Risk of major adverse cardiovascular events in patients with rheumatoid arthritis treated with conventional synthetic, biologic and targeted synthetic disease-modifying antirheumatic drugs: observational data from the German RABBIT register.

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.

Subcutaneous abatacept for the treatment of rheumatoid arthritis in routine clinical practice in Germany, Austria, and Switzerland: 2-year retention and efficacy by treatment line and serostatus.

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.

Physical Function of RA patients Tapering Treatment-A Post Hoc Analysis of the Randomized Controlled RETRO Trial.

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.

The efficacy and safety of systemic corticosteroids as first line treatment for granulomatous lymphocytic interstitial lung disease.

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.

[Apps in rheumatology : Is there a need for an app in therapy for axial spondyloarthritis?] / Apps in der Rheumatologie : Bedarf es einer App in der Therapie der axialen Spondyloarthritis?

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.

Safety and efficacy of secukinumab in patients with giant cell arteritis (TitAIN): a randomised, double-blind, placebo-controlled, phase 2 trial.

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.

Effectiveness of Different Rituximab Doses Combined with Leflunomide in the Treatment or Retreatment of Rheumatoid Arthritis: Part 2 of a Randomized, Placebo-Controlled, Investigator-Initiated Clinical Trial (AMARA).

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.

Clinical Utility of C-Reactive Protein and White Blood Cell Count for Scheduling an [18F]FDG PET/CT in Patients with Giant Cell Arteritis.

OBJECTIVES: 2-deoxy-2-[18F]fluoro-D-glucose ([18F]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 [18F]FDG scan. METHODS: 18 treatment-naïve GCA patients and 14 GCA subjects with anti-inflammatory treatment (glucocorticoids or comparable drugs), who underwent [18F]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, TBRVJ was 2.3±1.1 (95%CI, 2.2-2.5), TBRliver was 1.0±0.5 (95%CI, 0.9-1.0) and average TBRlung was 6.3±3.6 (95%CI, 5.8-6.8). No significant correlation was noted for either CRP (TBRVJ: R=-0.19; TBRliver: R=-0.03; TBRlung: R=-0.17; each P ≥ 0.44) or for WBC (TBRVJ: R=-0.40; TBRliver: R=-0.32; TBRlung: 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 (TBRVJ: R=-0.17; TBRliver: R=-0.28; TBRlung: R=-0.09; each P ≥ 0.32) or WBC (TBRVJ: R=-0.06; TBRliver: R=-0.13; TBRlung: 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 [18F]FDG PET/CT.

Calprotectin (S100A8/S100A9) detects inflammatory activity in rheumatoid arthritis patients receiving tocilizumab therapy.

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.

Responses to Ixekizumab in Male and Female Patients with Psoriatic Arthritis: Results from Two Randomized, Phase 3 Clinical Trials.

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.

Sarilumab reduces disease activity in rheumatoid arthritis patients with inadequate response to janus kinase inhibitors or tocilizumab in regular care in Germany.

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 safety and effectiveness of tocilizumab in elderly patients with rheumatoid arthritis and in patients with comorbidities associated with age.

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.

Lymphocyte subsets in the peripheral blood are disturbed in systemic sclerosis patients and can be changed by immunosuppressive medication.

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.

High Prevalence of Genital Human Papillomavirus Infection in Patients With Primary Immunodeficiencies.

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.

Whole-Body [18F]FDG PET/CT Can Alter Diagnosis in Patients with Suspected Rheumatic Disease.

The 2-deoxy-d-[18F]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 [18F]FDG PET/CT on change in initially suspected diagnosis in patients at the time of the scan. Thirty-four patients, who had undergone [18F]FDG PET/CT, were enrolled and the initially suspected diagnosis prior to [18F]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 [18F]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 [18F]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, [18F]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 [18F]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.

Immunological Adverse Events After Autologous Hematopoietic Stem Cell Transplantation in Systemic Sclerosis Patients.

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.

Efficacy and safety of secukinumab in patients with giant cell arteritis: study protocol for a randomized, parallel group, double-blind, placebo-controlled phase II trial.

