=0.06; each P ≥ 0.65)., Conclusions: In GCA patients with and without anti-inflammatory treatment, CRP and WBC did not substantially correlate with TBR at time of scan. Given the rather limited pretest probability of those parameters, such laboratory values may have less diagnostic utility to order an [ 18 F]FDG PET/CT., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Objectives: To examine the safety and effectiveness of long-term tocilizumab treatment in elderly patients with rheumatoid arthritis (RA) and patients with age-associated comorbidities., Methods: ICHIBAN (NCT01194401) was a prospective, non-interventional study that observed adult patients with active moderate-to-severe RA in German rheumatology clinics and practices for up to two years. Patients were to be treated according to the tocilizumab label. Here, we present safety and effectiveness data analysed according to patient age., Results: Of the 3,164 patients treated with at least one dose of tocilizumab, 924 patients were <50 years old, 1496 patients were 50-65 years old, and 744 patients were >65 years old at baseline. Patients >65 years had the highest baseline DAS28-ESR, CDAI, and HAQ-DI scores, along with the highest burden of comorbidities, such as diabetes, coronary heart disease, anaemia, and renal insufficiency. Under treatment with tocilizumab, patients >65 years had similar improvements in DAS28-ESR, CDAI and patient-reported outcomes (fatigue, pain, sleeplessness) with similar glucocorticoid savings compared to patient groups <65 years. Patients >65 years with late-onset RA achieved similar reductions in disease activity compared to early-onset patients. Despite numerically higher rates of adverse events (AEs), serious AEs and serious infections in patients >65 years, there were similar rates of AEs leading to withdrawal., Conclusions: Elderly patients in ICHIBAN experienced improvements similar to younger patients in most effectiveness endpoints with only slightly higher rates of AEs, indicating an overall net-positive risk-benefit ratio of tocilizumab treatment regardless of patient age.

Background: Assessing serological inflammation is difficult in tocilizumab (TCZ)-treated rheumatoid arthritis (RA) patients, as standard inflammation parameters, like erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are influenced by interleukin-6-receptor inhibition. Calprotectin in the serum, also named S100A8/S100A9, might be a more useful inflammation parameter in TCZ-treated patients., Methods: Sixty-nine RA patients taking TCZ were included. Serum-calprotectin levels were assessed, as well as ESR, CRP, need for a change in disease-modifying anti-rheumatic drugs due to RA activity (= active RA), and the RA clinical disease activity score (CDAI). Forty-five RA patients taking tumor-necrosis factor-inhibitors (TNFi) were investigated for the same parameters., Results: TCZ-treated patients with active RA had higher calprotectin values than not active RA patients (4155.5 [inter quartile range 1865.3-6068.3] vs 1040.0 [676.0-1638.0] ng/ml, P < 0.001). A calprotectin cut-off value of 1916.5 ng/ml resulted in a sensitivity and specificity of 80.0 %, respectively, for the detection of RA disease activity. Calprotectin values correlated with CDAI-scores (r = 0.228; P = 0.011). ESR and CRP were less suitable to detect RA activity in TCZ-treated patients. Also TNFi-treated patients with active RA had higher calprotectin values compared to not active RA (5422.0 [3749.0-8150.8] vs 1845.0 [832.0-2569.0] ng/ml, P < 0.001). The calprotectin value with the best sensitivity and specificity for detecting RA activity was 3690.5 ng/ml among TNFi-treated patients., Conclusion: Calprotectin in the serum can be a useful inflammation parameter despite TCZ-treatment., (© 2022. The Author(s).)

