Impact of DMARD treatment and systemic inflammation on all-cause mortality in patients with rheumatoid arthritis and interstitial lung disease: a cohort study from the German RABBIT register.

OBJECTIVES: To investigate the impact of disease activity and treatment with disease-modifying antirheumatic drugs (DMARDs) on all-cause mortality in patients with rheumatoid arthritis and prevalent interstitial lung disease (RA-ILD). METHODS: Patients with RA-ILD were selected from the biologics register Rheumatoid Arthritis: Observation of Biologic Therapy (RABBIT). Using time-varying Cox regression, the association between clinical measures and mortality was investigated. The impact of DMARDs was analysed by (1) Cox regression considering cumulative exposure (ie, treatment months divided by total months) and (2) time-varying Cox regression as main approach (treatment exposures at monthly level). RESULTS: Out of 15 566 participants, 381 were identified as RA-ILD cases with 1258 person-years of observation and 2.6 years median length of follow-up. Ninety-seven patients (25.5%) died and 34 (35.1%) of these were not receiving DMARD therapy at the time of death. Higher inflammatory biomarkers but not swollen and tender joint count were significantly associated with mortality. Compared with tumour necrosis factor inhibitors (TNFi), non-TNFi biologic DMARDs (bDMARDs) exhibited adjusted HRs (aHRs) for mortality below 1, lacking statistical significance. This finding was stable in various sensitivity analyses. Joint aHR for non-TNFi biologics and JAKi versus TNFi was 0.56 (95% CI 0.33 to 0.97). Receiving no DMARD treatment was associated with a twofold higher mortality risk compared with receiving any DMARD treatment, aHR 2.03 (95% CI 1.23 to 3.35). CONCLUSIONS: Inflammatory biomarkers and absence of DMARD treatment were associated with increased risk of mortality in patients with RA-ILD. Non-TNFi bDMARDs may confer enhanced therapeutic benefits in patients with RA-ILD.

Real-world experience with filgotinib for rheumatoid arthritis in Germany : A retrospective chart review.

BACKGROUND: Real-world data for filgotinib, a Janus kinase (JAK)1 inhibitor, are limited in patients with rheumatoid arthritis (RA). OBJECTIVES: To explore real-world filgotinib use in patients with RA in Germany. MATERIALS AND METHODS: This retrospective chart review included patients aged ≥ 18 years with confirmed moderate to severe RA who initiated filgotinib before December 1, 2021, with ≥ 6 months of medical records available prior to filgotinib initiation or after initial diagnosis. Patient characteristics, prior treatments, reasons for initiating/discontinuing filgotinib, disease activity, dose adjustments and concomitant treatments were recorded. RESULTS: In total, 301 patients from 20 German rheumatology outpatient units were included. One-third were aged ≥ 65 years and almost half had ≥ 1 cardiovascular (CV) risk factor. Most patients initiated filgotinib as monotherapy (83.7%; 12.7% of whom with glucocorticoids) and at the 200 mg dose (84.7%); higher proportions of those initiating the 100 versus 200 mg dose were aged ≥ 65 years and had renal impairment or ≥ 1 CV risk factor. Oral administration (78.4%), fast onset of action (66.8%) and administration as monotherapy (65.4%) were the most common reasons for initiating filgotinib. At 12 months, 41 (18.4%) patients had discontinued filgotinib, most commonly due to lack of effectiveness. After 6­months of follow-up, 36.8% of patients had achieved Clinical Disease Activity Index (CDAI) remission and 45.6% had achieved CDAI low disease activity. CONCLUSIONS: In clinical practice in Germany, reasons for initiating filgotinib in patients with RA were related to dosing flexibility and general JAK inhibitor attributes. Filgotinib was used predominantly as monotherapy and was effective and generally well tolerated; however, longer-term data in larger, prospective cohorts are needed.

[Infection prophylaxis in rheumatic diseases]. / Infektionsprophylaxe bei rheumatologischen Erkrankungen.

