Frank Pessler

Rapid and sustained remission of systemic juvenile idiopathic arthritis-associated macrophage activation syndrome through treatment with anakinra and corticosteroids.

We describe 2 patients with systemic juvenile idiopathic arthritis and macrophage activation syndrome. Treatment with recombinant interleukin 1 receptor antagonist (anakinra) and a corticosteroid rapidly induced remission, which could be maintained with anakinra monotherapy at a stable dose of 2 mg/kg per day. Pain at the injection site during the initial injections was the only adverse effect attributable to anakinra. Untoward effects of corticosteroid treatment were mild because prolonged therapy with high-dose corticosteroids could be avoided. These results suggest that early institution of interleukin 1 blockade merits further investigation for the treatment of macrophage activation syndrome and, perhaps, related conditions such as hemophagocytic lymphohistiocytosis.

Subintimal Ki-67 as a synovial tissue biomarker for inflammatory arthropathies

Objectives: Ki-67 is expressed in the nuclei of dividing cells and can be used to assess proliferation of synovial inflammatory and stromal cells. We evaluated subintimal Ki-67+ cell density as a tissue biomarker for inflammatory arthropathies and compared it to subintimal CD68, a synovial biomarker of RA. Methods: Subintimal Ki-67+ and CD68+ cell densities were measured immunohistochemically in synovial specimens obtained from patients with rheumatoid arthritis (RA; n = 19), osteoarthritis (OA; n = 18), “non-inflammatory” orthopaedic arthropathies (avascular necrosis, meniscus injury, femur fracture; n = 16), chronic septic arthritis (n = 9), and histologically normal synovium (n = 10). Results were correlated with a histological synovitis score. Utilising the areas under receiver operating characteristic curves (AUCs), we compared the abilities of Ki-67 and CD68 to differentiate among these arthropathies. Results: Ki-67 was expressed widely in the subintima of inflamed specimens and in RA pannus invading hard tissues. Compared to normal controls, it was highly overexpressed in RA (26.6-fold) and chronic septic arthritis (55-fold), and mildly elevated in OA (3.9-fold) and orthopaedic arthropathies (2.1-fold). Ki-67 and CD68 differentiated similarly well between RA and OA (AUC: Ki-67 = 0.91, CD68 = 0.94), Ki-67 better between chronic septic arthritis and RA, and CD68 better between OA and normal controls. Ki-67 (r = 0.80) and CD68 (r = 0.79) correlated positively with the synovitis score. Conclusions: Subintimal Ki-67 was overexpressed in inflammatory arthropathies, distinguished among differentially inflamed arthropathies, and correlated positively with the histological severity of synovitis. It may prove useful in synovial tissue classification and as a synovial marker of disease activity in clinical trials when biopsies are available.

Methicillin-sensitive and methicillin-resistant Staphylococcus aureus nasal carriage in a random sample of non-hospitalized adult population in northern Germany.

Objective The findings from truly randomized community-based studies on Staphylococcus aureus nasal colonization are scarce. Therefore we have examined point prevalence and risk factors of S. aureus nasal carriage in a non-hospitalized population of Braunschweig, northern Germany. Methods A total of 2026 potential participants were randomly selected through the residents registration office and invited by mail. They were requested to collect a nasal swab at home and return it by mail. S. aureus was identified by culture and PCR. Logistic regression was used to determine risk factors of S. aureus carriage. Results Among the invitees, 405 individuals agreed to participate and 389 provided complete data which was included in the analysis. The median age of the participants was 49 years (IQR: 39–61) and 61% were females. S. aureus was isolated in 85 (21.9%; 95% CI: 18.0–26.2%) of the samples, five of which were MRSA (1.29%; 95% CI: 0.55–2.98%). In multiple logistic regression, male sex (OR = 3.50; 95% CI: 2.01–6.11) and presence of allergies (OR = 2.43; 95% CI: 1.39–4.24) were found to be associated with S. aureus nasal carriage. Fifty five different spa types were found, that clustered into nine distinct groups. MRSA belonged to the hospital-associated spa types t032 and t025 (corresponds to MLST CC 22), whereas MSSA spa types varied and mostly belonged to spa-CC 012 (corresponds to MLST CC 30), and spa-CC 084 (corresponds to MLST CC 15). Conclusion This first point prevalence study of S. aureus in a non-hospitalized population of Germany revealed prevalence, consistent with other European countries and supports previous findings on male sex and allergies as risk factors of S. aureus carriage. The detection of hospital-associated MRSA spa types in the community indicates possible spread of these strains from hospitals into the community.

Equivalence of self- and staff-collected nasal swabs for the detection of viral respiratory pathogens.