Systemic sclerosis (SSc) is a severe chronic disease with a broad spectrum of clinical manifestations. SSc displays disturbed lymphocyte homeostasis. Immunosuppressive medications targeting T or B cells can improve disease manifestations. SSc clinical manifestations and immunosuppressive medication in itself can cause changes in lymphocyte subsets. The aim of this study was to investigate peripheral lymphocyte homeostasis in SSc with regards to the immunosuppression and to major organ involvement. 44 SSc patients and 19 healthy donors (HD) were included. Immunophenotyping of peripheral whole blood by fluorescence-activated cell sorting was performed. Cytokine secretions of stimulated B cell cultures were measured. SSc patients without immunosuppression compared to HD displayed lower γδ T cells, lower T helper cells (CD3 + /CD4 + ), lower transitional B cells (CD19 + /CD38 ++ /CD10 + /IgD + ), lower pre-switched memory B cells (CD19 + /CD27 + /IgD + ), and lower post-switched memory B cells (CD19 + /CD27 + /IgD - ). There was no difference in the cytokine production of whole B cell cultures between SSc and HD. Within the SSc cohort, mycophenolate intake was associated with lower T helper cells and lower NK cells (CD56 + /CD3 - ). The described differences in peripheral lymphocyte subsets between SSc and HD generate further insight in SSc pathogenesis. Lymphocyte changes under effective immunosuppression indicate how lymphocyte homeostasis in SSc might be restored., (© 2021. The Author(s).)

Introduction: Differences in psoriatic arthritis (PsA) treatment response between sexes for ixekizumab, an interleukin-17A antagonist, are largely unexplored. This analysis used data from randomized clinical trials (RCTs) evaluating ixekizumab to study differences in treatment response between male and female patients with PsA., Methods: We used pooled data from patients enrolled in SPIRIT-P1 and SPIRIT-P2 (NCT01695239 and NCT02349295, respectively), phase 3 RCTs evaluating ixekizumab every 4 and 2 weeks in patients with active PsA. Subgroups of patients were defined by sex (male, female). Efficacy was measured by the proportion of male and female patients achieving American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70), minimal disease activity or very low disease activity (MDA/VLDA), and Disease Activity Index for Psoriatic Arthritis (DAPSA) scores representing low disease activity (LDA) or remission through week 156. Changes from baseline in components of the above measures were also assessed through week 156., Results: Compared to male patients at baseline, female patients were older, had higher body mass index and lower C-reactive protein levels, and had worse tender joint count, Health Assessment Questionnaire Disability Index, and Leeds Enthesitis Index scores. Through week 156, female patients in all treatment arms had lower response rates than male patients in all analyzed composite measures (ACR20/50/70; MDA/VLDA; DAPSA LDA/remission), with significant differences observed at multiple timepoints in both ixekizumab treatment arms. Female patients also had smaller numeric changes from baseline in the composite measures' individual components., Conclusion: Compared to female patients, male patients had greater response rates in ACR20/50/70, MDA/VLDA, and DAPSA LDA/remission and numerically larger improvements in these measures' individual components, although clinical significance is unclear. Continued efforts to understand sex differences in treatment response may provide insights that can help optimize clinical decision making., Trial Registration: ClinicalTrials.gov identifiers, NCT01695239 and NCT02349295., (© 2022. The Author(s).)

