Mother of all bonds: Influences on spatial association across the lifespan in capuchins.

In humans, being more socially integrated is associated with better physical and mental health and/or with lower mortality. This link between sociality and health may have ancient roots: sociality also predicts survival or reproduction in other mammals, such as rats, dolphins, and non-human primates. A key question, therefore, is which factors influence the degree of sociality over the life course. Longitudinal data can provide valuable insight into how environmental variability drives individual differences in sociality and associated outcomes. The first year of life-when long-lived mammals are the most reliant on others for nourishment and protection-is likely to play an important role in how individuals learn to integrate into groups. Using behavioral, demographic, and pedigree information on 376 wild capuchin monkeys (Cebus imitator) across 20 years, we address how changes in group composition influence spatial association. We further try to determine the extent to which early maternal social environments have downstream effects on sociality across the juvenile and (sub)adult stages. We find a positive effect of early maternal spatial association, where female infants whose mothers spent more time around others also later spent more time around others as juveniles and subadults. Our results also highlight the importance of kin availability and other aspects of group composition (e.g., group size) in dynamically influencing spatial association across developmental stages. We bring attention to the importance of-and difficulty in-determining the social versus genetic influences that parents have on offspring phenotypes. RESEARCH HIGHLIGHTS: Having more maternal kin (mother and siblings) is associated with spending more time near others across developmental stages in both male and female capuchins. Having more offspring as a subadult or adult female is additionally associated with spending more time near others. A mother's average sociality (time near others) is predictive of how social her daughters (but not sons) become as juveniles and subadults (a between-mother effect). Additional variation within sibling sets in this same maternal phenotype is not predictive of how social they become later relative to each other (no within-mother effect).

Serum Uric Acid Associates with Systemic Complement C3 Activation in Severe ANCA-Associated Renal Vasculitides.

Involvement of the complement system is key to the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis, but immunometabolic implications, especially on serum uric acid (UA) levels, still need to be elucidated. A total of 34 patients with biopsy-proven ANCA-associated renal vasculitis between 2015 and 2020 were retrospectively enrolled. Serum UA levels were correlated with clinical and histopathological characteristics, separated for critically ill (CI, n = 19), myeloperoxidase (MPO)-ANCA (n = 21) and proteinase 3 (PR3)-ANCA (n = 13) subgroups. We here identified inverse correlations of serum UA levels and complement C3 levels in the total cohort (p = 0.005) and the CI subgroup (p < 0.001). Intrarenal complement C4d deposition in venules correlated with serum UA levels in the total cohort (p = 0.007) and in the CI subgroup (p = 0.016). Significant associations of serum UA levels and tubulitis in areas of scarred cortex (t-IFTA) were identified in the total cohort (p = 0.008), and both subgroups of CI (p = 0.034) and MPO-ANCA (p = 0.029). In PR3-ANCA, interstitial fibrosis (ci) was observed as the strongest association with serum UA levels (p = 0.022). Our observations broaden our current understanding of contributory metabolic factors that influence the initial disease course in ANCA-associated renal vasculitis.

[Therapeutic Pathways in Sarcoidosis. A Position Paper of the German Society of Respiratory Medicine (DGP)]. / Therapie der Sarkoidose. Ein Positionspapier der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin (DGP).

The present recommendations on the therapy of sarcoidosis of the German Respiratory Society (DGP) was written in 2023 as a German-language supplement and update of the international guidelines of the European Respiratory Society (ERS) from 2021. It contains 5 PICO questions (Patients, Intervention, Comparison, Outcomes) agreed in the consensus process, which are explained in the background text of the four articles: Confirmation of diagnosis and monitoring of the disease under therapy, general therapy recommendations, therapy of cutaneous sarcoidosis, therapy of cardiac sarcoidosis.

Anti-acid therapy in SSc-associated interstitial lung disease: long-term outcomes from the German Network for Systemic Sclerosis.

