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Abstract Dermatomyositis is a rare disease characterized by progressive muscle weakness and skin rashes. Estimates of incidence and prevalence are fundamental measures in epidemiology, but few studies have been conducted on dermatomyositis. To address this knowledge gap, we conducted a population-based study to determine the contemporary incidence (between 2013 and 2019) and prevalence (2019) of adults living with dermatomyositis using administrative health data in Alberta, Canada. We also described disease-related medication use, as there are very few approved medications for the treatment of dermatomyositis, and no Canadian therapeutic guidelines. The average age- and sex-standardized annual incidence of dermatomyositis was 2.8–3.0 cases per 100,000 adults, and prevalence was 28.6 cases per 100,000 adults, which is greater than reported in other cohorts. Dermatomyositis-related medication use decreased from 73% in the first year to 46% in the eighth year after diagnosis. Glucocorticoids were the most commonly used drug class, often taken concurrently with various immunomodulatory agents; this medication use aligns with empirically-based recommendations and the few therapeutic guidelines for dermatomyositis. Considering that Alberta may have one of the highest rates of dermatomyositis among adults, further research on the burden of disease is warranted for planning within the health care system.

IntroductionA group of SARS-CoV-2 infected individuals present lingering symptoms, defined as long COVID (LC), that may last months or years post the onset of acute disease. A portion of LC patients have symptoms similar to myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), which results in a substantial reduction in their quality of life. A better understanding of the pathophysiology of LC, in particular, ME/CFS is urgently needed.MethodsWe identified and studied metabolites and soluble biomarkers in plasma from LC individuals mainly exhibiting ME/CFS compared to age-sex-matched recovered individuals (R) without LC, acute COVID-19 patients (A), and to SARS-CoV-2 unexposed healthy individuals (HC).ResultsThrough these analyses, we identified alterations in several metabolomic pathways in LC vs other groups. Plasma metabolomics analysis showed that LC differed from the R and HC groups. Of note, the R group also exhibited a different metabolomic profile than HC. Moreover, we observed a significant elevation in the plasma pro-inflammatory biomarkers (e.g. IL-1α, IL-6, TNF-α, Flt-1, and sCD14) but the reduction in ATP in LC patients. Our results demonstrate that LC patients exhibit persistent metabolomic abnormalities 12 months after the acute COVID-19 disease. Of note, such metabolomic alterations can be observed in the R group 12 months after the acute disease. Hence, the metabolomic recovery period for infected individuals with SARS-CoV-2 might be long-lasting. In particular, we found a significant reduction in sarcosine and serine concentrations in LC patients, which was inversely correlated with depression, anxiety, and cognitive dysfunction scores.ConclusionOur study findings provide a comprehensive metabolomic knowledge base and other soluble biomarkers for a better understanding of the pathophysiology of LC and suggests sarcosine and serine supplementations might have potential therapeutic implications in LC patients. Finally, our study reveals that LC disproportionally affects females more than males, as evidenced by nearly 70% of our LC patients being female.

ObjectiveTo identify the factors that impact COVID-19 vaccine decision-making in vaccine-hesitant vasculitis patients, and compare their perceptions with other rheumatology patients, given existence of data suggesting rheumatology patients may have disease-specific factors that influence their COVID-19 vaccine decision-making.MethodsThis cross-sectional study surveyed adult rheumatology patients from the Kaye Edmonton Clinic Rheumatology Clinic, in Canada, between June and August 2021, using an anonymous online questionnaire. Survey responses were analyzed for statistical differences using chi-square analysis.ResultsThe COVID-19 Vaccine Perceptions Survey had a response rate of 70.9%. Of the total 231 respondents, 103 patients were diagnosed with vasculitis. At the time of the survey, 10.6% of vasculitis patients refused to receive a COVID-19 vaccine compared to 6.3% for other rheumatology patients. Compared to other rheumatology patients, vaccine-hesitant vasculitis patients were significantly more concerned about almost every aspect of available COVID-19 vaccines [e.g., safety (p < 0.001), components (p < 0.001)], and feared that they could contract SARS-CoV-2 from a vaccine (p < 0.001). These vaccine-hesitant patients were also significantly less pleased with the government's pandemic response, less confident in healthcare team-provided information (p < 0.001), and more likely to report that healthcare providers had no role in their COVID-19 vaccine decision-making (p < 0.001).ConclusionVaccine-hesitant vasculitis patients may have multiple considerations influencing COVID-19 vaccine hesitancy, including vaccine and disease-specific concerns, along with unfavorable perceptions of the healthcare system (government and healthcare providers). Healthcare providers can address some of these concerns by initiating patient-centered discussions around immunizations to help support educated decision-making.