Background The need for the timely collection of diagnostic biosamples during symptomatic episodes represents a major obstacle to large-scale studies on acute respiratory infection (ARI) epidemiology. This may be circumvented by having the participants collect their own nasal swabs. We compared self- and staff-collected swabs in terms of swabbing quality and detection of viral respiratory pathogens. Methodology/Principal Findings We conducted a prospective study among employees of our institution during the ARI season 2010/2011 (December-March). Weekly emails were sent to the participants (n = 84), reminding them to come to the study center in case of new symptoms. The participants self-collected an anterior nasal swab from one nostril, and trained study personnel collected one from the other nostril. The participants self-collected another two swabs (one from each nostril) on a subsequent day. Human β-actin DNA concentration was determined in the swabs as a quality control. Viral respiratory pathogens were detected by multiplex RT-PCR (Seeplex RV15 kit, Seegene, Eschborn, Germany). Of 84 participants, 56 (67%) reported at least one ARI episode, 18 participants two, and one participant three. Self-swabbing was highly accepted by the participants. The amount of β-actin DNA per swab was higher in the self- than in the staff-collected swabs (p = 0.008). β-actin concentration was lower in the self-swabs collected on day 1 than in those collected on a subsequent day (p<0.0001). A respiratory viral pathogen was detected in 31% (23/75) of staff- and in 35% (26/75) of self-collected swabs (p = 0.36). With both approaches, the most frequently identified pathogens were human rhinoviruses A/B/C (12/75 swabs, 16%) and human coronavirus OC43 (4/75 swabs, 5%). There was almost perfect agreement between self- and staff-collected swabs in terms of pathogen detection (agreement = 93%, kappa = 0.85, p<0.0001). Conclusions/Significance Nasal self-swabbing for identification of viral ARI pathogens proved to be equivalent to staff-swabbing in this population in terms of acceptance and pathogen detection.

Naturally Occurring Genetic Variants of Human Caspase‐1 Differ Considerably in Structure and the Ability to Activate Interleukin‐1β

Caspase‐1 (Interleukin‐1 Converting Enzyme, ICE) is a proinflammatory enzyme that plays pivotal roles in innate immunity and many inflammatory conditions such as periodic fever syndromes and gout. Inflammation is often mediated by enzymatic activation of interleukin (IL)‐1β and IL‐18. We detected seven naturally occurring human CASP1 variants with different effects on protein structure, expression, and enzymatic activity. Most mutations destabilized the caspase‐1 dimer interface as revealed by crystal structure analysis and homology modeling followed by molecular dynamics simulations. All variants demonstrated decreased or absent enzymatic and IL‐1β releasing activity in vitro, in a cell transfection model, and as low as 25% of normal ex vivo in a whole blood assay of samples taken from subjects with variant CASP1, a subset of whom suffered from unclassified autoinflammation. We conclude that decreased enzymatic activity of caspase‐1 is compatible with normal life and does not prevent moderate and severe autoinflammation.

E-mail-based symptomatic surveillance combined with self-collection of nasal swabs: a new tool for acute respiratory infection epidemiology

Summary Objective We examined the feasibility of combining communication by e-mail and self-collection of nasal swabs for the prospective detection of acute respiratory infections in a non-medical setting. Methods The study was conducted among a convenience sample of employees (n =53) at a research institution (December 2009–April 2010). Real-time data on the occurrence of acute respiratory symptoms and a nasal self-swab were collected prospectively, with automated weekly e-mails as a reminder mechanism. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect respiratory viral pathogens in the swabs. Results Fifty-one out of 53 participants completed the study. The study design was well accepted. Thirty (∼57%) participants reported at least one episode of acute respiratory infection and returned the nasal swab during the study period (eight participants reported two episodes). The majority had no difficulties taking the self-swab and preferred this to swabbing by study personnel. Most participants obtained and returned the swabs within the recommended time. Viral respiratory pathogens were detected in 19 of 38 swabs (50%), with coronaviruses 229E/NL63 and OC43 and rhinoviruses A and B constituting 17 positive swabs (89%). Conclusions Combining e-mail-based symptomatic surveillance with nasal self-swabbing promises to be a powerful tool for the real-time identification of incident cases of acute respiratory infections and the associated pathogens in population-based studies.

The transcription factor FBI-1/OCZF/LRF is expressed in osteoclasts and regulates RANKL-induced osteoclast formation in vitro and in vivo