OBJECTIVES: Gastroesophageal reflux disease (GERD) occurs frequently in patients with SSc. We investigated whether the presence of GERD and/or the use of anti-acid therapy, specifically proton-pump inhibitors (PPIs), are associated with long-term outcomes, especially in SSc-associated interstitial lung disease (SSc-ILD). METHODS: We retrospectively analysed patients with SSc and SSc-ILD from the German Network for Systemic Sclerosis (DNSS) database (2003 onwards). Kaplan-Meier analysis compared overall survival (OS) and progression-free survival (PFS) in patients with GERD vs without GERD (SSc and SSc-ILD), and PPI vs no PPI use (SSc-ILD only). Progression was defined as a decrease in either percentage predicted forced vital capacity of ≥10% or single-breath diffusing capacity for carbon monoxide of ≥15%, or death. RESULTS: It was found that 2693/4306 (63%) registered patients with SSc and 1204/1931 (62%) with SSc-ILD had GERD. GERD was not associated with decreased OS or decreased PFS in patients in either cohort. In SSc-ILD, PPI use was associated with improved OS vs no PPI use after 1 year [98.4% (95% CI: 97.6, 99.3); n = 760 vs 90.8% (87.9-93.8); n = 290] and after 5 years [91.4% (89.2-93.8); n = 357 vs 70.9% (65.2-77.1); n = 106; P < 0.0001]. PPI use was also associated with improved PFS vs no PPI use after 1 year [95.9% (94.6-97.3); n = 745 vs 86.4% (82.9-90.1); n = 278] and after 5 years [66.8% (63.0-70.8); n = 286 vs 45.9% (39.6-53.2); n = 69; P < 0.0001]. CONCLUSION: GERD had no effect on survival in SSc or SSc-ILD. PPIs improved survival in patients with SSc-ILD. Controlled, prospective trials are needed to confirm this finding.

Systemic sclerosis associated interstitial lung disease: a conceptual framework for subclinical, clinical and progressive disease.

OBJECTIVES: To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD). METHODS: A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification. RESULTS: Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration. CONCLUSIONS: Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT.

A Transcriptome Array-Based Approach Links Proteinuria and Distinct Molecular Signatures to Intrarenal Expression of Type I Interferon IFNA5 in Lupus Nephritis.

In systemic lupus erythematosus (SLE), the relevance of non-hematopoietic sources of type I interferon in human autoimmunity has recently been recognized. Particularly, type I interferon production precedes autoimmunity in early skin lesions related to SLE. However, the relevance of intrarenal type I interferon expression has not been shown in lupus nephritis. From transcriptome array datasets, median-centered log2 mRNA expression levels of IFNα (IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, and IFNA21), IFNω (IFNW1), and IFNß (IFNB1) in lupus nephritis were extracted specifically from microdissected tubulointerstitial (n = 32) and glomerular compartments (n = 32). We found an association between proteinuria and tubulointerstitial expression of type I interferon IFNA5 (p = 0.0142), while all others were not significantly associated. By contrast, no such correlation was observed between proteinuria and any type I interferon expression in the glomerular compartment in lupus nephritis. Interestingly, there was no difference between female and male patients (p = 0.8237) and no association between type I interferon IFNA5 expression and kidney function or lupus nephritis progression. Finally, we identified distinct molecular signatures involved in transcriptional regulation (GLI protein-regulated transcription, IRF7 activation, and HSF1-dependent transactivation) and receptor signaling (BMP signaling and GPCR ligand binding) in association with tubulointerstitial expression of type I interferon IFNA5 in the kidney. In summary, this transcriptome array-based approach links proteinuria to the tubulointerstitial expression of type I interferon IFNA5 in lupus nephritis. Because type I interferon receptor subunit I antagonism has recently been investigated in active SLE, the current study further emphasizes the role of type I interferons in lupus nephritis and might also be of relevance for mechanistic studies.

A Transcriptome Array-Based Approach to Link SGLT-2 and Intrarenal Complement C5 Synthesis in Diabetic Nephropathy.

