Identifying prior signals of bipolar disorder using primary care electronic health records: a nested case-control study.

BACKGROUND: Bipolar disorders are serious mental illnesses, yet evidence suggests that the diagnosis and treatment of bipolar disorder can be delayed by around 6 years. AIM: To identify signals of undiagnosed bipolar disorder using routinely collected electronic health records. DESIGN AND SETTING: A nested case-control study conducted using the UK Clinical Practice Research Datalink (CPRD) GOLD dataset, an anonymised electronic primary care patient database linked with hospital records. 'Cases' were adult patients with incident bipolar disorder diagnoses between 1 January 2010 and 31 July 2017. METHOD: The patients with bipolar disorder (the bipolar disorder group) were matched by age, sex, and registered general practice to 20 'controls' without recorded bipolar disorder (the control group). Annual episode incidence rates were estimated and odds ratios from conditional logistic regression models were reported for recorded health events before the index (diagnosis) date. RESULTS: There were 2366 patients with incident bipolar disorder diagnoses and 47 138 matched control patients (median age 40 years and 60.4% female: n = 1430/2366 with bipolar disorder and n = 28 471/47 138 without). Compared with the control group, the bipolar disorder group had a higher incidence of diagnosed depressive, psychotic, anxiety, and personality disorders and escalating self-harm up to 10 years before a bipolar disorder diagnosis. Sleep disturbance, substance misuse, and mood swings were more frequent among the bipolar disorder group than the control group. The bipolar disorder group had more frequent face-to-face consultations, and were more likely to miss multiple scheduled appointments and to be prescribed ≥3 different psychotropic medication classes in a given year. CONCLUSION: Psychiatric diagnoses, psychotropic prescriptions, and health service use patterns might be signals of unreported bipolar disorder. Recognising these signals could prompt further investigation for undiagnosed significant psychopathology, leading to timely referral, assessment, and initiation of appropriate treatments.

Mapping opportunities for the earlier diagnosis of psoriasis in primary care settings in the UK: results from two matched case-control studies.

BACKGROUND: The diagnosis of psoriasis may be missed or delayed in primary care settings. AIM: To examine trends in healthcare events before a diagnosis of psoriasis. DESIGN AND SETTING: Two matched case-control studies using electronic healthcare records delineated from the Clinical Practice Research Datalink (CPRD GOLD and Aurum) in the UK. METHOD: Individuals aged ≥18 years with an incident diagnosis of psoriasis (case group) between 1 January 2010 and 29 December 2017 were identified and matched by age, sex, and general practice with six individuals without psoriasis (control group). Healthcare activities were examined and annual incidence rates and incidence rate ratios (IRRs) with 95% confidence intervals (CIs) for 10 years before the index date were compared between case and control groups. RESULTS: There were 17 320 people with psoriasis and 99 320 controls included from CPRD GOLD, and 11 442 people with psoriasis and 65 840 controls extracted from CPRD Aurum. Data from CPRD GOLD showed that people with psoriasis were up to eight times more likely to be diagnosed with pityriasis rosea at 6 months (IRR 7.82, 95% CI = 4.09 to 14.95) before the index date than the control group. The case group were twice as likely to be diagnosed with eczema (IRR 1.90, 95% CI = 1.76 to 2.05) or tinea corporis (IRR 1.99, 95% CI = 1.74 to 2.27) 1 year before the index date. The case group were more likely to report dry skin, rash, skin texture changes, and itching than the control group up to 5 years before the index date. The most frequently reported clinical feature was rash with an IRR of 2.71 (95% CI = 2.53 to 2.92) at 1 year before the index date. The case group were prescribed topical corticosteroids (IRR 1.97, 95% CI = 1.88 to 2.07) or topical antifungals (IRR 1.92, 95% CI = 1.78 to 2.07) in the year before the index date twice as often as those in the control group. CONCLUSION: Findings suggest that the diagnosis of psoriasis may be missed or delayed in a UK primary care setting for up to 5 years for some individuals, hence leading to a potentially detrimental delay in establishing an appropriate treatment regimen.

Self-harm risk in pregnancy: recurrent-event survival analysis using UK primary care data.

