Auto-antibodies to post-translationally modified proteins in osteoarthritis.

OBJECTIVE: Autoantibodies (AutoAbs) have been observed in osteoarthritis (OA) with broad antigenicity, although their prevalence and role remain unclear. Post-translational modification (PTMs) of proteins (oxidation, carbamylation, citrullination) is associated with synovitis and can lead to AutoAb development. Given the prevalence of synovitis, we explored whether AutoAbs to PTM-antigens are common in OA compared with rheumatoid arthritis (RA). METHODS: Serum (n = 895) was obtained from healthy controls, OA and RA patients; and arthritic synovial fluid (SF, n = 290). ELISAs were used to quantify anti-citrullinated peptide (ACPA), anti-carbamylated protein (anti-CarP), anti-oxidized collagen (anti-ROS-CI/CII) antibodies. RESULTS: In sera, positivity for PTM-antigens AutoAbs was observed at a lower frequency in OA with 64.1% (95%CI: 57.2-70.1%) more ACPA+ and 29.8% (21.0-37.3%) more anti-CarP + patients in RA (both P < 0.0001). Levels of ACPA, anti-CarP were also lower in OA (P < 0.0001). Anti-ROS-CII positivity was lower in OA compared to RA (16.6%, 4.8-28.6%) less frequent, P = 0.033) but not anti-native-CII. There was no impact of age/gender on AutoAbs associations with diseases either looking at positivity or levels. In SF, OA patients were often ACPA+ (45.9%) although less frequently than in RA (P = 0.004). Anti-CarP were rarely observed (<5% all samples). All collagen AutoAbs were more frequent in RA compared to OA (all P < 0.010) but only levels of anti-CII and anti-ROS-CII were significantly higher in they RA (P < 0.050). CONCLUSION: Although the frequency of AutoAbs for PTM proteins were lower in OA sera compared to RA, a higher proportion of OA SF were positive. The relative retention of AutoAbs in the OA joint requires further investigation.

Mapping the undergraduate dermatology curriculum: a useful tool towards implementation of national recommendations.

BACKGROUND: Despite the high prevalence of skin complaints in primary care and secondary care, dermatology undergraduate (UG) education remains inconsistent across medical schools. The British Association of Dermatologists (BAD) published a revised national UG curriculum in 2016 to guide UK medical schools on the minimum competencies required in dermatology. AIM: The aim of the study was to determine the alignment of the BAD UG curriculum with the dermatology curriculum of the University of Nottingham School of Medicine. METHODS: A curriculum mapping study was undertaken with the development of an electronic searchable database tool to map key areas. RESULTS: Of the 70 intended learning outcomes (ILOs) for dermatology in the medical school, 55 (79%) were mapped to the BAD curriculum, while 14 (20%) required modifications to align them with the BAD ILOs. Two BAD ILOs were unspecified in the current curriculum, and one was deemed redundant. CONCLUSION: Curriculum mapping is a useful tool to standardize local dermatology ILOs to national recommendations and provides transparency to stakeholders for implementation of the dermatology curriculum.

Antipsychotic treatment resistance in first-episode psychosis: prevalence, subtypes and predictors.

BACKGROUND: We examined longitudinally the course and predictors of treatment resistance in a large cohort of first-episode psychosis (FEP) patients from initiation of antipsychotic treatment. We hypothesized that antipsychotic treatment resistance is: (a) present at illness onset; and (b) differentially associated with clinical and demographic factors. METHOD: The study sample comprised 323 FEP patients who were studied at first contact and at 10-year follow-up. We collated clinical information on severity of symptoms, antipsychotic medication and treatment adherence during the follow-up period to determine the presence, course and predictors of treatment resistance. RESULTS: From the 23% of the patients, who were treatment resistant, 84% were treatment resistant from illness onset. Multivariable regression analysis revealed that diagnosis of schizophrenia, negative symptoms, younger age at onset, and longer duration of untreated psychosis predicted treatment resistance from illness onset. CONCLUSIONS: The striking majority of treatment-resistant patients do not respond to first-line antipsychotic treatment even at time of FEP. Clinicians must be alert to this subgroup of patients and consider clozapine treatment as early as possible during the first presentation of psychosis.