Summary: Background: Persistent fatigue is a common complaint in ANCA-vasculitis (AAV) patients and has a profound impact on patient's quality of life. The symptoms associated with this fatigue mirror those found in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia. Etiologic and pathophysiologic differences exist between PR3- and MPO-ANCA disease, yet differences in their fatigue manifestations have not been well researched. We compared fatigue and its associations in healthy controls, AAV patients and fibromyalgia controls. Methods: The Canadian consensus criteria were used for ME/CFS diagnosis, and American College of Rheumatology criteria for fibromyalgia diagnosis. Factors such as cognitive failure, depression, anxiety, and sleep disturbances were assessed by patient reported questionnaires. Clinical factors such as BVAS, vasculitis damage index, CRP and BMI were also collected. Findings: Our AAV cohort comprised 52 patients, with a mean age of 44.7 (20–79), 57% (30/52) of the patients were female. We found 51.9% (27/52) of patients fulfilled the diagnostic criteria for ME/CFS, with 37% (10/27) of those having comorbid fibromyalgia. Rates of fatigue were higher in MPO-ANCA patients, than in PR3-ANCA patients, and their symptoms were more similar to the fibromyalgia controls. Fatigue in PR3-ANCA patients was related to inflammatory markers. These differences may be due to the varied pathophysiology of the PR3- and MPO-ANCA serotypes. Interpretation: A large proportion of AAV patients suffer from debilitating fatigue consequential enough to meet the diagnostic criteria for ME/CFS. Fatigue associations were not the same between PR3- and MPO-ANCA patients, suggesting that the underlying mechanisms may be different. Future studies should consider ANCA serotype, as further research may inform different clinical treatment strategies for AAV patients suffering from ME/CFS. Funding: This manuscript was funded by the Dutch Kidney Foundation (17PhD01).

Background/ObjectiveThe most significant adverse events following SARS-CoV-2 vaccination are myocarditis and pericarditis. Myositis and dermatomyositis have been reported following SARS-CoV-2 infection, but vaccine-induced dermatomyositis (DM) has not been reported. Our case series aimed to characterize new onset dermatomyositis or disease-related flares following SARS-CoV-2 vaccination.Materials and methodsA total of 53 patients from our institution with a new or pre-existing diagnosis of DM were recruited and consented. Phone interviews were conducted to obtain vaccination status and symptoms following vaccination. Electronic medical records were reviewed to extract age, sex, autoantibody profiles, comorbidities, immunomodulatory therapies, creatine kinase (CK) values, and SARS-CoV-2 vaccination dates from the provincial vaccination registry. For patients who reported disease flares, records were reviewed for the onset and nature of symptoms, extent of organ involvement and changes in immunomodulation.ResultsOn average, patients received 2.62 vaccine doses (range 1–3 doses). A total of 3 of 51 patients (5.88%) experienced dermatomyositis symptoms following vaccination. Two patients were newly diagnosed with dermatomyositis, one requiring hospitalization. Reported symptom onset following vaccination ranged from 1 to 30 days. Of note, all of these patients had normal CK values, even though there was muscle biopsy-confirmed myositis in one patient. Eight patients in the cohort (15.1%) had asymptomatic CK elevation (

Symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are common in rheumatic diseases, but no studies report the frequency of these in early systemic sclerosis. There are no known biomarkers that can distinguish between patients with ME/CFS, although mitochondrial abnormalities are often demonstrated. We sought to assess the prevalence of ME/CFS in limited cutaneous SSc (lcSSc) patients early in their disease (