BACKGROUND: Perinatal self-harm is of concern but poorly understood. AIMS: To determine if women's risk of self-harm changes in pregnancy and the first postpartum year, and if risk varies by mental illness, age and birth outcome. METHOD: This was a retrospective cohort study of 2 666 088 women aged 15-45 years from the 1 January 1990 to 31 December 2017 linked to 1 102 040 pregnancies and their outcomes, utilising the Clinical Practice Research Datalink and Pregnancy Register. We identified self-harm events and mental illness (depression/anxiety/addiction/affective/non-affective psychosis/eating/personality disorders) from clinical records and grouped women's age into 5-year bands. They calculated the rate of self-harm during discrete non-perinatal, pregnant and postpartum periods. We used a gap-time, stratified Cox model to manage multiple self-harm events, and calculated the unadjusted and adjusted hazard ratios (adjHR) of self-harm associated with pregnancy and the postpartum compared with non-perinatal periods. Pre-planned interactions tested if risk varied by mental illness, age and birth outcome. RESULTS: The analysis included 57 791 self-harm events and 14 712 319 person-years of follow-up. The risk of self-harm shrank in pregnancy (2.07 v. 4.01 events/1000 person-years, adjHR = 0.53, 95% CI 0.49-0.58) for all women except for 15- to 19-year-olds (adjHR = 0.95, 95% CI 0.84-1.07) and the risk reduced most for women with mental illness (adjHR = 0.40, 95% CI 0.36-0.44). Postpartum, self-harm risk peaked at 6-12 months (adjHR = 1.08, 95% CI 1.02-1.15), at-risk groups included young women and women with a pregnancy loss or termination. CONCLUSIONS: Maternity and perinatal mental health services are valuable. Family planning services might have psychological benefit, particularly for young women.

How Do Glucocorticoids Used in Rheumatic Disease Affect Body Weight? A Narrative Review of the Evidence.

Glucocorticoids (GCs) are widely used to effectively treat inflammatory disease, but GCs have a number of recognized side effects. Patients and clinicians view these side effects differently, with clinicians most concerned with serious side effects such as osteoporosis and diabetes mellitus. Consequently, these side effects are well researched with clinical guidelines and recommendations. A side effect of particular concern to patients is weight gain, but this topic has not been well researched, and consequently clinicians find it difficult to provide patients with accurate information about the potential of weight gain. The aim of this review is to provide an overview of GC use specifically in rheumatic disease, patient views on GC therapy, and GC-induced weight gain. We will discuss the evidence, including the extent and the impact of weight gain on the patient, and highlight areas that warrant further investigation.

Self-harm in a primary care cohort of older people: incidence, clinical management, and risk of suicide and other causes of death.

BACKGROUND: Self-harm is a major risk factor for suicide, with older adults (older than 65 years) having reportedly greater suicidal intent than any other age group. With the aging population rising and paucity of research focus in this age group, the extent of the problem of self-harm needs to be established. In a primary care cohort of older adults we aimed to investigate the incidence of self-harm, subsequent clinical management, prevalence of mental and physical diagnoses, and unnatural-cause mortality risk, including suicide. METHODS: The UK Clinical Practice Research Datalink contains anonymised patient records from general practice that routinely capture clinical information pertaining to both primary and secondary care services. We identified 4124 adults aged 65 years and older with a self-harm episode ascertained from Read codes recorded during 2001-14. We calculated standardised incidence and in 2854 adults with at least 12 months follow-up examined the frequency of psychiatric referrals and prescription of psychotropic medication after self-harm. We estimated prevalence of mental and physical illness diagnoses before and after self-harm and, using Cox regression in a matched cohort, we examined cause-specific mortality risks. FINDINGS: Overall incidence of self-harm in older adults aged 65 years and older was 4·1 per 10 000 person-years with stable gender-specific rates observed over the 13-year period. After self-harm, 335 (11·7%) of 2854 adults were referred to mental health services, 1692 (59·3%) were prescribed an antidepressant, and 336 (11·8%) were prescribed a tricyclic antidepressant (TCA). Having a diagnosed previous mental illness was twice as prevalent in the self-harm cohort as in the comparison cohort (prevalence ratio 2·10 [95% CI 2·03-2·17]) and with a previous physical health condition prevalence was 20% higher in the self-harm cohort compared to the comparison cohort (1·20 [1·17-1·23]). Adults from the self-harm cohort (n=2454) died from unnatural causes an estimated 20 times more frequently than the comparison cohort (n=48 921) during the first year. A markedly elevated risk of suicide (hazard ratio 145·4 [95% CI 53·9-392·3]) was observed in the self-harm cohort. INTERPRETATION: Within primary care, we have identified a group of older adults at high risk from unnatural death, particularly within the first year of self-harm. We have highlighted a high frequency of prescription of TCAs, known to be potentially fatally toxic in overdose. We emphasise the need for early intervention, careful alternative prescribing, and increased support when older adults consult after an episode of self-harm and with other health conditions. FUNDING: National Institute for Health Research Greater Manchester Patient Safety Translational Research Centre.