Diabetic nephropathy is a common microvascular complication of diabetes mellitus. It is characterized by progressive chronic kidney disease (CKD) with decline of kidney function by hyperfiltration. On a mechanistic level, activation of the complement system has been implicated in the pathogenesis of diabetic nephropathy. Therefore, here we pursued a transcriptome array-based approach to link intrarenal SGLT-2 and the synthesis of distinct complement components in diabetic nephropathy. Publicly available datasets for SLC5A2 (encoding SGLT-2) and complement system components were extracted specifically from microdissected tubulointerstitial (healthy controls: n = 31, diabetic nephropathy: n = 17) and glomerular compartments (healthy controls: n = 21, diabetic nephropathy: n = 12). First, we compared tubulointerstitial and glomerular log2SLC5A2 mRNA expression levels and confirmed a predominant synthesis within the tubulointerstitial compartment. Among various complement components and receptors, the only significant finding was a positive association between SLC5A2 and the tubulointerstitial synthesis of the complement component C5 in diabetic nephropathy (p = 0.0109). Finally, intrarenal expression of SLC5A2 was associated predominantly with pathways involved in metabolic processes. Interestingly, intrarenal complement C5 synthesis was also associated with enrichment of metabolic signaling pathways, overlapping with SLC5A2 for "metabolism" and "biological oxidations". These observations could be of relevance in the pathogenesis of diabetic nephropathy and implicate a mechanistic link between SGLT-2 and intrarenal complement synthesis.

C-Reactive Protein Levels Are Associated with Complement C4 Deposits and Interstitial Arteritis in ANCA-Associated Renal Vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a potentially life-threatening systemic small-vessel vasculitis that is characterized by pauci-immune glomerulonephritis in case of kidney involvement, representing a major denominator of AAV mortality. Innate immunity with complement system activation is increasingly recognized in the pathogenesis of AAV and as an attractive therapeutic target. Although C-reactive protein (CRP) was thought to be a passive, nonspecific marker of inflammation, recent studies indicate that CRP plays a key role in the innate immune system by recognizing pathogens and altered self-determinants. Elevated baseline CRP at disease onset of AAV has already been described as a determinant of poor long-term outcomes. However, its clinical implications at disease onset of AAV, with respect to vasculitis manifestations and complement system activation that might also affect long-term outcomes, remain elusive. CRP levels were retrospectively analyzed in 53 kidney-biopsy-confirmed cases of ANCA-associated renal vasculitis; a total of 138 disease controls were also evaluated. Univariate and multivariate regression analysis was performed on clinicopathological parameters associated with CRP levels in ANCA-associated renal vasculitis. Results: Compared to disease controls, CRP elevation was common in ANCA-associated renal vasculitis and associated with de novo disease (p = 0.0169), critical illness (p = 0.0346), and severe deterioration of kidney function (p = 0.0167), independent of extrarenal disease manifestations. As confirmed by multiple regression analysis, CRP levels were correlated with active lesions predominated by interstitial arteritis in renal vasculitis, specifically with MPO-ANCA seropositivity (p = 0.0017). Based on analysis of systemic complement system activation and intrarenal complement deposits, CRP elevation was correlated specifically with complement C4 deposits in interstitial arteries in the subgroup with myeloperoxidase (MPO)-ANCA seropositivity (p = 0.039). Finally, this association was independent of systemic complement system activation, as reflected by the consumption of respective complement components. Here, we expand our current understanding of CRP in ANCA-associated renal vasculitis not only as an inflammatory marker, but potentially also as being involved in the pathogenesis of kidney injury by interaction with the complement system.

High heritability of telomere length and low heritability of telomere shortening in wild birds.

Telomere length and telomere shortening predict survival in many organisms. This raises the question of the contribution of genetic and environmental effects to variation in these traits, which is still poorly known, particularly for telomere shortening. We used experimental (cross-fostering) and statistical (quantitative genetic "animal models") means to disentangle and estimate genetic and environmental contributions to telomere length variation in pedigreed free-living jackdaws (Corvus monedula). Telomere length was measured twice in nestlings, at ages 4 (n = 715) and 29 days (n = 474), using telomere restriction fragment (TRF) analysis, adapted to exclude interstitial telomeric sequences. Telomere length shortened significantly over the nestling period (10.4 ± 0.3 bp day-1 ) and was highly phenotypically (rP  = 0.95 ± 0.01) and genetically (rG  > 0.99 ± 0.01) correlated within individuals. Additive genetic effects explained a major part of telomere length variation among individuals, with its heritability estimated at h2  = 0.74 on average. We note that TRF-based studies reported higher heritabilities than qPCR-based studies, and we discuss possible explanations. Parent-offspring regressions yielded similar heritability estimates for mothers and fathers when accounting for changes in paternal telomere length over life. Year effects explained a small but significant part of telomere length variation. Heritable variation for telomere shortening was low (h2  = 0.09 ± 0.11). The difference in heritability between telomere length (high) and telomere shortening (low) agrees with evolutionary theory, in that telomere shortening has stronger fitness consequences in this population. Despite the high heritability of telomere length, its evolvability, which scales the additive genetic variance by mean telomere length, was on average 0.48%. Hence, evolutionary change of telomere length due to selection is likely to be slow.