Introduction: Nailfolds of patients with systemic sclerosis (SSc) provide an opportunity to directly visualize microvascular remodeling in SSc. Nailfold video capillaroscopy (NVC) remains the gold standard for assessing nailfold capillaroscopy (NFC). However, access to NVC is limited by expense and expertise. This review aims to synthesize current research on other NFC devices compared to NVC. Methods: The literature search included the primary research of adult patients with SSc as defined by the 2013 ACR/EULAR criteria. Methods of assessing NFC included stereomicroscopy/wide-field microscopy, ophthalmoscopy, dermatoscopy, smartphone devices, and digital USB microscopy. Primary outcomes included both qualitative (normal vs. abnormal nailfolds, overall pattern recognition, presence/absence of giant capillaries, hemorrhages, and abnormal morphology) and quantitative (capillary density and dimension) measures. Results: The search yielded 471 studies, of which 9 were included. Five studies compared NVC to dermatoscopy, two compared it to widefield/stereomicroscopy, one to smartphone attachments, and one to USB microscopy. In dermatoscopy studies, NVC had a higher percentage of images that were interpretable (63–77% vs. 100%), classifiable (70% vs. 84%), or gradable (70% vs. 79.3%) across three studies. Dermatoscopy had a lower sensitivity (60.2% vs. 81.6%) and higher specificity (92.5% vs. 84.6%) compared to NVC. One stereomicroscopy study found a significant difference between methods in capillary density in limited cutaneous SSc, while another found correlations in all parameters between stereomicroscopy and NVC. One smartphone lens had good agreement with NVC on abnormal capillary morphology and density. USB microscopy was able to differentiate between SSc and healthy controls using mean capillary width but not by capillary density. Discussion: A dermatoscope may serve as a more portable and affordable screening tool to identify a normal “scleroderma pattern”, and images that need further corroboration by NVC. NFC parameters reported are heterogenous and the standardization of these parameters is important, especially in non-gold-standard devices.

Objectives: The aim of this study was to determine the relationship between disease activity in adult patients with dermatomyositis (DM) and other biomarkers of disease activity such as C-reactive protein creatinine kinase and nailfold video capillaroscopy (NVC).Methods: We performed a prospective single center study of 15 adult patients with DM. Study participants underwent two assessments at least 9 months apart including clinical, laboratory and NVC evaluations. Patients received immunosuppressive medications for their dermatomyositis, and ongoing disease activity was measured by the Myositis Intention to Treat Index (MITAX). NVC evaluation included assessment of capillary density, capillary apical diameter (mm), and the number of microhemorrhages per digit.Results: Microvascular abnormalities were present in most DM patients. Of these, capillary density (4.71 vs. 6.84, p = 0.006) and mean apical diameter (56.09 vs. 27.79 μm, p = 0.003) significantly improved over the study period in concordance with improving disease control (MITAX 8.53 vs. 2.64, p = 0.002). Longitudinal analysis demonstrated that capillary density was independently associated with MITAX (β = −1.49 [CI −2.49, −0.33], p = 0.013), but not other parameters such as C-reactive protein and creatinine kinase.Conclusions: Nailfold capillary density is a dynamic marker of global disease activity in adult DM. NVC may be utilized as a non-invasive point-of-care tool to monitor disease activity and inform treatment decisions in patients with DM.

Background:. Cognitive impairment is frequently reported by silicone breast implant (SBI) patients. The aim of our study is to investigate whether subjective cognitive failure indeed is more frequent in a cohort of SBI patients compared with healthy controls (HCs). Furthermore, the severity of this cognitive failure and a possible relation to other symptoms as well as the duration of SBI exposure was examined. In addition, we assessed the effect of ruptures and reinterventions on cognitive failure severity. Methods:. A cohort study was performed, including 376 women and consisting of 3 different groups of patients; 143 SBI patients (group 1), 94 age- and sex-matched HC patients (group 2), and 139 women with SBI and health issues who registered themselves at a Dutch foundation for women with illness due to SBI (group 3). All patients filled in the Cognitive Failure Questionnaire (CFQ). The American College of Rheumatology Fibromyalgia Diagnostic Criteria (2010) were used to score other symptoms. Results:. Completed CFQ data from 222 patients were available for analysis: n = 79 for group 1, n = 62 for group 2, and n = 81 for group 3. SBI patients from group 3 had a significantly higher prevalence of subjective cognitive dysfunction (CFQ score ≥ 43) compared with SBI patients from group 1 and HC (60.5% versus 13.9% and 12.9%; P = 0.000). Linear regression showed a statistically significant relation between subjective cognitive functioning scores and other symptoms (P = 0.000). Implant duration as well as rupture rate and reinterventions were not found to significantly influence CFQ scores. Conclusion:. An increased risk of cognitive failure in consecutive SBI patients when compared with HCs could not be found.