Incidence, clinical management, and mortality risk following self harm among children and adolescents: cohort study in primary care.

Objectives To examine temporal trends in sex and age specific incidence of self harm in children and adolescents, clinical management patterns, and risk of cause specific mortality following an index self harm episode at a young age.Design Population based cohort study.Setting UK Clinical Practice Research Datalink-electronic health records from 647 general practices, with practice level deprivation measured ecologically using the index of multiple deprivation. Patients from eligible English practices were linked to hospital episode statistics (HES) and Office for National Statistics (ONS) mortality records.Participants For the descriptive analytical phases we examined data pertaining to 16 912 patients aged 10-19 who harmed themselves during 2001-14. For analysis of cause specific mortality following self harm, 8638 patients eligible for HES and ONS linkage were matched by age, sex, and general practice with up to 20 unaffected children and adolescents (n=170 274).Main outcome measures In the first phase, temporal trends in sex and age specific annual incidence were examined. In the second phase, clinical management was assessed according to the likelihood of referral to mental health services and psychotropic drug prescribing. In the third phase, relative risks of all cause mortality, unnatural death (including suicide and accidental death), and fatal acute alcohol or drug poisoning were estimated as hazard ratios derived from stratified Cox proportional hazards models for the self harm cohort versus the matched unaffected comparison cohort.Results The annual incidence of self harm was observed to increase in girls (37.4 per 10 000) compared with boys (12.3 per 10 000), and a sharp 68% increase occurred among girls aged 13-16, from 45.9 per 10 000 in 2011 to 77.0 per 10 000 in 2014. Referrals within 12 months of the index self harm episode were 23% less likely for young patients registered at the most socially deprived practices, even though incidences were considerably higher in these localities. Children and adolescents who harmed themselves were approximately nine times more likely to die unnaturally during follow-up, with especially noticeable increases in risks of suicide (deprivation adjusted hazard ratio 17.5, 95% confidence interval 7.6 to 40.5) and fatal acute alcohol or drug poisoning (34.3, 10.2 to 115.7).Conclusions Gaining a better understanding of the mechanisms responsible for the recent apparent increase in the incidence of self harm among early-mid teenage girls, and coordinated initiatives to tackle health inequalities in the provision of services to distressed children and adolescents, represent urgent priorities for multiple public agencies.

Evaluation of the immunogenicity and impact on the latent HIV-1 reservoir of a conserved region vaccine, MVA.HIVconsv, in antiretroviral therapy-treated subjects.

INTRODUCTION: Vaccines may be key components of a curative strategy for HIV-1. We investigated whether a novel immunogen, HIVconsv, designed to re-direct T cell responses to conserved viral epitopes, could impact the HIV-1 reservoir in chronic antiretroviral therapy (ART)-treated subjects when delivered by modified vaccinia virus Ankara (MVA). METHODS: Nineteen virologically suppressed individuals were randomized to receive vaccinations with MVA.HIVconsv (5.5 × 107 plaque-forming units, pfu, n = 8; 2.2 × 108 pfu, n = 7) or placebo (n = 4) at 0, 4 and 12 weeks. Magnitude, breadth and antiviral function of vaccine-induced T cells, cell-associated HIV-1 DNA in circulating CD4+ T cells and residual viremia in plasma were measured before and after vaccination. RESULTS: 90% of subjects completed the vaccine regimen; there were no serious vaccine-related adverse events. The magnitude of HIVconsv-specific IFN-γ-secreting T cells was not significantly boosted in vaccinees when compared with placebos in ex vivo Elispot assays, due to greater than expected variation in HIV-specific T cell responses in the latter during the observation period. Ex vivo CD8+ T cell viral inhibitory capacity was modest but significantly increased post-vaccination with MVA.HIVconsv at the higher dose (p = 0.004) and was positively correlated with the frequency of HIVconsv-specific CD8+ CD107+ IFN-α± T cells (r = 0.57, p = 0.01). Total HIV-1 DNA and residual viral load did not change significantly from baseline in any group. CONCLUSIONS: Homologous prime-boost vaccination with MVA.HIVconsv was safe in HIV-positive ART-treated subjects but showed modest immunogenicity and did not significantly change the size of the viral reservoir. MVA.HIVconsv may be more effective when used in a heterologous prime-boost vaccination regimen and when combined with a latency-reversing agent. CLINICAL TRIALS REGISTRATION: NCT01024842.