Objectives: The aim was to evaluate the safety and effectiveness of sarilumab in RA patients after inadequate response (IR) to janus kinase inhibitors (JAKi) and tocilizumab., Methods: The prospective, observational, 24-month single-arm PROSARA study (SARILL08661) is currently running in Germany at 96 sites. RA patients were prospectively selected at the physician's discretion according to label. This interim analysis included 536 patients over a treatment course of ≤6 months. Patients were stratified in four groups according to pretreatment before the start of sarilumab therapy: last prior treatment JAKi (JAKi-IR); last prior treatment tocilizumab (tocilizumab-IR); any other biological DMARD (bDMARD) in treatment history (bDMARD TH); and patients who had not received any bDMARDs or targeted synthetic (ts) DMARDs (b/tsDMARD naive) before., Results: For this preplanned interim analysis, 536 patients were included in the baseline population, of whom 502 patients had at least one corresponding post-baseline effectiveness assessment documented (main analysis population). In all analysed cohorts, safety was consistent with the anticipated profile of sarilumab, without new safety signals. Six months of sarilumab treatment attenuated disease activity in JAKi-IR, tocilizumab-IR, bDMARD TH and b/tsDMARD-naive patients to a very similar extent. Physical function did not change substantially over the course of treatment. Rates of premature study discontinuation were comparable between cohorts., Conclusion: Sarilumab treatment was effective in patients with IR to JAKi and tocilizumab, with an expectable safety profile and drug retention over 6 months. Confirmation of these promising results should encourage further studies on this treatment sequence, which is of high practical relevance., Study Registration: Paul-Ehrlich-Institut-Federal Institute for Vaccine and Biomedics, SARILL08661., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Systemic sclerosis (SSc) patients often need immunosuppressive medication (IS) for disease control. If SSc is progressive despite IS, autologous hematopoietic stem cell transplantation (aHSCT) is a treatment option for selected SSc patients. aHSCT is effective with good available evidence, but not all patients achieve a treatment-free remission after aHSCT. Thus far, data about the need of IS after aHSCT in SSc is not published. The aim of this study was to investigate the use of IS after aHSCT, its efficacy, and the occurrence of severe adverse events (SAEs)., Methods: Twenty-seven patients with SSc who had undergone aHSCT were included in this single-center retrospective cohort study. Clinical data, including IS, SAEs, and lung function data, were collected., Results: Sixteen of 27 (59.3%) patients received IS after aHSCT. Methotrexate, rituximab, mycophenolate, cyclophosphamide, and hydroxychloroquine were most commonly used. The main reason for starting IS was SSc progress. Nine patients received rituximab after aHSCT and showed an improvement in modified Rodnan skin score and a stabilization of lung function 2 years after rituximab. SAEs in patients with IS after aHSCT (50.0%) were not more common than in patients without IS (54.6%). SAEs were mostly due to SSc progress, secondary autoimmune diseases, or infections. Two deaths after aHSCT were transplantation related and three during long-term follow-up due to pulmonary arterial hypertension., Conclusion: Disease progression and secondary autoimmune diseases may necessitate IS after aHSCT in SSc. Rituximab seems to be an efficacious treatment option in this setting. Long-term data on the safety of aHSCT is reassuring., Competing Interests: MG received travel grants from AbbVie, Chugai, Eli Lilly, Hexal, Janssen-Cilag, Novartis, Pfizer, and compensation for board memberships from Takeda. H-PT received speaker’s fees, travel grants, research funding, or compensation for consultancies or board memberships from AbbVie, BMS, Chugai/Roche, Eli Lilly, Gilead, Janssen, Novartis, Sandoz/Hexal, Sanofi Aventis, UCB, and Takeda (Shire). ES received speaker’s fees, travel grants, research funding, or compensation for consultancies or board memberships from AbbVie, Chugai/Roche, Janssen-Cilag, Eli Lilly, Novartis, Pfizer, and Takeda (Shire). MF received travel grants from AbbVie, Novartis, Janssen, Eli Lilly, and compensation for board memberships from AbbVie. MS received speaker’s fees, travel grants, research funding, or compensation for consultancies or board memberships from AbbVie, Actelion, Amgen, AstraZeneca, BMS, Boehringer/Ingelheim, Celgene, Chugai/Roche, Eli Lilly, EUSA-Pharma, Genzyme, Gilead, Hexal/Sandoz, Janssen-Cilag, medac, MSD, Mylan, Novartis, Pfizer, Sanofi Pasteur, Takeda (Shire), and UCB., (Copyright © 2022 Gernert, Tony, Fröhlich, Schwaneck and Schmalzing.)