How Individualized Niches Arise: Defining Mechanisms of Niche Construction, Niche Choice, and Niche Conformance.

Organisms interact with their environments in various ways. We present a conceptual framework that distinguishes three mechanisms of organism-environment interaction. We call these NC3 mechanisms: niche construction, in which individuals make changes to the environment; niche choice, in which individuals select an environment; and niche conformance, in which individuals adjust their phenotypes in response to the environment. Each of these individual-level mechanisms affects an individual's phenotype-environment match, its fitness, and its individualized niche, defined in terms of the environmental conditions under which the individual can survive and reproduce. Our framework identifies how individuals alter the selective regimes that they and other organisms experience. It also places clear emphasis on individual differences and construes niche construction and other processes as evolved mechanisms. The NC3 mechanism framework therefore helps to integrate population-level and individual-level research.

Male social niche conformance? Effects of manipulated opportunity for extra-pair mating on behavior and hormones of male zebra finches.

Success in sperm competition is an important determinant of male fitness in mating systems with female multiple mating. Thus, sperm competition risk represents a key dimension of the male social environment to which individual males are expected to adaptively adjust their reproductive phenotype. Such adaptive phenotypic adjustment we here refer to as male social niche conformance. In this pre-registered study, we investigated how male zebra finches, Taeniopygia guttata, adjust their behavior to sperm competition risk. We experimentally manipulated the opportunity for extra-pair mating to create two levels of sperm competition risk: 1) Single-pair, no sperm competition risk; 2) Double-pair, sperm competition risk. We compared male courtship, mate guarding, copulation rates, and aggression between the treatment groups. To identify hormonal correlates of male behavioral adjustment, we measured plasma testosterone and corticosterone levels before and after the social treatment started. Contrary to our pre-registered predictions, males from the Double-pair treatment group decreased courtship rates compared to those from the Single-pair group, and Double-pair males responded less aggressively towards intruders than Single-pair males. Testosterone levels decreased over the breeding cycle, but social treatment had no effect on either testosterone or corticosterone levels. Our results indicate that male zebra finches do not intensify courtship or competitive reproductive behaviors, or upregulate key hormones when another breeding pair is present. Although we found no evidence for the predicted adaptive behavioral responses to sperm competition risk, we show that male zebra finches plastically adjust their behavior to their social environment.

Genetic, maternal, and environmental influences on sociality in a pedigreed primate population.

Various aspects of sociality in mammals (e.g., dyadic connectedness) are linked with measures of biological fitness (e.g., longevity). How within- and between-individual variation in relevant social traits arises in uncontrolled wild populations is challenging to determine but is crucial for understanding constraints on the evolution of sociality. We use an advanced statistical method, known as the 'animal model', which incorporates pedigree information, to look at social, genetic, and environmental influences on sociality in a long-lived wild primate. We leverage a longitudinal database spanning 20 years of observation on individually recognized white-faced capuchin monkeys (Cebus capucinus imitator), with a multi-generational pedigree. We analyze two measures of spatial association, using repeat sampling of 376 individuals (mean: 53.5 months per subject, range: 6-185 months per subject). Conditioned on the effects of age, sex, group size, seasonality, and El Niño-Southern Oscillation phases, we show low to moderate long-term repeatability (across years) of the proportion of time spent social (posterior mode [95% Highest Posterior Density interval]: 0.207 [0.169, 0.265]) and of average number of partners (0.144 [0.113, 0.181]) (latent scale). Most of this long-term repeatability could be explained by modest heritability (h2social: 0.152 [0.094, 0.207]; h2partners: 0.113 [0.076, 0.149]) with small long-term maternal effects (m2social: 0.000 [0.000, 0.045]; m2partners: 0.000 [0.000, 0.041]). Our models capture the majority of variance in our behavioral traits, with much of the variance explained by temporally changing factors, such as group of residence, highlighting potential limits to the evolvability of our trait due to social and environmental constraints.