Objectives: The activation and inhibition of T-cells has been well-studied under physiological conditions. Co-inhibition is an important mechanism to keep effector T-cells in check. Co-inhibitors mediate peripheral self-tolerance and limit the immune response. Dysfunctional co-inhibition is associated with loss of T-cell regulation and induction of autoimmunity. Therefore, we investigated the co-inhibitor B- and T-Lymphocyte attenuator (BTLA) in ANCA-associated vasculitis (AAV).Methods: Fifty-six AAV patients and 32 healthy controls (HC) were recruited. Flow cytometry was performed to investigate the expression of BTLA on T-cells. Double negative T-cells were defined as CD3+CD4−CD8−. To assess the functionality of BTLA, CFSE-labeled T-cells were stimulated in presence or absence of an agonistic anti-BTLA antibody. In addition, impact of BTLA-mediated co-inhibition on Th17 cells was studied.Results: AAV patients in remission had a decreased expression of BTLA on double negative T-cells (CD3+CD4−CD8−). On all other subtypes of T-cells, expression of BTLA was comparable to healthy controls. TCR-independent stimulation of T-cells resulted in down-regulation of BTLA on Th cells in AAV and HC, being significantly lower in HC. Co-inhibition via BTLA led to suppression of T-cell proliferation in AAV as well as in HC. As a result of BTLA mediated co-inhibition, Th17 cells were suppressed to the same extent in AAV and HC.Conclusion: BTLA expression is altered on double negative T-cells but not on other T-cell subsets in quiescent AAV. BTLA-induced co-inhibition has the capacity to suppress Th17 cells and is functional in AAV. Thus, BTLA-mediated co-inhibition might be exploited for future targeted therapies in AAV.

Objective: The objective of our study is to investigate the Fc glycosylation profiles of both antigen-specific IgG targeted against proteinase 3 (PR3-ANCA) and total IgG as prognostic markers of relapse in patients with Granulomatosis with Polyangiitis (GPA). Methods: Seventy-five patients with GPA and a PR3-ANCA rise during follow-up were included, of whom 43 patients relapsed within a median period of 8 (2–16) months. The N-glycan at Asn297 of affinity-purified and denatured total IgG and PR3-ANCA was determined by mass spectrometry of glycopeptides in samples obtained at the time of the PR3-ANCA rise and at the time of the relapse or time-matched during remission. Results: Patients with total IgG1 exhibiting low galactosylation or low sialylation were highly prone to relapse after an ANCA rise (HR 3.46 [95%-CI 1.73–6.96], p

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in significant morbidity and mortality across the world, with no current effective treatments available. Recent studies suggest the possibility of a cytokine storm associated with severe COVID-19, similar to the biochemical profile seen in hemophagocytic lymphohistiocytosis (HLH), raising the question of possible benefits that could be derived from targeted immunosuppression in severe COVID-19 patients. We reviewed the literature regarding the diagnosis and features of HLH, particularly secondary HLH, and aimed to identify gaps in the literature to truly clarify the existence of a COVID-19 associated HLH. Diagnostic criteria such as HScore or HLH-2004 may have suboptimal performance in identifying COVID-19 HLH-like presentations, and criteria such as soluble CD163, NK cell activity, or other novel biomarkers may be more useful in identifying this entity.