Infections affect morbidity and mortality of patients suffering from rheumatic diseases in an important way. Risk of infection is influenced generally by age and existing comorbidities as well as especially by activity of the rheumatic disease and immunosuppressive treatment. Correspondingly best possible reduction of disease activity and elimination or at least successful treatment of comorbidities are able to reduce infection risk. Patients at high risk of infection should be identified and be monitored in an intensified way. Furthermore risk is influenced by antirheumatic treatment, e.g. enhanced by long-term glucocorticoid treatment, reduced by optimisied use of disease-modifying antirheumatic drugs leading to best possible disease control. Finally protective antibiotic or antiviral treatment (e.g. in case of latent tuberculosis or hepatitis) as well as optimised vaccination status are able to reduce risk of infection further.

[Rheumatic diseases and vaccination]. / Rheuma und Impfen.

Recommendations for vaccination of patients with rheumatic Diseases. Patients with rheumatic diseases are particularly at risk from infections. Vaccinations are suitable to reduce this risk. Current Recommendations of national (STIKO and Wagner et al.) and international committees (EULAR) provide a basis for the secure and effective use of vaccinations.Important new developments, such as sequential vaccination against pneumococcus or the approval of a vaccine against Herpes Zoster, improve the possibilities of an effective infection protection. Special attention must be paid to the current recommendations for the use of live vaccines like MMR vaccination in patients under immunosuppressive therapy.

New insights into the prevalence of depressive symptoms and depression in rheumatoid arthritis - Implications from the prospective multicenter VADERA II study.

OBJECTIVES: To investigate the prevalence of depressive symptoms in rheumatoid arthritis (RA) patients using two previously validated questionnaires in a large patient sample, and to evaluate depressive symptoms in the context of clinical characteristics (e.g. remission of disease) and patient-reported impact of disease. METHODS: In this cross-sectional study, the previously validated Patient Health Questionnaire (PHQ-9) and Beck-Depression Inventory II (BDI-II) were used to assess the extent of depressive symptoms in RA patients. Demographic background, RA disease activity score (DAS28), RA impact of disease (RAID) score, comorbidities, anti-rheumatic therapy and antidepressive treatment, were recorded. Cut-off values for depressive symptomatology were PHQ-9 ≥5 or BDI-II ≥14 for mild depressive symptoms or worse and PHQ-9 ≥ 10 or BDI-II ≥ 20 for moderate depressive symptoms or worse. Prevalence of depressive symptomatology was derived by frequency analysis while factors independently associated with depressive symptomatology were investigated by using multiple logistic regression analyses. Ethics committee approval was obtained, and all patients provided written informed consent before participation. RESULTS: In 1004 RA-patients (75.1% female, mean±SD age: 61.0±12.9 years, mean disease duration: 12.2±9.9 years, DAS28 (ESR): 2.5±1.2), the prevalence of depressive symptoms was 55.4% (mild or worse) and 22.8% (moderate or worse). Characteristics independently associated with depressive symptomatology were: age <60 years (OR = 1.78), RAID score >2 (OR = 10.54) and presence of chronic pain (OR = 3.25). Of patients classified as having depressive symptoms, only 11.7% were receiving anti-depressive therapy. CONCLUSIONS: Mild and moderate depressive symptoms were common in RA patients according to validated tools. In routine clinical practice, screening for depression with corresponding follow-up procedures is as relevant as incorporating these results with patient-reported outcomes (e.g. symptom state), because the mere assessment of clinical disease activity does not sufficiently reflect the prevalence of depressive symptoms. CLINICAL TRIAL REGISTRATION NUMBER: This study is registered in the Deutsches Register Klinischer Studien (DRKS00003231) and ClinicalTrials.gov (NCT02485483).

Tuberculosis and Takayasu arteritis: case-based review.

This report presents a case of co-occurrence of Takayasu arteritis (TA) and multiorgan tuberculosis (TB) in a 20-year-old female and provides a review of 18 previously reported cases of co-occurring TA and TB. All patients were between 9 and 24 years of age. Most reports describe a concomitant diagnosis of active TB and TA. TB lymphadenitis was described in 11 cases (57.9%), and microbiologically confirmed in 4 of these. All patients received antituberculous therapy and most received corticosteroids (89.5%). In our and two other cases, TA relapses necessitating additional immunosuppressive therapy were observed.