Background: Genital human papillomavirus (HPV)-infections are common in the general population and are responsible for relevant numbers of epithelial malignancies. Much data on the HPV-prevalence is available for secondary immunodeficiencies, especially for patients with human immunodeficiency virus (HIV)-infection. Little is known about the genital HPV-prevalence in patients with primary immunodeficiencies (PIDs)., Methods: We performed a cross-sectional study of patients with PIDs and took genital swabs from male and female patients, which were analyzed with polymerase chain reaction for the presence of HPV-DNA. Clinical and laboratory data was collected to identify risk factors., Results: 28 PID patients were included in this study. 10 of 28 (35.7%) had HPV-DNA in their genital swabs. 6 patients had high-risk HPV-types (21.4%). Most patients had asymptomatic HPV-infections, as genital warts were rare (2 of 28 patients) and HPV-associated malignancy was absent. Differences in the HPV-positivity regarding clinical PID-diagnosis, duration of PID, age, sex, immunosuppression, immunoglobulin replacement, or circumcision in males were not present. HPV-positive PID patients had higher numbers of T cells (CD3 + ), of cytotoxic T cells (CD3 + /CD8 + ), of transitional B cells (CD19 + /CD38 ++ /CD10 + /IgD + ), and of plasmablasts (CD19 + /CD38 + /CD27 ++ /IgD - ) compared to HPV-negative., Conclusion: PID patients exhibit a high rate of genital HPV-infections with a high rate of high-risk HPV-types. Regular screening for symptomatic genital HPV-infection and HPV-associated malignancy in PID patients seems recommendable., Competing Interests: MG received travel grants from AbbVie, Chugai, Eli Lilly, Hexal, Janssen, Novartis, Pfizer and compensation for board membership from Takeda. MF received travel grants from AbbVie, Novartis, Janssen, Eli Lilly and compensation for board memberships from AbbVie. P-PS received travel grants from AbbVie, Eli Lilly, Janssen-Cilag. JP received travel grants from AbbVie and Janssen-Cilag. H-PT received speaker’s fees, travel grants, research funding, or compensation for consultancies or board memberships from AbbVie, Chugai/Roche, Eli Lilly, Gilead, Janssen, Novartis, Sandoz/Hexal, Sanofi Aventis, Takeda (Shire). MS received speaker’s fees, travel grants, research funding, or compensation for consultancies or board memberships from AbbVie, Actelion, BMS, Boehringer/Ingelheim, Celgene, Chugai/Roche, Eli Lilly, Genzyme, Gilead, Hexal/Sandoz, Janssen-Cilag, MSD, Novartis, Pfizer, Sanofi Pasteur, Takeda (Shire), UCB. ES received speaker’s fees, travel grants, research funding, or compensation for consultancies or board memberships from AbbVie, Chugai/Roche, Janssen-Cilag, Eli Lilly, Novartis, Pfizer, Takeda (Shire). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gernert, Kiesel, Fröhlich, Renner, Strunz, Portegys, Tony, Schmalzing and Schwaneck.)

The 2-deoxy-d-[ 18 F]fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) is widely utilized to assess the vascular and articular inflammatory burden of patients with a suspected diagnosis of rheumatic disease. We aimed to elucidate the impact of [ 18 F]FDG PET/CT on change in initially suspected diagnosis in patients at the time of the scan. Thirty-four patients, who had undergone [ 18 F]FDG PET/CT, were enrolled and the initially suspected diagnosis prior to [ 18 F]FDG PET/CT was compared to the final diagnosis. In addition, a semi-quantitative analysis including vessel wall-to-liver (VLR) and joint-to-liver (JLR) ratios was also conducted. Prior to [ 18 F]FDG PET/CT, 22/34 (64.7%) of patients did not have an established diagnosis, whereas in 7/34 (20.6%), polymyalgia rheumatica (PMR) was suspected, and in 5/34 (14.7%), giant cell arteritis (GCA) was suspected by the referring rheumatologists. After [ 18 F]FDG PET/CT, the diagnosis was GCA in 19/34 (55.9%), combined GCA and PMR (GCA + PMR) in 9/34 (26.5%) and PMR in the remaining 6/34 (17.6%). As such, [ 18 F]FDG PET/CT altered suspected diagnosis in 28/34 (82.4%), including in all unclear cases. VLR of patients whose final diagnosis was GCA tended to be significantly higher when compared to VLR in PMR (GCA, 1.01 ± 0.08 (95%CI, 0.95-1.1) vs. PMR, 0.92 ± 0.1 (95%CI, 0.85-0.99), p = 0.07), but not when compared to PMR + GCA (1.04 ± 0.14 (95%CI, 0.95-1.13), p = 1). JLR of individuals finally diagnosed with PMR (0.94 ± 0.16, (95%CI, 0.83-1.06)), however, was significantly increased relative to JLR in GCA (0.58 ± 0.04 (95%CI, 0.55-0.61)) and GCA + PMR (0.64 ± 0.09 (95%CI, 0.57-0.71); p < 0.0001, respectively). In individuals with a suspected diagnosis of rheumatic disease, an inflammatory-directed [ 18 F]FDG PET/CT can alter diagnosis in the majority of the cases, particularly in subjects who were referred because of diagnostic uncertainty. Semi-quantitative assessment may be helpful in establishing a final diagnosis of PMR, supporting the notion that a quantitative whole-body read-out may be useful in unclear cases.