When facing an acute viral infection, our immune systems need to function with finite precision to enable the elimination of the pathogen, whilst protecting our bodies from immune-related damage. In many instances however this “perfect balance” is not achieved, factors such as ageing, cancer, autoimmunity and cardiovascular disease all skew the immune response which is then further distorted by viral infection. In SARS-CoV-2, although the vast majority of COVID-19 cases are mild, as of 24 August 2020, over 800,000 people have died, many from the severe inflammatory cytokine release resulting in extreme clinical manifestations such as acute respiratory distress syndrome (ARDS) and hemophagocytic lymphohistiocytosis (HLH). Severe complications are more common in elderly patients and patients with cardiovascular diseases. Natural killer (NK) cells play a critical role in modulating the immune response and in both of these patient groups, NK cell effector functions are blunted. Preliminary studies in COVID-19 patients with severe disease suggests a reduction in NK cell number and function, resulting in decreased clearance of infected and activated cells, and unchecked elevation of tissue-damaging inflammation markers. SARS-CoV-2 infection skews the immune response towards an overwhelmingly inflammatory phenotype. Restoration of NK cell effector functions has the potential to correct the delicate immune balance required to effectively overcome SARS-CoV-2 infection.

We examined the association between statin use and the risk of rheumatoid arthritis (RA), with special focus on describing the patterns of risks of RA during statin exposure in a large population-based cohort in the United Kingdom. In the Clinical Practice Research Datalink, patients aged ≥40 years with at least one prescription of statins (1995-2009) were selected, and matched by age (+/-5 years), sex, practice and date of first prescription of statins to non-users. The follow-up period of statin use was divided into periods of current, recent and past exposure, with patients moving between these three exposure categories over time. Time-dependent Cox models were used to derive hazard ratios (HRs) of RA, adjusted for disease history and previous drug use. The study population included 1,023,240 patients, of whom 511,620 were statin users. No associations were found between RA and current (HRadj,1.06;99%CI:0.88-1.27) or past statin users (HRadj,1.18;99%CI:0.88-1.57). However, in patients who currently used statins, hazard rates were increased shortly after the first prescription of statins and then gradually decreased to baseline level. The risk of developing RA was increased in recent statin users, as compared to non-users (HRadj,1.39;99%CI:1.01-1.90). The risk of RA is substantially increased in the first year after the start of statins and then diminishes to baseline level. These findings may suggest that statins might accelerate disease onset in patients susceptible to develop RA, but in other patients, statins are probably safe and well tolerated, even after prolonged use. Alternatively, we cannot rule out that confounding by cardiovascular risk factors and ascertainment bias may have influenced the findings.

INTRODUÇÃO: A associação entre infecções e doenças autoimunes (DAIs) está bem descrita na literatura médica. Vários agentes infecciosos foram implicados como indutores de respostas autoimunes, tais como o parvovírus B19, o vírus Epstein-Barr, o citomegalovírus e os vírus da hepatite. PACIENTES E MÉTODOS: Foram examinamos 1.173 soros de pacientes com 14 doenças autoimunes diferentes e 238 soros de controles saudáveis pareados geograficamente na busca por evidência de infecção rubeólica prévia. Todas as amostras foram testadas para a presença de anticorpos séricos contra rubéola usando-se o sistema Bio-Rad BioPlex 2200. RESULTADOS: Como um grupo, os pacientes com DAIs apresentaram maior prevalência de anticorpos IgM antirrubéola em comparação aos controles saudáveis (11,7% versus 5,4%; P = 0,001). A prevalência de anticorpos IgM antirrubéola foi significativamente maior em 5/14 DAIs, a saber: arterite de células gigantes (33,3%), cirrose biliar primária (24%), síndrome antifosfolipídica (20,6%), polimiosite (16%) e doença intestinal inflamatória (16%). Detectou-se prevalência semelhante de anticorpos IgM antirrubéola nos controles de diferentes países. Detectou-se alta prevalência de anticorpos IgG antirrubéola em pacientes com DAIs (89,9%) e controles. CONCLUSÃO: A prevalência aumentada de anticorpos IgM antirrubéola em DAIs sugere que a rubéola possa desempenhar um papel na etiopatogênese de várias DAIs.INTRODUCTION: The association between infections and autoimmune diseases (AID) has been well described in the medical literature. Several infectious agents have been implicated as inducers of autoimmune responses, such as Parvovirus B19, Epstein-Barr virus, cytomegalovirus, and hepatitis viruses. PATIENTS AND METHODS: We examined 1,173 sera from patients with 14 different AID and 238 sera from geographically matched healthy controls, for evidence of prior infection with rubella. All samples were tested for the presence of serum antibodies against rubella using the Bio-Rad BioPlex 2200 system. RESULTS: As a group, patients with AID had a higher prevalence of IgM anti-rubella antibodies as compared to healthy controls (11.7% versus 5.4%; P = 0.001). The prevalence of IgM anti-rubella antibodies was significantly higher in 5/14 AID, namely in patients with giant cell arteritis (33.3%), primary biliary cirrhosis (24%), antiphospholipid syndrome (20.6%), polymyositis (16%), and inflammatory bowel disease (16%). A similar prevalence of IgM anti-rubella antibodies was detected among controls from different countries. A high prevalence of IgG anti-rubella antibodies was detected among patients with AID (89.9%) and controls. CONCLUSION: The increased prevalence of IgM anti-rubella antibodies in AID suggests a possible role for rubella in the etiopathogenesis of several AID.