OBJECTIVE Since transcription factors expressed in osteoclasts are possible targets for regulation of bone destruction in bone disorders, we investigated the expression of the transcription factor FBI-1/OCZF/LRF (in humans, factor that binds to inducer of short transcripts of human immunodeficiency virus type 1; in rats, osteoclast-derived zinc finger; in mice, leukemia/lymphoma-related factor) in patients with rheumatoid arthritis (RA), and assessed its role in osteoclastogenesis in vivo. METHODS Expression of FBI-1/OCZF was investigated in subchondral osteoclasts in human RA and in rat adjuvant-induced arthritis (AIA) using immunostaining and in situ hybridization, respectively. Transgenic mice overexpressing OCZF (OCZF-Tg) under the control of the cathepsin K promoter were generated, and bone mineral density and bone histomorphometric features were determined by peripheral quantitative computed tomography, calcein double-labeling, and specific staining for osteoclasts and osteoblasts. LRF/OCZF expression and the consequence of LRF inhibition were assessed in vitro with RANKL-induced osteoclast differentiation. RESULTS FBI-1/OCZF was detected in the nuclei of osteoclasts in rat AIA and human RA. RANKL increased the levels of LRF messenger RNA and nuclear-localized LRF protein in primary macrophages. In OCZF-Tg mice, bone volume was significantly decreased, the number of osteoclasts, but not osteoblasts, was increased in long bones, and osteoclast survival was promoted. Conversely, inhibition of LRF expression suppressed the formation of osteoclasts from macrophages in vitro. CONCLUSION FBI-1/OCZF/LRF regulates osteoclast formation and apoptosis in vivo, and may become a useful marker and target in treating disorders leading to reduced bone density, including chronic arthritis.

Serial home-based self-collection of anterior nasal swabs to detect Staphylococcus aureus carriage in a randomized population-based study in Germany

OBJECTIVES Participant-collected serial nasal swabs would be a cost-efficient feature of prospective population-based microbiological studies. We examined the feasibility of serial anterior nasal self-swabbing for Staphylococcus aureus detection in a prospective population-based study in Braunschweig, Germany, and assessed the impact of three interventions on participation and compliance. METHODS Two thousand twenty-six inhabitants were selected randomly from the resident registries and asked to self-collect a nasal swab monthly from July 2012 to January 2013 and return it by mail. The swabs were tested for the presence of S. aureus. Participation and compliance were assessed in four study groups (incremental cash incentive, participation in a lottery, reminder by mail, and control group without incentive or reminder). RESULTS Baseline participation was highest in the cash incentive group (24%; 123/504) and lowest in the reminder group (16%; 83/509). Approximately 90% of the participants in all groups returned the swabs each month, demonstrating high compliance irrespective of the intervention. Laboratory analyses showed that most swabs were usable for bacteriological studies. S. aureus was detected at the expected frequency of 20-27%. CONCLUSIONS Home-based serial nasal self-swabbing proved to be feasible and highly acceptable and promises to be a cost-efficient tool for large-scale prospective population-based studies on bacterial infection or colonization.

Synovial Infiltration with CD79a-positive B Cells, But Not Other B Cell Lineage Markers, Correlates with Joint Destruction in Rheumatoid Arthritis

Objective. The efficacy of B cell depletion in the treatment of patients with rheumatoid arthritis (RA) has revitalized interest in the pathogenic role(s) of B cells in RA. We evaluated the distribution of synovial B lineage cells and their correlation with histologic disease activity and joint destruction in RA. Methods. Synovial tissue samples were obtained by closed-needle biopsy from 69 Chinese patients with active RA, from 14 patients with osteoarthritis (OA), and from 15 with orthopedic arthropathies (OrthA) as disease controls. Serial tissue sections were stained immunohistochemically for CD79a (pro-B cell to plasma cell), CD20 (B cells), CD38 (plasma cells), CD21 (follicular dendritic cells), CD68 (macrophages), CD3 (T cells), and CD34 (endothelial cells). Densities of positive-staining cells were determined and correlated with histologic disease activity (Krenn 3-component synovitis score) and radiographic joint destruction (Sharp score). Results. Mean sublining CD79a-positive cell density was significantly higher in RA than in OA (p <0.001) or OrthA (p = 0.003). Receiver operating characteristic curve analysis showed that CD79a-positive cell density differentiated RA well from OA [area under the curve (AUC) = 0.79] or OrthA (AUC = 0.75). Spearman’s rank order correlation showed significant correlations between sublining CD79a-positive cell density and the synovitis score (r = 0.714, p < 0.001), total Sharp score (r = 0.490, p < 0.001), and the erosion subscore (r = 0.545, p < 0.001), as well as the joint space narrowing subscore (r = 0.468, p = 0.001) in RA. Conclusion. Synovial CD79a-positive B cells may be a helpful biomarker for histologic disease activity in RA and may be involved in the pathogenesis of joint destruction in RA.

Self-collected nasal swabs to detect infection and colonization: a useful tool for population-based epidemiological studies?

Population-based epidemiological studies on infectious diseases are limited by methodological problems that may not be encountered in other fields of epidemiology. The acute or asymptomatic nature of many infections hinders a timely diagnosis by trained personnel in a study centre, indicating the need for new collection methods of biological specimens. One alternative approach is to have the participants collect the specimens themselves, for instance nasal swabs for the detection of bacterial or viral pathogens. Although self-collection is widely accepted in clinical studies of specific populations (e.g., self-collection of vaginal swabs by young women to diagnose sexually transmitted infections), it has not been employed much in population-based studies. Here, we review recent experience with self-collection of nasal swabs for the detection of microorganisms and discuss future prospects and applications for this technique.