Spine Fractures in Ankylosing Diseases: Recommendations of the Spine Section of the German Society for Orthopaedics and Trauma (DGOU).

STUDY DESIGN: Review of literature and case series. OBJECTIVES: Update and review of current treatment concepts for spine fractures in patients with ankylosing spinal disorders. METHODS: Case presentation and description of a diagnostic and therapeutic algorithm for unstable spinal injuries with an underlying ankylosing spinal disorder (ASD) of the cervical and thoracolumbar spine. RESULTS: Nondisplaced fractures can be missed easily using conventional X-rays. Thus, computed tomography (CT) scans are recommended for all trauma patients with ASD. In doubt or presence of any neurologic involvement additional magnetic resonance imaging (MRI) scans should be obtained. Spine precautions should be maintained all times and until definitive treatment (<24 h). Nonoperative fracture treatment is not recommended given the mechanical instability of the most commonly seen fracture patterns (AOSpine B- and C-type, M2) in patients with ASD and inherent high risk of secondary neurologic deterioration. For patients with ankylosing spondylitis (AS) or diffuse idiopathic hyperostosis (DISH) sustaining cervical spine fractures, a combined anterior-posterior instrumentation for fracture fixation is recommended. Closed reduction and patient positioning can be challenging in presence of preexisting kyphotic deformities. In the thoracolumbar (TL) spine, a posterior instrumentation extending 2 to 3 levels above and below the fracture level is recommended to maintain adequate reduction and stability until fracture healing. Minimally invasive percutaneous pedicle screws and cement augmentation can help to minimize the surgical trauma and strengthen the construct stability in patients with diminished minor bone quality (osteopenia, osteoporosis). CONCLUSIONS: Current concepts, treatment options, and recommendations of the German Orthopedic Trauma Society-Spine Section for spinal fractures in the ankylosed spine have been outlined.

Decreased IgG4 ACPA levels in responders and increased CD1c+ classical dendritic cells in non-responders of patients with rheumatoid arthritis under therapy.

The treatment options for patients suffering from rheumatoid arthritis expanded over the last years. However, reliable biomarkers to guide therapy decisions are still warranted. Therefore, we here evaluated the value of antibodies against citrullinated peptide antigens (ACPA) IgG subclasses and peripheral blood antigen presenting cells as biomarkers to monitor and predict therapy response of patients with rheumatoid arthritis. Thirty-four ACPA-positive RA patients were enrolled and monitored for 3 months after therapy begin. ACPA IgG1 and IgG4 serum levels were quantified by ELISA. Phenotyping of the B cell, monocytic, and dendritic cell lineages was performed via flow cytometry. Three months after therapy begin, the responders showed a significant decrease in IgG4 ACPA levels, and this was independent of the individual treatment regimen. The non-responders showed a significant increase in CD1c+ classical dendritic cells (cDC). Furthermore, the baseline disease activity score 28 and the baseline percentage of cDC allowed for some prediction of future therapy responses. We here suggest IgG4 ACPA levels as biomarkers to monitor therapy response in RA. The increase in CD1c+ cDC among non-responders to therapy remains enigmatic and requires future elucidation of the underlying mechanisms.

Selective blood sampling for FGF-23 in tumor-induced osteomalacia.