The influence of behavioural and psychological factors on medication adherence over time in rheumatoid arthritis patients: a study in the biologics era.

OBJECTIVES: To investigate levels of self-reported adherence to biologic treatment and establish the contribution of demographic, physical and psychological factors to biologic medication adherence in an RA cohort. METHODS: Adalimumab-treated patients were recruited through the British Society for Rheumatology Biologics Register for RA between May 2007 and April 2009. Demographic and baseline psychological measures including illness and medication beliefs were collected. Disease activity (28-item DAS), physical function (HAQ) and quality of life (36-item Short Form Health Survey) were also measured at baseline and at 6, 12 and 18 months. Adherence was assessed at each follow-up using the patient self-completed Compliance Questionnaire for Rheumatology (CQR). Multilevel mixed effects modelling analysis was performed to investigate predictors of adherence. RESULTS: Of the 329 Adalimumab-treated patients included, low adherence (CQR score <65) was reported in 23%, with 41% reporting low adherence at at least one time point. After controlling for age and disease duration, factors independently predictive of increased adherence were increased belief in medication necessity, with baseline effect diminishing over time [ß coefficient 1.68 (s.e. 0.19), P = 0.0001], lower medication concerns [0.50 (0.15), P = 0.001], with this effect remaining throughout follow-up, increased professional or family member support [0.81 (0.32), P = 0.01], strong views of illness being chronic [0.32 (0.14), P = 0.025] and increased treatment control [0.41 (0.19), P = 0.032]. CONCLUSION: Wider recognition of the importance of psychological factors, particularly medication beliefs, in driving medication adherence could have substantial clinical and health economic benefits in RA. The psychological factors we have identified are putative targets for strategies to improve adherence in RA.

Impact of inadequate adherence on response to subcutaneously administered anti-tumour necrosis factor drugs: results from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort.

OBJECTIVE: Non-adherence to DMARDs is common, but little is known about adherence to biologic therapies and its relationship to treatment response. The purpose of this study was to investigate the association between self-reported non-adherence to s.c. anti-TNF therapy and response in individuals with RA. METHODS: Participants about to start s.c. anti-TNF therapy were recruited to a large UK multicentre prospective observational cohort study. Demographic information and disease characteristics were assessed at baseline. Self-reported non-adherence, defined as whether the previous due dose of biologic therapy was reported as not taken on the day agreed with the health care professional, was recorded at 3 and 6 months following the start of therapy. The 28-joint DAS (DAS28) was recorded at baseline and following 3 and 6 months of therapy. Multivariate linear regression was used to examine these relationships. RESULTS: Three hundred and ninety-two patients with a median disease duration of 7 years [interquartile range (IQR) 3-15] were recruited. Adherence data were available in 286 patients. Of these, 27% reported non-adherence to biologic therapy according to the defined criteria at least once within the first 6-month period. In multivariate linear regression analysis, older age, lower baseline DAS28 and ever non-adherence at either 3 or 6 months from baseline were significantly associated with a poorer DAS28 response at 6 months to anti-TNF therapy. CONCLUSION: Patients with RA who reported not taking their biologic on the day agreed with their health care professional showed poorer clinical outcomes than their counterparts, emphasizing the need to investigate causes of non-adherence to biologics.

Impact of psychological factors on subjective disease activity assessments in patients with severe rheumatoid arthritis.