Objective: To investigate the efficacy and safety of rituximab + LEF in patients with RA., Methods: In this investigator-initiated, randomized, double-blind, placebo-controlled phase 3 trial, patients with an inadequate response to LEF who had failed one or more DMARD were randomly assigned 2:1 to i.v. rituximab 1000 mg or placebo on day 1 and 15 plus ongoing oral LEF. The primary efficacy outcome was the difference between ≥50% improvement in ACR criteria (ACR50 response) rates at week 24 (P ≤ 0.025). Secondary endpoints included ACR20/70 responses, ACR50 responses at earlier timepoints and adverse event (AE) rates. The planned sample size was not achieved due to events beyond the investigators' control., Results: Between 13 August 2010 and 28 January 2015, 140 patients received rituximab (n = 93) or placebo (n = 47) plus ongoing LEF. Rituximab + LEF resulted in an increase in the ACR50 response rate that was significant at week 16 (32 vs 15%; P = 0.020), but not week 24 (27 vs 15%; P = 0.081), the primary endpoint. Significant differences favouring the rituximab + LEF arm were observed in some secondary endpoints, including ACR20 rates from weeks 12 to 24. The rituximab and placebo arms had similar AE rates (71 vs 70%), but the rituximab arm had a higher rate of serious AEs (SAEs 20 vs 2%), primarily infections and musculoskeletal disorders., Conclusion: The primary endpoint was not reached, but rituximab + LEF demonstrated clinical benefits vs LEF in secondary endpoints. Although generally well tolerated, the combination was associated with additional SAEs and requires monitoring., Trial Registration: EudraCT: 2009-015950-39; ClinicalTrials.gov: NCT01244958., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Owing to increasing remission rates, the management of patients with rheumatoid arthritis in sustained remission is of growing interest. The Rheumatoid Arthritis in Ongoing Remission (RETRO) study investigated tapering and withdrawal of disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis in stable remission to test whether remission could be retained without the need to take DMARD therapy despite an absence of symptoms., Methods: RETRO was an investigator-initiated, multicentre, prospective, randomised, controlled, open-label, parallel-group phase 3 trial in patients aged at least 18 years with rheumatoid arthritis for at least 12 months before randomisation who were in sustained Disease Activity Score using 28 joints with erythrocyte sedimentation rate (ESR) remission (score <2·6 units). Eligible patients were recruited consecutively from 14 German hospitals or rheumatology practices and randomly assigned (1:1:1) without stratification and regardless of baseline treatment, using a sequence that was computer-generated by the study statistician, to continue 100% dose DMARD (continue group), taper to 50% dose DMARD (taper group), or 50% dose DMARD for 6 months before stopping DMARDs (stop group). Neither patients nor investigators were masked to the treatment assignment. Patients were assessed every 3 months and screened for disease activity and relapse. The primary endpoint was the proportion of patients in sustained DAS28-ESR remission without relapse at 12 months, analysed using a log-rank test of trend and Cox regression. Analysis by a trained statistician of the primary outcome and safety was done in a modified intention-to-treat population that included participants with non-missing baseline data. This study is completed and closed to new participants and is registered with ClinicalTrials.gov (NCT02779114)., Findings: Between May 26, 2010, and May 29, 2018, 303 patients were enrolled and allocated to continue (n=100), taper (n=102), or stop DMARDs (n=101). 