Tumor-induced osteomalacia (TIO) is caused by the hormone fibroblast growth factor 23 (FGF-23). It is mainly produced in the tissue of mesenchymal tumors. Patients with TIO frequently suffer from a chronic decompensated pain syndrome and/or muscle weakness with postural deformity. Despite the severity of the disease, the diagnosis is frequently established late. In some cases, it takes several years to establish the condition. This case report concerning a 68-year old woman demonstrates the selective blood sampling for FGF-23 as path-breaking diagnostics to confirm the diagnosis of a neuroendocrine tumor. LEARNING POINTS: Tumor-induced osteomalacia is a rare condition compared to other paraneoplastic syndromes.It causes complex symptoms such as progressive reduction of physical capacity, exhaustion, fatigue, a decompensated pain syndrome of the musculoskeletal system and fractures of several bones.Elevated serum levels of FGF-23 implicate massive phosphate elimination and resulting hypophosphatemia.The diagnosis is often established over a period of several years because the localization of small FGF-23-producing tumors is complicated.It is the combination of MRI and selective blood sampling for FGF-23 which permits reliable identification of tumors causing TIO and leads to accurate localization.In a patient with generalized pain and reduced physical capacity, osteological parameters such as phosphate, 25-OH vitamin D3 and 1,25-(OH)2D3, as well as bone-specific alkaline phosphatase levels in serum should be determined. Hypophosphatemia should always lead to further diagnostic investigations aiming at the detection of an FGF-23-producing tumor.

Validation of Standardized Questionnaires Evaluating Symptoms of Depression in Rheumatoid Arthritis Patients: Approaches to Screening for a Frequent Yet Underrated Challenge.

OBJECTIVE: To validate standard self-report questionnaires for depression screening in patients with rheumatoid arthritis (RA) and compare these measures to one another and to the Montgomery-Åsberg Depression Rating Scale (MADRS), a standardized structured interview. METHODS: In 9 clinical centers across Germany, depressive symptomatology was assessed in 262 adult RA patients at baseline (T0) and at 12 ± 2 weeks followup (T1) using the World Health Organization 5-Item Well-Being Index (WHO-5), the Patient Health Questionnaire (PHQ-9), and the Beck Depression Inventory II (BDI-II). The construct validity of these depression questionnaires (using convergent and discriminant validity) was evaluated using Spearman's correlations at both time points. The test-retest reliability of the questionnaires was evaluated in RA patients who had not undergone a psychotherapeutic intervention or received antidepressants between T0 and T1. The sensitivity and the specificity of the questionnaires were calculated using the results of the MADRS, a structured interview, as the gold standard. RESULTS: According to Spearman's correlation coefficients, all questionnaires met convergent validity criteria (ρ > |0.50|), with the BDI-II performing best, while correlations with age and disease activity for all questionnaires met the criteria for discriminant validity (ρ < |0.50|). The only questionnaire to meet the predefined retest reliability criterion (ρ ≥ 0.70) was the BDI-II (rs = 0.77), which also achieved the best results for both sensitivity and specificity (>80%) when using the MADRS as the gold standard. CONCLUSION: The BDI-II best met the predefined criteria, and the PHQ-9 met most of the validity criteria, with lower sensitivity and specificity.

The presence of FCGR2B promoter or transmembrane region variant alleles leads to reduced serum IL-6 levels in rheumatoid arthritis.

The inhibitory FcγRIIB plays an important role for the peripheral B cell tolerance and plasma cell homeostasis, and any malfunctioning is predicted to result in humoral autoimmunity. An association between rheumatoid arthritis (RA) and FCGR2B promoter and TM region variant alleles, both of which result in a reduced functionality, is only insufficiently elucidated. We here set out to investigate the impact of these variants on disease progression in European RA patients. One hundred and five ACPA-positive RA patients were genotyped for the FCGR2B -386G>C promoter and the 695T>C transmembrane region variants. Moreover, serum titers for IL-6, TNFα, CTX-1 and ACPAs were measured and peripheral blood T cell and B cell populations analyzed for expression of the activation markers CTLA-4 and CD86. The presence of an FCGR2B variant allele results in reduced serum IL-6, a trend toward later disease onset and reduced requirement for biological treatment, but does not seem to aggravate RA. Likewise, the presence of the TM region variant allele is associated with a lower activation state of the Tregs and of naïve and memory B cells. The observation of a malfunctioning FcγRIIb not aggravating RA is counterintuitive at first. However, the etiology of RA is linked to inflammatory episodes, and the lack of B cell inhibition may support an accelerated antibody-mediated clearance of the disease initiating and perpetuating agents. It would thereby shorten inflammatory episodes, postpone the onset of disease and result in a less severe course of RA in carriers of FCGR2B variant alleles.