AIMS: New strategies to overcome complications of cardiovascular diseases are needed. Since it has been demonstrated that atherosclerosis is an inflammatory disease, modulation of the immune system may be a promising approach. Previously, it was suggested that antibodies may confer protective effects on the development of atherosclerosis. In this study, we hypothesised that passive immunization with anti-oxLDL IgM antibodies specific for hypochlorite (HOCl) may be athero-protective in mice. METHODS AND RESULTS: Monoclonal mouse IgM antibodies were produced and the antibody with specificity for hypochlorite-oxLDL (HOCl-oxLDL) (Moab A7S8) was selected. VH sequence determination revealed that Moab A7S8 is a natural IgM antibody. Atherosclerosis in LDLr(-/-) mice was induced by a perivascular collar placement around the right carotid artery in combination with feeding a high-fat diet. Subsequently, the mice were treated every six days with 500 µg Moab A7S8, non-relevant IgM or with PBS and the carotid arteries and aortic roots were studied for atherosclerosis. Passive immunization with this Moab A7S8 resulted in a significant reduced plaque volume formation in LDLr(-/-) mice when compared with PBS treatment (P = 0.002 and P = 0.035). Cholesterol levels decreased by 20% when mice were treated with Moab A7S8 compared to PBS. Furthermore, anti-oxLDL specific IgM and IgG antibody production increased significantly in the Moab A7S8 treated mice in comparison with PBS treated mice. CONCLUSION: Our data show that passive immunization with a natural IgM antibody, directed to HOCl-oxLDL, can reduce atherosclerotic plaque development. We postulate that specific antibody therapy may be developed for use in human cardiovascular diseases.

It has been suggested that statins can both stimulate and suppress the immune system, and thereby, may influence autoimmune diseases. Therefore, we studied effects of statins on innate and adaptive immunity, and self-tolerance by measuring serological levels of C-reactive protein (CRP), neopterin, immunoglobulin E (IgE) antibodies and the presence of autoantibodies (antinuclear antibodies (ANA) and IgM rheumatoid factor (RF)) in the general population. We conducted a nested case-control study within the population-based Doetinchem cohort. Data from health questionnaires, serological measurements and information on medication from linkage to pharmacy-dispensing records were available. We selected 332 statin users (cases) and 331 non-users (controls), matched by age, sex, date of serum collection, history of cardiovascular diseases, diabetes mellitus type II and stroke. Multivariate regression analyses were performed to estimate effect of statins on the immune system. The median level of CRP in statin users (1.28 mg/L, interquartile range (IQR): 0.59-2.79) was lower than in non-users (1.62 mg/L, IQR: 0.79-3.35), which after adjustment was estimated to be a 28% lower level. We observed an inverse association between duration of statin use and CRP levels. Elevated levels of IgE (>100 IU/mL) were more prevalent in statin users compared to non-users. A trend towards increased levels of IgE antibodies in statin users was observed, whereas no associations were found between statin use and levels of neopterin or the presence of autoantibodies. In this general population sub-sample, we observed an anti-inflammatory effect of statin use and a trend towards an increase of IgE levels, an surrogate marker for Th (helper) 2 responses without a decrease in neopterin levels, a surrogate marker for Th1 response and/or self-tolerance. We postulate that the observed decreased inflammatory response during statin therapy may be important but is insufficient to induce loss of self-tolerance.