282 (93%) of 303 patients were analysed (93 [93%] of 100 for continue, 93 [91%] of 102 for taper, and 96 [95%] of 101 for stop). Remission was maintained at 12 months by 81·2% (95% CI 73·3-90·0) in the continue group, 58·6% (49·2-70·0) in the taper group, and 43·3% (34·6-55·5) in the stop group (p=0·0005 with log-rank test for trend). Hazard ratios for relapse were 3·02 (1·69-5·40; p=0.0003) for the taper group and 4·34 (2·48-7·60; p<0.0001)) for the stop group, in comparison with the continue group. The majority of patients who relapsed regained remission after reintroduction of 100% dose DMARDs. Serious adverse events occurred in ten of 93 (11%) patients in the continue group, seven of 93 (8%) patients in taper group, and 13 of 96 (14%) patients in the stop group. None were considered to be related to the intervention. The most frequent type of serious adverse event was injuries or procedural complications (n=9)., Interpretation: Reducing antirheumatic drugs in patients with rheumatoid arthritis in stable remission is feasible, with maintenance of remission occurring in about half of the patients. Because relapse rates were significantly higher in patients who tapered or stopped antirheumatic drugs than in patients who continued with a 100% dose, such approaches will require tight monitoring of disease activity. However, remission was regained after reintroduction of antirheumatic treatments in most of those who relapsed in this study. These results might help to prevent overtreatment in a substantial number of patients with rheumatoid arthritis., Funding: None., Competing Interests: Declaration of interests KT reports payments for lectures from Gilead and Union Chimique Belge. BM reports consulting fees from MSD and Novartis and payments for lectures from AbbVie, Roche, Pfizer, MSD, Janssen, and Sanofi. SF reports payments for lectures from Amgen, Lilly, Novartis, Pfizer, Roche, and Union Chimique Belge; support for attending meetings from AbbVie, Amgen, Novartis, Pfizer, Roche, and Union Chimique Belge; and Advisory Board participation for Novartis and Amgen. SK reports payments for lectures from Celgene and AbbVie. MFl reports payments for lectures from Actelion, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Chugai Pharmaceutical, Janssen, Medac, Novartis, Pfizer, and Roche. RA reports grants from AbbVie, Bristol Myers Squibb, Celltrion, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, and Roche; payments for lectures from AbbVie, Bristol Myers Squibb, Celltrion, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, and Roche; and Advisory Board participation for AbbVie, Bristol Myers Squibb, Celltrion, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, and Roche. JH reports payments for lectures from AbbVie, Actelion, Bristol Myers Squibb, Boehringer Ingelheim, Janssen, Lilly, Novartis, Pfizer, Roche, Swedish Orphan Biovitrum, and Union Chimique Belge; support for attending meetings from AbbVie, Boehringer Ingelheim, Janssen, Lilly, Novartis, and Union Chimique Belge; and Advisory Board participation for AbbVie, Actelion, Boehringer Ingelheim, Janssen, Novartis Pfizer, and Swedish Orphan Biovitrum. GS reports consulting fees from Lilly, Janssen, and Novartis and payments for lectures from AbbVie, Bristol Myers Squibb, Lilly, Gilead, Janssen, Novartis, Pfizer, and Union Chimique Belge. JR reports consulting fees from AbbVie, Biogen, Bristol Myers Squibb, Chugai Pharmaceutical, Lilly, GlaxoSmithKline, Jannsen, MSD, Novartis, Roche, Sanofi, and Union Chimique Belge and payments for lectures from AbbVie, Biogen, Bristol Myers Squibb, Chugai Pharmaceutical, Lilly, GlaxoSmithKline, Jannsen, MSD, Novartis, Roche, Sanofi, and Union Chimique Belge. All other authors declare no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