Biological and psychosocial risk factors for psychotic major depression.

AIMS: Few studies have investigated risk factors for psychotic major depression (PMD). We aimed to investigate the biological and psychosocial risk factors associated with PMD compared with other psychotic disorders. METHODS: Based on the aetiology and ethnicity in schizophrenia and other psychoses (ÆSOP) study, we used a case-control study to identify and recruit, at baseline and 10-year follow-up, all first episode cases of psychosis, presenting for the first time to specialist mental health services in defined catchment areas in the UK. Population-based controls were recruited from the same areas. Data were collected on: sociodemographics; social isolation; childhood adversity; life events; minor physical anomalies; and neurological soft signs. RESULTS: Living alone (aOR = 2.26, CI = 1.21-4.23), basic level qualification (aOR = 2.89, CI = 1.08-7.74), being unemployed (aOR = 2.12, CI = 1.13-3.96), having contact with friends less than monthly (aOR = 4.24, CI = 1.62-11.14), having no close confidants (aOR = 4.71, CI = 2.08-10.68), having experienced childhood adversity (aOR = 2.57, CI = 1.02-6.44), family history of mental illness (aOR = 10.68, CI = 5.06-22.52), family history of psychosis (aOR = 12.85, CI = 5.24-31.51), and having more neurological soft signs (aOR = 1.15, CI = 1.07-1.24) were all associated with a follow-up diagnosis of PMD and schizophrenia. Few variables associated with PMD were also associated with a diagnosis of bipolar disorder. Minor physical anomalies were associated with a follow-up diagnosis of schizophrenia and bipolar disorder, but not PMD. CONCLUSIONS: Risk factors associated with PMD appear to overlap with those for schizophrenia, but less so for bipolar disorder. Future work on the differential aetiology of PMD, from other psychoses is needed to find the 'specifier' between PMD and other psychoses. Future research on aetiology in PMD, and perhaps other psychoses, should account for diagnostic change.

Diagnostic change 10 years after a first episode of psychosis.

BACKGROUND: A lack of an aetiologically based nosology classification has contributed to instability in psychiatric diagnoses over time. This study aimed to examine the diagnostic stability of psychosis diagnoses using data from an incidence sample of psychosis cases, followed up after 10 years and to examine those baseline variables which were associated with diagnostic change. METHOD: Data were examined from the ÆSOP and ÆSOP-10 studies, an incidence and follow-up study, respectively, of a population-based cohort of first-episode psychosis cases from two sites. Diagnosis was assigned using ICD-10 and DSM-IV-TR. Diagnostic change was examined using prospective and retrospective consistency. Baseline variables associated with change were examined using logistic regression and likelihood ratio tests. RESULTS: Slightly more (59.6%) cases had the same baseline and lifetime ICD-10 diagnosis compared with DSM-IV-TR (55.3%), but prospective and retrospective consistency was similar. Schizophrenia, psychotic bipolar disorder and drug-induced psychosis were more prospectively consistent than other diagnoses. A substantial number of cases with other diagnoses at baseline (ICD-10, n = 61; DSM-IV-TR, n = 76) were classified as having schizophrenia at 10 years. Many variables were associated with change to schizophrenia but few with overall change in diagnosis. CONCLUSIONS: Diagnoses other than schizophrenia should to be regarded as potentially provisional.

The effect of the environment on symptom dimensions in the first episode of psychosis: a multilevel study.