OBJECTIVE: The Disease Activity Score in 28 joints (DAS28), used to assess disease activity in rheumatoid arthritis (RA), is a composite score comprising clinical, biochemical, and patient self-report measures. We hypothesized that psychological factors (cognitions and mood) would be more strongly associated with patient-reported components of the DAS28 than clinical or biochemical components. METHODS: A cross-sectional, observational study of 322 RA patients with active disease (mean DAS28 6.0) awaiting therapy with a biologic agent was undertaken. Patients' illness beliefs, treatment beliefs, and mood were measured using the Brief Illness Perception Questionnaire (IPQ), the Beliefs about Medicines Questionnaire (BMQ), and the Hospital Anxiety and Depression Scale (HADS), respectively. Relationships between psychological factors and 1) total DAS28 and 2) individual components of the DAS28 were analyzed using linear regression. RESULTS: Total DAS28 produced significant but weak associations with 2 of the Brief IPQ items, but no associations with BMQ or HADS scores. There were larger significant associations between the patient-reported visual analog scale (VAS) with 5 items of the Brief IPQ and with HADS depression. Low illness coherence was associated with higher tender joint count. Three Brief IPQ items and HADS anxiety scores were significantly associated with C-reactive protein level or erythrocyte sedimentation rate. No psychological factors were associated with the swollen joint count. CONCLUSION: One of the subjective components of the DAS28, patient VAS, was highly correlated with cognitive factors and depression in those with severe RA. By reporting individual DAS28 components, clinicians may be better able to assess the impact of therapies on each component, adjusting approaches according to patients' needs.

Using lifestyle factors to identify individuals at higher risk of inflammatory polyarthritis (results from the European Prospective Investigation of Cancer-Norfolk and the Norfolk Arthritis Register--the EPIC-2-NOAR Study).

OBJECTIVES: To investigate the association of lifestyle factors with risk of inflammatory polyarthritis (IP) and rheumatoid arthritis (RA). METHODS: The European Prospective Investigation of Cancer, Norfolk, UK (EPIC-Norfolk) gathered lifestyle data from participants aged 40-79 years from 1993 to 1997. Individuals who subsequently developed IP were identified by linkage with the Norfolk Arthritis Register. A Cox proportional hazard model was developed, and a score assigned to each risk factor to calculate the odds of developing IP. RESULTS: 25 455 EPIC participants were followed for a median (IQR) of 14.2 (12.9, 15.3) years; 184 developed incident IP (138 cumulatively fulfilled criteria for RA; 107 were seropositive). Pack-years of smoking were associated with increased risk of IP and RA in men (HR 1.21 (95% CI 1.08 to 1.37) per 10-pack-years) and seropositive IP (HR 1.24 (95% CI 1.10 to 1.41)) for all. Diabetes mellitus was associated with increased risk of IP (HR 2.54 (95% CI 1.26 to 5.09)), while alcohol (HR 0.86 (95% CI 0.74 to 0.99) per unit/day) and higher social class (HR 0.36 (95% CI 0.15 to 0.89) for professionals vs manual workers) were associated with reduced risk. Body mass index was associated with seronegative IP (HR 2.75 (95% CI 1.39 to 5.46) for obese vs normal-weight participants). In women, parity (HR 2.81 (95% CI 1.37 to 5.76) for ≥2 vs no children) was associated with increased risk, and breast feeding (HR 0.66 (95% CI 0.46 to 0.94) for every 52 weeks of breast feeding) was inversely associated with risk. Risk factors from the model were used to generate a 'risk score'. A total of 1159 (8.4%) women had scores reflecting a >3-fold increased risk of IP over those with a score of 0. CONCLUSIONS: Several easily ascertained clinical and lifestyle factors can be used to stratify populations for risk of IP.

Modifiable risk factors for RA: prevention, better than cure?

OBJECTIVE: To perform a meta-synthesis of the evidence for modifiable lifestyle risk factors for inflammatory polyarthritis (IP) and RA. METHODS: We performed a MEDLINE literature search. Case-control and cohort studies and systematic reviews published from 1948 through February 2011 and studying modifiable risk factors for RA were retrieved. The main outcome measure was diagnosis of RA according to the standard criteria. RESULTS: Smoking contributes up to 25% of the population burden of RA. The risk is dose related, stronger in males and especially strong for anti-citrullinated peptide antibody positive (ACPA(+)) RA through an interaction with the shared epitope. After smoking cessation, there is, however, a latency of up to 20 years to return to baseline risk. Other associations are less definitive; however, prospective studies suggest that dietary antioxidants and breastfeeding may be protective and that high coffee consumption may increase RA risk. An inverse association with alcohol intake (especially in smokers) and with education/social class (especially seropositive RA) and an increased risk with obesity (seronegative RA) is also noted. CONCLUSION: There is a need for further large-scale prospective studies with a consistent definition of RA phenotype (undifferentiated IP through to ACPA(+)/RF(+) disease). This will ultimately afford the opportunity to evaluate preventative population strategies for RA akin to the well-established programmes for cardiovascular disease and cancer, targeting common risk factors.