BACKGROUND: One key pathological finding in giant cell arteritis (GCA) is the presence of interferon-gamma and interleukin (IL)-17 producing T helper (Th) 1 and Th17 cells in affected arteries. There is anecdotal evidence of successful induction and maintenance of remission with the monoclonal anti-IL-17A antibody secukinumab. Inhibition of IL-17A could therefore represent a potential new therapeutic option for the treatment of GCA. METHODS: This is a randomized, parallel-group, double-blind, placebo-controlled, multi-center, phase II study in which patients, treating physicians, and the associated clinical staff as well as the sponsor clinical team are blinded. It is designed to evaluate efficacy and safety of secukinumab compared to placebo in combination with an open-label prednisolone taper regimen. Patients included are naïve to biological therapy and have newly diagnosed or relapsing GCA. Fifty patients are randomly assigned in a 1:1 ratio to receive either 300 mg secukinumab or placebo subcutaneously at baseline, weeks 1, 2 and 3, and every 4 weeks from week 4. Patients in both treatment arms receive a 26-week prednisolone taper regimen. The study consists of a maximum 6-week screening period, a 52-week treatment period (including the 26-week tapering), and an 8-week safety follow-up, with primary and secondary endpoint assessments at week 28. Patients who do not achieve remission by week 12 experience a flare after remission or cannot adhere to the prednisolone tapering will enter the escape arm and receive prednisolone at a dose determined by the investigator's clinical judgment. The blinded treatment is continued. Two optional imaging sub-studies are included (ultrasound and contrast-media enhanced magnetic resonance angiography [MRA]) to assess vessel wall inflammation and occlusion before and after treatment. The primary endpoint is the proportion of patients in sustained remission until week 28 in the secukinumab group compared to the proportion of patients in the placebo group. A Bayesian approach is applied. DISCUSSION: The trial design allows the first placebo-controlled data collection on the efficacy and safety of secukinumab in patients with GCA. TRIAL REGISTRATION: ClinicalTrials.gov NCT03765788 . Registration on 5 December 2018, prospective registration, EudraCT number 2018-002610-12; clinical trial protocol number CAIN457ADE11C.

Induction of IL-9 in Peripheral Lymphocytes of Rheumatoid Arthritis Patients and Healthy Donors by Th17-Inducing Cytokine Conditions.

IL-9-producing Th9 cells display a group of helper T cells with similarities to Th17 and Th2 T cells and have been shown to be involved in synovial inflammation in rheumatoid arthritis (RA) patients. So far, it is unclear which parameters drive Th9 differentiation in lymphocytes derived from RA patients compared to immunologically healthy individuals and whether autocrine mechanisms are able to enhance Th9 polarization. Further, parallel pathways of induction of IL-17-producing cells with Th9 phenotype have to be distinguished from exclusively Th9-inductive mechanisms. Thus, the present study aimed to determine the parameters of Th9 induction by simulation in a standardized inflammatory cytokine milieu.Peripheral naive and non-naive T cells of RA patients and healthy donors (HD) were cultured under Th9 and Th17-driving conditions and phenotypically analyzed by flow cytometry and molecular analysis.Our findings indicate a similar differentiation pathway of Th9 and Th17 cells and similar distributions of IL-9+ T cells in RA and HD regardless of Th9- or Th17-promoting cytokine milieus. Whereas the magnitude and direction of Th9- or Th17-polarization was about the same in RA and HD, IL-17+ CD4+ T cells were significantly stimulated by Th17-inducing conditions in HD. In conclusion, the results indicate that Th9- and Th17-inducing cytokine conditions mimicking autoimmune inflammation in RA may have similar stimulatory effects regarding polarization of peripheral naive and non-naive T cells into Th9 or Th17 cells. The results suggest that the differentiation of Th9 cells may be also induced by Th17-driving conditions.

Clonal expansion of large granular lymphocytes in patients with spondyloarthritis and psoriatic arthritis treated with TNFα inhibitors.

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.