Bone resorption correlates with the frequency of CD5⁺ B cells in the blood of patients with rheumatoid arthritis.

OBJECTIVE: The prevention of bone resorption and subsequent joint destruction is one of the main challenges in the treatment of patients suffering from RA. Various mechanisms have previously been described that contribute to bone resorption in tightly defined cohorts. Here we analysed a cross-sectional cohort of RA patients and searched for humoral and cellular markers in the peripheral blood associated with bone resorption. METHODS: We enrolled 61 consecutive RA patients positive for ACPA. Blood was analysed by flow cytometry to determine the percentages of regulatory T cells and B cell subpopulations. Cytokine (TNF-α, IL-6, IL-10) and ACPA levels as well as the bone resorption marker CTX-1 were determined from the patients' sera. Standard clinical disease parameters were included. RESULTS: Multivariate analyses showed that the percentages of CD5(+) B cells were positively correlated with CTX-1 serum levels. However, neither low-avidity ACPA nor serum IL-6 levels, both known to be produced by CD5(+) cells, were associated with CTX-1 in patients' sera. There was no correlation between CTX-1 levels and clinical parameters or ACPA levels. CONCLUSION: In summary, we found that the CD5(+) B cell population is associated with bone resorption as measured via serum CTX-1 levels in a cross-sectional cohort of RA patients. However, a possible functional link between CD5(+) B cells and bone resorption still needs to be defined.

Soluble and transmembrane TNF-like weak inducer of apoptosis differentially activate the classical and noncanonical NF-kappa B pathway.

TNF-like weak inducer of apoptosis, TWEAK, is a typical member of the TNF ligand family. Thus, it is initially expressed as a type II transmembrane protein from which a soluble variant can be released by proteolytic processing. In this study, we show that membrane TWEAK is superior to soluble variant of TWEAK (sTWEAK) with respect to the activation of the classical NF-kappaB pathway, whereas both TWEAK variants are potent inducers of TNFR-associated factor-2 depletion, NF-kappaB-inducing kinase accumulation and p100 processing, hallmarks of activation of the noncanonical NF-kappaB pathway. Like other soluble TNF ligands with a poor capability to activate their corresponding receptor, sTWEAK acquires an activity resembling those of the transmembrane ligand by oligomerization or cell surface-immobilization. Blockade of the Fn14 receptor inhibited NF-kappaB signaling irrespective of the TWEAK form used for stimulation, indicating that the differential activities of the two TWEAK variants on classical and noncanonical NF-kappaB signaling is not related to the use of different receptors.

Membrane tumor necrosis factor (TNF) induces p100 processing via TNF receptor-2 (TNFR2).

Tumor necrosis factor (TNF) elicits its biological activities by stimulation of two receptors, TNFR1 and TNFR2, both belonging to the TNF receptor superfamily. Whereas TNFR1-mediated signal transduction has been intensively studied and is understood in detail, especially with respect to activation of the classical NFkappaB pathway, cell death induction, and MAP kinase signaling, TNFR2-associated signal transduction is poorly defined. Here, we demonstrate in various tumor cell lines and primary T-cells that TNFR2, but not TNFR1, induces activation of the alternative NFkappaB pathway. In accord with earlier findings demonstrating that only membrane TNF, but not soluble TNF, properly activates TNFR2, we further show by use of TNFR1- and TNFR2-specific mutants of soluble TNF and membrane TNF that soluble ligand trimers fail to activate the alternative NFkappaB pathway. In accord with the known inhibitory role of TRAF2 in the alternative NFkappaB pathway, TNFR2-, but not TNFR1-specific TNF induced depletion of cytosolic TRAF2. Thus, we identified activation of the alternative NFkappaB pathway as a TNF signaling effect that can be specifically assigned to TNFR2 and membrane TNF.