Treatment and outcomes in anti-HMG-CoA reductase-associated immune-mediated necrotising myopathy. Comparative analysis of a single-centre cohort and published data.

OBJECTIVES: Anti-hydroxy-methyl-glutaryl-coenzyme A reductase (HMGCR) antibody-associated myopathy was recognised as a new form of immune-mediated necrotising myopathy (IMNM) a decade ago. Due to the rarity of the disease, only limited data on clinical manifestations and therapeutic outcomes are available. METHODS: We retrospectively analysed a monocentric cohort of HMGCR-associated IMNM patients treated at the University Medical Centre Göttingen. Clinical, laboratory, and biopsy data, as well as treatment outcomes, were analysed. In addition, a literature search was performed on published HMGCR IMNM cohorts in Medline and Web of Science. RESULTS: We identified nine patients; five were female. The median age was 68 years (47-77). Six were statin-exposed and older than statin-naive patients (71 years [65-77] vs. 51 years [47-67]). All had muscle weakness, seven myalgias. Strength (MRC sum score) was 53/65 (46-61) at baseline and increased to 63/65 (50-65) with therapy. Creatine kinase (CK) levels decreased from a median level of 12837 U/L (range 6346-25011) to 624 U/L (35-1564 U/L). All received glucocorticoids (GC) and at least one immunosuppressive therapy. The literature review identified 26 studies comprising 691 patients. 57.9% were female, 61.3% statin exposed. 95.2% had weakness, 39.1% myalgia. Dysphagia affected 28.8%. 84.9% received GC and a median of 1.5 additional immunosuppressants. Compared to published data, our patients had higher baseline CK values (12837 [6346-25011] vs. 6951 [2539-10500], p<0.001), and we used azathioprine and intravenous immunoglobulins (p<0.001) more frequently but methotrexate and rituximab less frequently (p<0.001). CONCLUSIONS: HMGCR-associated IMNM is a rare subset of myositis. With systemic treatment, patients usually achieve partial or complete remission. Optimal treatment has not been established, but glucocorticoids, azathioprine, and methotrexate are generally effective with or without intravenous immunoglobulins.

Epigenetic inheritance of telomere length in wild birds.

Telomere length (TL) predicts health and survival across taxa. Variation in TL between individuals is thought to be largely of genetic origin, but telomere inheritance is unusual, because zygotes already express a TL phenotype, the TL of the parental gametes. Offspring TL changes with paternal age in many species including humans, presumably through age-related TL changes in sperm, suggesting an epigenetic inheritance mechanism. However, present evidence is based on cross-sectional analyses, and age at reproduction is confounded with between-father variation in TL. Furthermore, the quantitative importance of epigenetic TL inheritance is unknown. Using longitudinal data of free-living jackdaws Corvus monedula, we show that erythrocyte TL of subsequent offspring decreases with parental age within individual fathers, but not mothers. By cross-fostering eggs, we confirmed the paternal age effect to be independent of paternal age dependent care. Epigenetic inheritance accounted for a minimum of 34% of the variance in offspring TL that was explained by paternal TL. This is a minimum estimate, because it ignores the epigenetic component in paternal TL variation and sperm TL heterogeneity within ejaculates. Our results indicate an important epigenetic component in the heritability of TL with potential consequences for offspring fitness prospects.

[Myositis]. / Myositis.