To determine the prevalence of clonal T-large granular lymphocyte (T-LGL) cells in patients with spondyloarthritis (SpA) and psoriatic arthritis (PsA) and to define possible risk factors for this condition. We present a cross-sectional analysis with retrospective and prospective aspects. 115 SpA patients, 48 PsA patients and 51 controls were recruited between December 28, 2017 and January 23, 2019. Flow cytometry (FACS) was performed to screen for aberrant T-LGL cells. Molecular analysis was then employed to confirm the diagnosis in patients with suggestive FACS findings. Patients with clonal T-LGL populations were followed prospectively by FACS analysis. Electronic patient files were retrospectively analyzed to determine risk factors. Median age was 49 years for SpA, 55.5 years for PsA, and 54 years for controls. Median disease duration of SpA and PsA was 15 years and 11 years, respectively. 79.8% of patients had received biologics at some point, 75.5% had ever received tumor necrosis factor (TNF) inhibitors. 59.5% were treated with TNF inhibitors at the time of study inclusion. We identified clonal T-LGL expansions in 13 individuals equaling a prevalence of 6% (13/214). T-LGL patients were taking TNF inhibitors more frequently at the time of study inclusion (p = 0.022) and were more likely to have ever been treated with TNF inhibition (p = 0.046). Clonal T-LGL expansions can be detected in patients with SpA, PsA and also in healthy controls. Confirming earlier results, exposure to TNFα-blocking agents appears to increase the risk of developing clonal expansions of T-LGL cells., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Autologous hematopoietic stem cell transplantation (aHSCT) represents an effective treatment for systemic sclerosis (SSc), but it also can cause immunological adverse events (iAEs). Therefore, we aimed to determine the frequency of iAEs [engraftment syndrome (ES) and secondary autoimmune disorder (sAD)] and to identify potential risk factors for their development in a retrospective analysis on 22 patients similarly transplanted due to SSc. While nine patients (41%) suffered from ESs, seven sADs occurred in six patients (27%). Patients who developed ES were older in our cohort (52.45 vs. 42.58 years, p = .0433, Cohen's d = 0.86), and cardiac involvement by SSc was associated with development of ES (OR = 40.11, p = .0017). Patients with manifestation of sAD had a higher modified Rodnan skin score (mRSS) reduction after aHSCT (90.50% vs. 60.00%, p = .0064, r = .65). Thus, IAEs are common after aHSCT for SSc and can occur in different stages during and after aHSCT with characteristic clinical manifestations. Good cutaneous response after aHSCT might be considered as a risk factor for sAD, and higher age at aHSCT and cardiac involvement might be considered as risk factors for the development of ES., Competing Interests: P-PS received travel grants from Janssen-Cilag and AbbVie. MF reported travel grants from AbbVie, Novartis, Janssen, and Eli Lilly and compensation for board memberships from AbbVie. MG received travel grants from AbbVie, Chugai, Eli Lilly, Hexal, Janssen-Cilag, Novartis, and Pfizer. Janssen, Eli Lilly, Chugai, Roche, Takeda (Shire), AbbVie, and Novartis supported ES. H-PT received speaker’s fees, travel grants, research funding, or compensation for consultancies or board memberships from AbbVie, BMS, Chugai/Roche, Eli Lilly, Gilead, Janssen, Novartis, Sandoz/Hexal, Sanofi Aventis, and Takeda (Shire). JH reported speaker’s fees, travel grants, and research funding from AbbVie, BMS, Boehringer/Ingelheim, Celgene, Chugai/Roche, Eli Lilly, Janssen-Cilag, Novartis, SOBI, Pfizer, and UCB. MS received speaker’s fees, travel grants, research funding, or compensation for consultancies or board memberships from AbbVie, Actelion, AstraZeneca, BMS, Boehringer/Ingelheim, Celgene, Chugai/Roche, Eli Lilly, Genzyme, Gilead, Hexal/Sandoz, Janssen-Cilag, MSD, Novartis, Pfizer, Sanofi Pasteur, Takeda (Shire), and UCB (less than $10,000 each). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Strunz, Froehlich, Gernert, Schwaneck, Fleischer, Pecher, Tony, Henes and Schmalzing.)