Immunosuppression is cornerstone treatment of antineutrophil cytoplasmic antibody associated vasculitis (AAV) but is later complicated by infection, cancer, cardiovascular and chronic kidney disease. Caveolin-1 is an essential structural protein for small cell membrane invaginations known as caveolae. Its functional role has been associated with these complications. For the first time, caveolin-1 (CAV1) gene variation is studied in AAV.CAV1 single nucleotide polymorphism rs4730751 was analysed in genomic DNA from 187 white patients with AAV from Birmingham, United Kingdom. The primary outcome measure was the composite endpoint of time to all-cause mortality or renal replacement therapy. Secondary endpoints included time to all-cause mortality, death from sepsis or vascular disease, cancer and renal replacement therapy. Validation of results was sought from 589 white AAV patients, from two European cohorts.The primary outcome occurred in 41.7% of Birmingham patients. In a multivariate model, non-CC genotype variation at the studied single nucleotide polymorphism was associated with increased risk from: the primary outcome measure [HR 1.86; 95% CI: 1.14-3.04; p=0.013], all-cause mortality [HR:1.83; 95% CI: 1.02-3.27; p=0.042], death from infection [HR:3.71; 95% CI: 1.28-10.77; p=0.016], death from vascular disease [HR:3.13; 95% CI: 1.07-9.10; p=0.037], and cancer [HR:5.55; 95% CI: 1.59-19.31; p=0.007]. In the validation cohort, the primary outcome rate was far lower (10.4%); no association between genotype and the studied endpoints was evident.The presence of a CC genotype in Birmingham is associated with protection from adverse outcomes of immunosuppression treated AAV. Lack of replication in the European cohort may have resulted from low clinical event rates. These findings are worthy of further study in larger cohorts.

The ANCA consensus prescribes screening by indirect immunofluorescence on neutrophils. We evaluated the first automated ANCA-pattern recognition system. C-ANCA and P-ANCA samples were selected from patients with ANCA-associated vasculitis (AAV). Non-AAV controls included sera from healthy controls , sera with possible interfering antibodies , or miscellaneous ANCA reactivity . ANCA slides were analysed by AKLIDES and routine fluorescence microscopy. The C-ANCA pattern was recognized by routine microscopy in 92% and 97% on ethanol- and formalin-fixed slides, respectively. AKLIDES reported C-ANCA in 74% and 95%, respectively. P-ANCA was recognized by routine microscopy on ethanol-fixed neutrophils in 90%, while AKLIDES reported P-ANCA in 80%. Typically, only 65% and 33% of these samples showed the expected C-ANCA on formalin-fixed neutrophils by routine microscopy and AKLIDES, respectively. A C- or P-ANCA pattern was observed on ethanol-fixed neutrophils in 28% and 23% of the controls by routine microscopy and AKLIDES, respectively. Only 5% of the controls revealed C-ANCA on formalin-fixed neutrophils by routine microscopy and AKLIDES. Altogether, automated ANCA-pattern recognition by AKLIDES is promising. Distinction of C- and P-ANCA is good, but sensitivity on ethanol-fixed neutrophils needs improvement. When optimized, pattern recognition software may play an important role in AAV diagnostics.

OBJECTIVE: To assess whether there is an association between statin use and the occurrence of polymyalgia rheumatic (PMR) in the spontaneous reporting database of the World Health Organisation (WHO). METHODS: We conducted a case/non-case study based on individual case safety reports (ICSR) in the WHO global ICSR database (VigiBase). Case reports containing the adverse event term polymyalgia rheumatica (WHOART or MedDRA Preferred Term) were defined as cases. Non-cases were all case reports containing other adverse event terms. Each case was matched to five non-cases by age, gender, and time of reporting. Case reports regarding a statin as suspected or concomitant drug were identified using the Anatomical Therapeutic Chemical (ATC) classification. Multivariate logistic regression was used to calculate reporting odds ratios (RORs) with 95% confidence intervals (CI). RESULTS: We identified 327 reports of PMR as cases and 1635 reports of other ADRs as non-cases. Among cases, statins were more frequently reported as suspected agent (29.4%) compared to non-cases (2.9%). After adjustment for several covariates, statins were significantly associated with reports of PMR (ROR 14.21; 95% CI 9.89-20.85). CONCLUSION: The results of this study lends support to previous anecdotal case reports in the literature suggesting that the use of a statin may be associated with the occurrence of PMR. Further studies are needed to study the strength of the association in more detail and to elucidate the underlying mechanism.