BACKGROUND: The extent to which different symptom dimensions vary according to epidemiological factors associated with categorical definitions of first-episode psychosis (FEP) is unknown. We hypothesized that positive psychotic symptoms, including paranoid delusions and depressive symptoms, would be more prominent in more urban environments. METHOD: We collected clinical and epidemiological data on 469 people with FEP (ICD-10 F10-F33) in two centres of the Aetiology and Ethnicity in Schizophrenia and Other Psychoses (AESOP) study: Southeast London and Nottinghamshire. We used multilevel regression models to examine neighbourhood-level and between-centre differences in five symptom dimensions (reality distortion, negative symptoms, manic symptoms, depressive symptoms and disorganization) underpinning Schedules for Clinical Assessment in Neuropsychiatry (SCAN) Item Group Checklist (IGC) symptoms. Delusions of persecution and reference, along with other individual IGC symptoms, were inspected for area-level variation. RESULTS: Reality distortion [estimated effect size (EES) 0.15, 95% confidence interval (CI) 0.06-0.24] and depressive symptoms (EES 0.21, 95% CI 0.07-0.34) were elevated in people with FEP living in more urban Southeast London but disorganized symptomatology was lower (EES -0.06, 95% CI -0.10 to -0.02), after controlling for confounders. Delusions of persecution were not associated with increased neighbourhood population density [adjusted odds ratio (aOR) 1.01, 95% CI 0.83-1.23], although an effect was observed for delusions of reference (aOR 1.41, 95% CI 1.12-1.77). Hallucinatory symptoms showed consistent elevation in more densely populated neighbourhoods (aOR 1.32, 95% CI 1.09-1.61). CONCLUSIONS: In people experiencing FEP, elevated levels of reality distortion and depressive symptoms were observed in more urban, densely populated neighbourhoods. No clear association was observed for paranoid delusions; hallucinations were consistently associated with increased population density. These results suggest that urban environments may affect the syndromal presentation of psychotic disorders.

Reappraising the long-term course and outcome of psychotic disorders: the AESOP-10 study.

BACKGROUND: Studies of the long-term course and outcome of psychoses tend to focus on cohorts of prevalent cases. Such studies bias samples towards those with poor outcomes, which may distort our understanding of prognosis. Long-term follow-up studies of epidemiologically robust first-episode samples are rare. METHOD: AESOP-10 is a 10-year follow-up study of 557 individuals with a first episode of psychosis initially identified in two areas in the UK (South East London and Nottingham). Detailed information was collated on course and outcome in three domains (clinical, social and service use) from case records, informants and follow-up interviews. RESULTS: At follow-up, of 532 incident cases identified, at baseline 37 (7%) had died, 29 (6%) had emigrated and eight (2%) were excluded. Of the remaining 458, 412 (90%) were traced and some information on follow-up was collated for 387 (85%). Most cases (265, 77%) experienced at least one period of sustained remission; at follow-up, 141 (46%) had been symptom free for at least 2 years. A majority (208, 72%) of cases had been employed for less than 25% of the follow-up period. The median number of hospital admissions, including at first presentation, was 2 [interquartile range (IQR) 1-4]; a majority (299, 88%) were admitted a least once and a minority (21, 6%) had 10 or more admissions. Overall, outcomes were worse for those with a non-affective diagnosis, for men and for those from South East London. CONCLUSIONS: Sustained periods of symptom remission are usual following first presentation to mental health services for psychosis, including for those with a non-affective disorder; almost half recover.

Modelling the interplay between childhood and adult adversity in pathways to psychosis: initial evidence from the AESOP study.

BACKGROUND: There is evidence that a range of socio-environmental exposures is associated with an increased risk of psychosis. However, despite the fact that such factors probably combine in complex ways to increase risk, the majority of studies have tended to consider each exposure separately. In light of this, we sought to extend previous analyses of data from the AESOP (Aetiology and Ethnicity in Schizophrenia and Other Psychoses) study on childhood and adult markers of disadvantage to examine how they combine to increase risk of psychosis, testing both mediation (path) models and synergistic effects. METHOD: All patients with a first episode of psychosis who made contact with psychiatric services in defined catchment areas in London and Nottingham, UK (n = 390) and a series of community controls (n = 391) were included in the AESOP study. Data relating to clinical and social variables, including parental separation and loss, education and adult disadvantage, were collected from cases and controls. RESULTS: There was evidence that the effect of separation from, but not death of, a parent in childhood on risk of psychosis was partially mediated through subsequent poor educational attainment (no qualifications), adult social disadvantage and, to a lesser degree, low self-esteem. In addition, there was strong evidence that separation from, but not death of, a parent combined synergistically with subsequent disadvantage to increase risk. These effects held for all ethnic groups in the sample. CONCLUSIONS: Exposure to childhood and adult disadvantage may combine in complex ways to push some individuals along a predominantly sociodevelopmental pathway to psychosis.

