When is Burkholderia cepacia complex truly eradicated in adults with cystic fibrosis? A 20-year follow up study.

BACKGROUND: Burkholderia cepacia complex (BCC) infection in cystic fibrosis (CF) is associated with increased morbidity and mortality. Current UK guidance recommends segregation of people with CF according to infection status. To date there is no universally agreed consensus on the number of negative samples or time interval since last isolation of BCC for eradication to be deemed successful. METHODS: All cases of new BCC isolation at Manchester Adult Cystic Fibrosis Centre were followed-up between May 2002-May 2022. The number of subsequent positive and negative sputum samples for BCC were recorded, as well as eradication treatment received. Eradication was deemed successful if there were ≥3 negative sputum samples and no further positive sputum samples for the same species and strain ≥12 months until the end of follow-up. RESULTS: Of 46 new BCC isolation, 25 were successfully eradicated and 21 resulted in chronic infection. 5 (16.7%) cases with exclusively negative sputum samples 6-12 months after initial isolation had subsequent samples that were culture-positive for BCC and 3 (10.7%) cases with exclusively negative sputum samples after 12-24 months had subsequent culture-positive samples. Cases where BCC was eradicated had a greater median number of days of eradication treatment (42, IQR 21-63) compared to those in whom BCC isolation resulted in chronic infection (28, IQR 14-42), p = 0.04. CONCLUSIONS: A cautious approach to segregation should be maintained after new isolation of BCC in CF, as some individuals with ≥3 negative samples 12-24 months after initial isolation had subsequent sputum samples culture-positive for BCC.

Antibody predictors of mortality and lung function trends in myositis spectrum interstitial lung disease.

OBJECTIVES: The impact of autoantibody profiles on prognosis of idiopathic inflammatory myositis associated interstitial lung disease (IIM-ILD) and myositis spectrum ILD with Myositis Specific Antibodies (MSA) remains unclear. This retrospective cohort study examines whether serological profiles are associated with mortality and longitudinal lung function change. METHODS: Baseline clinical/demographic characteristics and follow-up lung function of consecutive adult patients with IIM-ILD or Interstitial Pneumonia with Autoimmune Features (IPAF) positive for MSAs were extracted from three hospitals. Univariate and multi-variate Cox-Proportional Hazards analyses were used to compare mortality between autoantibodies. Regression models were used to analyse lung function trends. RESULTS: Of 430 included patients, 81% met IIM criteria, 19% were IPAF-MSA. On univariate analysis, risk factors associated with mortality included higher age, Charlson Co-morbidity Index and CRP; and lower BMI, baseline TLCO% and FEV1%. Compared to anti-MDA5-negativity, anti-MDA5-positivity (MDA5+) was associated with high mortality in the first 3 months (HR 65.2. 95%CI 14.1, 302.0), while no significant difference was seen thereafter (HR 0.55, 95%CI 0.14, 2.28). On multi-variate analysis, combined anti-synthetase antibodies carried a reduced risk of mortality (HR 0.63), although individually, mortality was reduced in anti-Jo1 + (HR 0.61, 95%CI 0.4-0.87) and increased in anti-PL7+ patients (HR 2.07, 95%CI 1.44-2.99). Anti-MDA5+ was associated with slow improvement in %FVC over the first 3 years, while anti-PL7+ was linked with a slow decline from 12 months onwards. CONCLUSIONS: Among autoantibody profiles in myositis spectrum disorders, anti-MDA5+ and anti-PL7+ confer higher mortality risks. Survivors of an early peak of mortality in anti-MDA5+ disease appear to have a favourable prognosis.

Specialist follow-up contraceptive support after abortion-Impact on effective contraceptive use at six months and subsequent abortions: A randomised controlled trial.