BackgroundA poor vitamin D status has been associated with a high disease activity of multiple sclerosis (MS). Recently, we described associations between vitamin D status and peripheral T cell characteristics in relapsing remitting MS (RRMS) patients. In the present study, we studied the effects of high dose vitamin D3 supplementation on safety and T cell related outcome measures.Methodology/principal findingsFifteen RRMS patients were supplemented with 20,000 IU/d vitamin D3 for 12 weeks. Vitamin D and calcium metabolism were carefully monitored, and T cell characteristics were studied by flowcytometry. All patients finished the protocol without side-effects, hypercalcaemia, or hypercalciuria. The median vitamin D status increased from 50 nmol/L (31-175) at week 0 to 380 nmol/L (151-535) at week 12 (PConclusion/significanceTwelve week supplementation of high dose vitamin D3 in RRMS patients was well tolerated and did not induce decompensation of calcium metabolism. The skewing towards an anti-inflammatory cytokine profile supports the evidence on vitamin D as an immune-modulator, and may be used as outcome measure for upcoming randomized placebo-controlled trials.Trial registrationClinicaltrials.gov NCT00940719.

In several autoimmune diseases, including multiple sclerosis (MS), a compromised regulatory T cell (Treg) function is believed to be critically involved in the disease process. In vitro, the biologically active metabolite of vitamin D has been shown to promote Treg development. A poor vitamin D status has been linked with MS incidence and MS disease activity. In the present study, we assess a potential in vivo correlation between vitamin D status and Treg function in relapsing remitting MS (RRMS) patients.Serum levels of 25-hydroxyvitamin D (25(OH)D) were measured in 29 RRMS patients. The number of circulating Tregs was assessed by flow-cytometry, and their functionality was tested in vitro in a CFSE-based proliferation suppression assay. Additionally, the intracellular cytokine profile of T helper cells was determined directly ex-vivo by flow-cytometry. Serum levels of 25(OH)D correlated positively with the ability of Tregs to suppress T cell proliferation (R = 0.590, P = 0.002). No correlation between 25(OH)D levels and the number of Tregs was found. The IFN-gamma/IL-4 ratio (Th1/Th2-balance) was more directed towards IL-4 in patients with favourable 25(OH)D levels (R = -0.435, P = 0.023).These results show an association of high 25(OH)D levels with an improved Treg function, and with skewing of the Th1/Th2 balance towards Th2. These findings suggest that vitamin D is an important promoter of T cell regulation in vivo in MS patients. It is tempting to speculate that our results may not only hold for MS, but also for other autoimmune diseases. Future intervention studies will show whether modulation of vitamin D status results in modulation of the T cell response and subsequent amelioration of disease activity.

In animal models of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), the proportion of CD45RC T cell subsets is important for disease susceptibility. Their human counterparts are, however, functionally ill defined. In this report, we studied their distribution in healthy controls (HC), AAV patients and in Systemic lupus erythematous (SLE) patients as disease controls. We showed that CD45RC expression level on human CD4 and CD8 T cells identifies subsets that are highly variable among individuals. Interestingly, AAV patients exhibit an increased proportion of CD45RC(low) CD4 T cells as compared to HC and SLE patients. This increase is stable over time and independent of AAV subtype, ANCA specificity, disease duration, or number of relapses. We also analyzed the cytokine profile of purified CD4 and CD8 CD45RC T cell subsets from HC, after stimulation with anti-CD3 and anti-CD28 mAbs. The CD45RC subsets exhibit different cytokine profiles. Type-1 cytokines (IL-2, IFN-gamma and TNF-alpha) were produced by all CD45RC T cell subsets, while the production of IL-17, type-2 (IL-4, IL-5) and regulatory (IL-10) cytokines was restricted to the CD45RC(low) subset. In conclusion, we have shown that CD45RC expression divides human T cells in functionally distinct subsets that are imbalanced in AAV. Since this imbalance is stable over time and independent of several disease parameters, we hypothesize that this is a pre-existing immune abnormality involved in the etiology of AAV.