Individualized prediction of illness course at the first psychotic episode: a support vector machine MRI study.

BACKGROUND: To date, magnetic resonance imaging (MRI) has made little impact on the diagnosis and monitoring of psychoses in individual patients. In this study, we used a support vector machine (SVM) whole-brain classification approach to predict future illness course at the individual level from MRI data obtained at the first psychotic episode. METHOD: One hundred patients at their first psychotic episode and 91 healthy controls had an MRI scan. Patients were re-evaluated 6.2 years (s.d.=2.3) later, and were classified as having a continuous, episodic or intermediate illness course. Twenty-eight subjects with a continuous course were compared with 28 patients with an episodic course and with 28 healthy controls. We trained each SVM classifier independently for the following contrasts: continuous versus episodic, continuous versus healthy controls, and episodic versus healthy controls. RESULTS: At baseline, patients with a continuous course were already distinguishable, with significance above chance level, from both patients with an episodic course (p=0.004, sensitivity=71, specificity=68) and healthy individuals (p=0.01, sensitivity=71, specificity=61). Patients with an episodic course could not be distinguished from healthy individuals. When patients with an intermediate outcome were classified according to the discriminating pattern episodic versus continuous, 74% of those who did not develop other episodes were classified as episodic, and 65% of those who did develop further episodes were classified as continuous (p=0.035). CONCLUSIONS: We provide preliminary evidence of MRI application in the individualized prediction of future illness course, using a simple and automated SVM pipeline. When replicated and validated in larger groups, this could enable targeted clinical decisions based on imaging data.

The differential effect of illicit drug use on cognitive function in first-episode psychosis and healthy controls.

OBJECTIVE: Illicit drug use can result in impairment in cognitive function in healthy individuals. Individuals with a psychotic disorder also show a deficit in cognitive function. Drug use may simply contribute to the characteristic cognitive deficit found in psychosis or alternatively result in a 'double deficit'. This study aims to investigate the association between drug use and cognitive function at the first-episode of psychosis and in community-matched controls. METHOD: One hundred and seventy-seven patients at the first episode of psychosis completed a battery of neuropsychological tests. Those that had used drugs in the previous year (n = 80) were compared with those who had not used drugs in the previous year (n = 97). A subsample of the first-episode psychosis patients were compared with community-matched controls (n = 110) according to drug-use status. RESULTS: Patients with a first episode of psychosis who had used drugs performed equally to those who had not used drugs on neuropsychological tests. In contrast, healthy controls who had used drugs in the previous year performed worse on tests of executive function and working memory compared with those controls that had not used drugs. CONCLUSION: There are differential associations of illicit drug misuse with cognitive function for first-episode psychosis patients and healthy controls.

Inhibition of the B cell by CD22: a requirement for Lyn.

Mice in which the Lyn, Cd22, or Shp-1 gene has been disrupted have hyperactive B cells and autoantibodies. We find that in the absence of Lyn, the ability of CD22 to become tyrosine phosphorylated after ligation of mIg, to recruit SHP-1, and to suppress mIg-induced elevation of intracellular [Ca2+] is lost. Therefore, Lyn is required for the SHP-1-mediated B cell suppressive function of CD22, accounting for similarities in the phenotypes of these mice.

The varying impact of type, timing and frequency of exposure to childhood adversity on its association with adult psychotic disorder.