The S2e guidelines on myositis were completely updated and revised under the leadership of the German Society for Neurology and the participation of many other specialist societies. Immune-mediated necrotizing myopathy and antisynthetase syndrome are now regarded as independent entities in the classification of myositis. With respect to the diagnostics, the guidelines provide concrete recommendations on dysphagia screening, especially for inclusion body myositis and for cancer diagnostics in certain forms of myositis. Following the positive ProDERM study, the use of intravenous immunoglobulins (Octagam®) is available for treatment as an approved substance. Based on the INBUILD study, antifibrotic treatment with nintedanib is available for progressive fibrosing pulmonary involvement. For rheumatologists, the updated guidelines represent a document relevant for daily practice with many recommendations for the treatment of patients with myositis.

ERS clinical practice guidelines on treatment of sarcoidosis.

BACKGROUND: The major reasons to treat sarcoidosis are to lower the morbidity and mortality risk or to improve quality of life (QoL). The indication for treatment varies depending on which manifestation is the cause of symptoms: lungs, heart, brain, skin or other manifestations. While glucocorticoids remain the first choice for initial treatment of symptomatic disease, prolonged use is associated with significant toxicity. Glucocorticoid-sparing alternatives are available. The presented treatment guidelines aim to provide guidance to physicians treating the very heterogenous sarcoidosis manifestations. METHODS: A European Respiratory Society Task Force committee composed of clinicians, methodologists and patients with experience in sarcoidosis developed recommendations based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) methodology. The committee developed eight PICO (Patients, Intervention, Comparison, Outcomes) questions and these were used to make specific evidence-based recommendations. RESULTS: The Task Force committee delivered 12 recommendations for seven PICOs. These included treatment of pulmonary, cutaneous, cardiac and neurologic disease as well as fatigue. One PICO question regarding small-fibre neuropathy had insufficient evidence to support a recommendation. In addition to the recommendations, the committee provided information on how they use alternative treatments, when there was insufficient evidence to support a recommendation. CONCLUSIONS: There are many treatments available to treat sarcoidosis. Given the diverse nature of the disease, treatment decisions require an assessment of organ involvement, risk for significant morbidity, and impact on QoL of the disease and treatment.

Improvement of lupus-associated fatigue with modafinil: Report of two cases.

Fatigue is a frequently reported and disabling symptom in patients with systemic lupus erythematosus (SLE). The management of Lupus-associated fatigue (LAF) is complex and requires the exclusion of disease activity and comorbidities as potentially treatable causes. Standard of care recommendations includes psychological counselling and regular physical activity. However, many SLE patients still report the persistence of LAF despite these measures. Therefore, pharmacological management may be required, which has been insufficiently investigated in clinical trials. Here, we report two patients who improved with pharmacological treatment with modafinil (MODA), a central nervous system stimulant. Both patients had an overall low disease activity (SLEDAI-2K score of 0). Their FACIT fatigue scores were 15 and 20, respectively (with a maximum score of 52, where 52 indicates the best quality of life). With MODA treatment, the first patient's FACIT fatigue score improved from 15 to 42, the second patient's score from 20 to 37. In the latter patient, it returned to 21 after stopping the drug and increased back again to 37 after re-treatment.In conclusion, our report demonstrates, for the first time, that MODA treatment is a potential pharmacological treatment option in selected patients with LAF. Clinical trials in SLE are required to confirm our observations.

Bowman's capsule rupture links glomerular damage to tubulointerstitial inflammation in ANCA-associated glomerulonephritis.

OBJECTIVES: We have recently described the frequency of Bowman's capsule (BC) rupture in a considerable subset of patients with antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GN). Interestingly, recent reports established a better performance of glomerulocentric ANCA scoring systems after adding BC rupture to these classification systems, suggesting that characteristics of this lesion are independent from glomerular lesions. Since BC rupture may link glomerular damage to tubulointerstitial lesions via direct interaction with the surrounding interstitium, we here aimed to expand our current knowledge of this distinct lesion by a systematic description of tubulointerstitial lesions analogous to the Banff classification in association with the presence of BC rupture in ANCA GN. METHODS: A total number of 44 kidney biopsies with confirmed renal involvement of ANCA GN were retrospectively included between 2015 till 2020 in a single-centre observational study. RESULTS: We here show that presence of BC rupture was associated with severe deterioration of kidney function at disease onset, similar to previous findings regarding long-term renal survival. Furthermore, BC rupture in ANCA GN was associated with tubulointerstitial inflammation and ultrastructural analysis revealed direct cellular exchange between Bowman's space and the interstitium, potentially contributing to the observed deterioration of kidney function and worse renal outcome in ANCA GN. CONCLUSIONS: BC rupture is associated with renal outcome in ANCA GN, therefore underscoring the need for further studies with regard to the glomerular-tubulointerstitial interaction in this disease.