BACKGROUND: Childhood adversity has been associated with onset of psychosis in adulthood but these studies have used only general definitions of this environmental risk indicator. Therefore, we sought to explore the prevalence of more specific adverse childhood experiences amongst those with and without psychotic disorders using detailed assessments in a large epidemiological case-control sample (AESOP). METHOD: Data were collected on 182 first-presentation psychosis cases and 246 geographically matched controls in two UK centres. Information relating to the timing and frequency of exposure to different types of childhood adversity (neglect, antipathy, physical and sexual abuse, local authority care, disrupted living arrangements and lack of supportive figure) was obtained using the Childhood Experience of Care and Abuse Questionnaire. RESULTS: Psychosis cases were three times more likely to report severe physical abuse from the mother that commenced prior to 12 years of age, even after adjustment for other significant forms of adversity and demographic confounders. A non-significant trend was also evident for greater prevalence of reported severe maternal antipathy amongst those with psychosis. Associations with maternal neglect and childhood sexual abuse disappeared after adjusting for maternal physical abuse and antipathy. Paternal maltreatment and other forms of adversity were not associated with psychosis nor was there evidence of a dose-response effect. CONCLUSIONS: These findings suggest that only specific adverse childhood experiences are associated with psychotic disorders and only in a minority of cases. If replicated, this greater precision will ensure that research into the mechanisms underlying the pathway from childhood adversity to psychosis is more fruitful.

Illicit substance use and its correlates in first episode psychosis.

OBJECTIVE: To determine if substance use (particularly cannabis) is more frequent among first episode psychosis patients and associated with a more problematic clinical presentation. METHOD: All first episode psychosis (FEP) patients presenting to secondary services were recruited from London and Nottingham, over 2 years, in the Aetiology and Ethnicity of Schizophrenia and Other Psychoses study broad framework. Clinical and sociodemographic variables were assessed using a set of standardized instruments. A schedule was created to retrospectively collate substance use data from patients, relatives and clinicians. RESULTS: Five hundred and eleven FEP were identified. They used three to five times more substances than general population. Substance use was associated with poorer social adjustment and a more acute mode of onset. Cannabis use did not affect social adjustment, but was associated with a more acute mode of onset. CONCLUSION: Cannabis has a different impact on FEP than other substances. Large epidemiological studies are needed to disentangle cannabis effect.

A role in B cell activation for CD22 and the protein tyrosine phosphatase SHP.

CD22 is a membrane immunoglobulin (mIg)-associated protein of B cells. CD22 is tyrosine-phosphorylated when mIg is ligated. Tyrosine-phosphorylated CD22 binds and activates SHP, a protein tyrosine phosphatase known to negatively regulate signaling through mIg. Ligation of CD22 to prevent its coaggregation with mIg lowers the threshold at which mIg activates the B cell by a factor of 100. In secondary lymphoid organs, CD22 may be sequestered away from mIg through interactions with counterreceptors on T cells. Thus, CD22 is a molecular switch for SHP that may bias mIg signaling to anatomic sites rich in T cells.

Ethnicity, social disadvantage and psychotic-like experiences in a healthy population based sample.

OBJECTIVE: We sought to investigate the prevalence and social correlates of psychotic-like experiences in a general population sample of Black and White British subjects. METHOD: Data were collected from randomly selected community control subjects, recruited as part of the AESOP study, a three-centre population based study of first-episode psychosis. RESULTS: The proportion of subjects reporting one or more psychotic-like experience was 19% (n = 72/372). These were more common in Black Caribbean (OR 2.08) and Black African subjects (OR 4.59), compared with White British. In addition, a number of indicators of childhood and adult disadvantage were associated with psychotic-like experiences. When these variables were simultaneously entered into a regression model, Black African ethnicity, concentrated adult disadvantage, and separation from parents retained a significant effect. CONCLUSION: The higher prevalence of psychotic-like experiences in the Black Caribbean, but not Black African, group was explained by high levels of social disadvantage over the life course.