Severely destructive unilateral wrist arthritis as a rare variant of rheumatoid arthritis: analysis of clinical and imaging features.

OBJECTIVES: Rheumatoid arthritis (RA) is a common autoimmune disease typically affecting joints symmetrically. A small number of patients develop unilateral and severely destructive wrist arthritis (DWA). The objective of our study was to characterise patients with this type of affection. METHODS: This was a retrospective cohort study of RA patients with positive RF/anti-CCP antibodies. Clinical characteristics, including, age, gender, disease duration, dexterity, occupational history, smoking status, and the number of prescribed DMARDs were recorded. Conventional radiographs were evaluated using the modified Sharp/van der Heijde scoring (mSS) method. RESULTS: We analysed our laboratory database of 1247 patients and identified 559 patients with a clinical diagnosis of RA. For 395 of the patients, radiographs of the hands were available for evaluation. 25 patients had extensive unilateral DWA, corresponding to a prevalence of 6.3% (25 of 395 patients). 11 patients were excluded due to incomplete data. Of the remaining 14 patients, 13 were female with a median age of 61 (33-83) years, and median disease duration of 18 (1-33) years. 8 of 11 (72.7%) patients were smokers; in three, smoking status was not known. 80% with known dexterity developed unilateral DWA in the dominant hand. Total mSS was significantly higher on the affected side (39, interquartile range 35.25-46.25) versus non-affected (13, IQR 3-23). MSS were not different if the carpal bones were excluded from scoring. Side of involvement (left vs. right), or dominant versus non-dominant hand, did not result in a different mSS. CONCLUSIONS: Unilateral DWA is a rare variant of RA which predominantly affects women who smoke.

Complement Components C3 and C4 Indicate Vasculitis Manifestations to Distinct Renal Compartments in ANCA-Associated Glomerulonephritis.

Acute kidney injury (AKI) is a common and severe complication of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) causing progressive chronic kidney disease (CKD), end-stage renal disease (ESRD) or death. Pathogenic ANCAs, in particular proteinase 3 (PR3) and myeloperoxidase (MPO), trigger a deleterious immune response resulting in pauci-immune necrotizing and crescentic glomerulonephritis (GN), a common manifestation of glomerular injury in AAV. However, there is growing evidence that activation of the complement pathway contributes to the pathogenesis and progression of AAV. We here aimed to compare glomerular and tubulointerstitial lesions in ANCA GN and extrarenal manifestation of AAV in association with levels of circulating complement components C3c and C4. METHODS: Plasma levels of C3c and C4 in a total number of 53 kidney biopsies with ANCA GN were retrospectively included between 2015 and 2020. Glomerular and tubulointerstitial lesions were evaluated according to established scoring systems for ANCA GN and analogous to the Banff classification. RESULTS: We here show that circulating levels of C3c and C4 in ANCA GN were comparable to the majority of other renal pathologies. Furthermore, hypocomplementemia was only detectable in a minor subset of ANCA GN and not correlated with renal or extrarenal AAV manifestations. However, low levels of circulating C3c correlated with AKI severity in ANCA GN independent of systemic disease activity or extrarenal AAV manifestation. By systematic scoring of glomerular and tubulointerstitial lesions, we provide evidence that low levels of circulating C3c and C4 correlated with vasculitis manifestations to distinct renal compartments in ANCA GN. CONCLUSIONS: We here expand our current knowledge about distinct complement components in association with vasculitis manifestations to different renal compartments in ANCA GN. While low levels of C4 correlated with glomerulitis, our observation that low levels of circulating complement component C3c is associated with interstitial vasculitis manifestation reflected by intimal arteritis implicates that C3c contributes to tubulointerstitial injury in ANCA GN.