Early sustained recovery following first episode psychosis: Evidence from the AESOP10 follow-up study.

OBJECTIVE: To describe the characteristics of individuals with early sustained recovery following first episode psychosis. METHODS: Individuals with a first episode psychosis were followed-up for ten years. Comparisons were made between those with Early Sustained Recovery and those with Other Course types. RESULTS: Of 345 individuals, n=43 (12.5%) had Early Sustained Recovery. They were more likely than those with Other Course types to be female (OR=2.45; 95% CI: 1.25-4.81); employed (OR=2.39; 95% CI: 1.22-4.69); in a relationship (OR=2.68; 95% CI: 1.35-5.32); have a short DUP (OR=2.86; 95% CI: 1.37-5.88); and have a diagnosis other than schizophrenia, particularly mania (OR=6.39; 95% CI: 2.52-16.18) or brief psychosis (OR=3.64; 95% CI: 1.10-12.10). CONCLUSIONS: Sustained recovery from first episode psychosis occurs in a minority.

A novel two-score system for interferon status segregates autoimmune diseases and correlates with clinical features.

Measurement of type I interferon (IFN-I) has potential to diagnose and stratify autoimmune diseases, but existing results have been inconsistent. Interferon-stimulated-gene (ISG) based methods may be affected by the modularity of the ISG transcriptome, cell-specific expression, response to IFN-subtypes and bimodality of expression. We developed and clinically validated a 2-score system (IFN-Score-A and -B) using Factor Analysis of 31 ISGs measured by TaqMan selected from 3-IFN-annotated modules. We evaluated these scores using in-vitro IFN stimulation as well as in sorted cells then clinically validated in a cohort of 328 autoimmune disease patients and healthy controls. ISGs varied in response to IFN-subtypes and both scores varied between cell subsets. IFN-Score-A differentiated Systemic Lupus Erythematosus (SLE) from both Rheumatoid Arthritis (RA) and Healthy Controls (HC) (both p < 0.001), while IFN-Score-B differentiated SLE and RA from HC (both p < 0.001). In SLE, both scores were associated with cutaneous and hematological (all p < 0.05) but not musculoskeletal disease activity. Comparing with bimodal (IFN-high/low) classification, significant differences in IFN-scores were found between diagnostic groups within the IFN-high group. Our continuous 2-score system is more clinically relevant than a simple bimodal classification of IFN status. This system should allow improvement in diagnosis, stratification, and therapy in IFN-mediated autoimmunity.

Publisher Correction: A novel two-score system for interferon status segregates autoimmune diseases and correlates with clinical features.

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Activation of B lymphocytes: integrating signals from CD19, CD22 and Fc gamma RIIb1.

Three accessory membrane proteins, CD19, CD22 and Fc gamma RIIb1, alter signaling through membrane immunoglobulin of B cells by binding cytosolic proteins containing SH2 domains. Recent biochemical and genetic studies have shown that these receptors enable B cells to amplify responses to certain T-cell-dependent antigens (CD19), to restrict their response to T-cell zones of secondary lymphoid organs (CD22), and to dampen their response to antigens for which IgG is already available (Fc gamma RIIb1).

Minor physical anomalies across ethnic groups in a first episode psychosis sample.

Minor physical anomalies (MPAs) are more prevalent amongst individuals with psychosis, supporting a neurodevelopmental model for psychotic disorders. The aim of this study was to investigate the possibility that neurodevelopmental adversity contributes to the excess of psychosis found in some ethnic groups in the UK. Subjects with first onset psychosis and healthy neighbourhood controls were enrolled in the AESOP study in South East London and Nottingham between 1997 and 1999. MPA rates were estimated in four broad ethnic groupings (White, African Caribbean, Black African and Other). Patients (n=245) had a higher mean total MPA score than healthy controls (n=158). This held true across each of the four ethnic groupings. The results of this study suggest that neurodevelopmental factors play a role in the aetiology of psychosis across all ethnic groups.