OBJECTIVES: To assess the impact of specialist contraceptive support after abortion on effective contraceptive use at six months and subsequent abortions within two years. METHODS: Multicentre randomised controlled trial among women undergoing induced abortion in three London boroughs. Allocation was through electronically concealed stratified randomisation by centre, blinding clinicians and participants to arm allocation until interventions. Control group received standard care, comprising advice to follow up with their general practitioner or contraceptive clinic as needed. Intervention group additionally received specialist contraceptive support via telephone or face-to-face consultation at 2-4 weeks and 3 months post-abortion. Primary outcome was rate of effective contraceptive use at six months post-abortion. Secondary outcomes were subsequent abortions within two years. RESULTS: 569 women were recruited between October 2011 and February 2013, randomised to intervention (282) and control (287) groups; 290 (142 intervention, 148 control) were available for primary outcome analysis. Intention-to-treat analysis showed no significant difference between the two groups in effective contraceptive use after abortion (62%, vs 54%, p = 0·172), long-acting contraceptive use (42% versus 32%, p = 0·084), and subsequent abortion (similar rates, at 1 year: 10%, p = 0·895, between 1-2 years: 6%, p = 0·944). Per-protocol analysis showed those who received the complete intervention package were significantly more likely to use effective contraception (67% versus 54%, p = 0·048), in particular long-acting contraception (49% versus 32%, p = 0·010) and showed a non-significant reduction in subsequent abortions within 2 years (at 1 year: 5% versus 10%, p = 0·098; and between 1-2 years: 3% versus 6%, p = 0·164, respectively). CONCLUSIONS: Structured specialist support post-abortion did not result in significant use of effective contraception at six months or reduction in subsequent abortions within two years. Participants engaging with the intervention showed positive effect on effective contraception at six months post-abortion. The potential benefit of such intervention may become evident through further studies with increased patient participation.

Changing clinical patterns in rheumatoid arthritis management over two decades: sequential observational studies.

BACKGROUND: Rheumatoid arthritis (RA) treatment paradigms have shifted over the last two decades. There has been increasing emphasis on combination disease modifying anti-rheumatic drug (DMARD) therapy, newer biologic therapies have become available and there is a greater focus on achieving remission. We have evaluated the impact of treatment changes on disease activity scores for 28 joints (DAS28) and disability measured by the health assessment questionnaire scores (HAQ). METHODS: Four cross-sectional surveys between 1996 and 2014 in two adjacent secondary care rheumatology departments in London evaluated changes in drug therapy, DAS28 and its component parts and HAQ scores (in three surveys). Descriptive statistics used means and standard deviations (SD) or medians and interquartile ranges (IQR) to summarise changes. Spearman's correlations assessed relationships between assessments. RESULTS: 1324 patients were studied. Gender ratios, age and mean disease duration were similar across all cohorts. There were temporal increases in the use of any DMARDs (rising from 61% to 87% of patients from 1996-2014), combination DMARDs (1% to 41%) and biologic (0 to 32%). Mean DAS28 fell (5.2 to 3.7), active disease (DAS28 > 5.1) declined (50% to 18%) and DAS28 remission (DAS28 < 2.6) increased (8% to 28%). In contrast HAQ scores were unchanged (1.30 to 1.32) and correlations between DAS28 and HAQ weakened (Spearman's rho fell from 0.56 to 0.44). CONCLUSIONS: Treatment intensity has increased over time, disease activity has fallen and there are more remissions. However, these improvements in controlling synovitis have not resulted in comparable reductions in disability measured by HAQ. As a consequence the relationship between DAS28 and HAQ has become weaker over time. Although the reasons for this divergence between disease activity and disability are uncertain, focussing treatment entirely in suppressing synovitis may be insufficient.

Pain thresholds in rheumatoid arthritis: the effect of tender point counts and disease duration.

OBJECTIVE: We evaluated the influence of demographic and clinical factors on pain thresholds in patients with rheumatoid arthritis (RA). METHODS: A cross-sectional observational study (105 patients with RA) assessed pain thresholds using an algometer. Regression analysis examined the influence of demographic and clinical assessments. RESULTS: Pain thresholds (median 289, interquartile range 89-434) correlated with assessments of disease activity (tender joint counts), disability (Health Assessment Questionnaire), fatigue, depression, and anxiety. Ordinal logistic regression showed tender point counts and disease duration were the dominant contributors. CONCLUSION: These findings suggest that low pain thresholds reflect "fibromyalgic" RA (many tender points) and central pain sensitization with prolonged disease duration.

Perceived barriers to integrated care in rheumatoid arthritis: views of recipients and providers of care in an inner-city setting.

BACKGROUND: A number of recent reports published in the UK have put the quality of care of adults with Rheumatoid Arthritis (RA) centre stage. These documents set high standards for health care professionals and commissioning bodies that need to be implemented into routine clinical practice. We therefore have obtained the views of recipients and providers of care in inner city settings as to what they perceive are the barriers to providing integrated care. METHODS: We conducted focus groups and face to face interviews between 2005-8 with 79 participants (patients, carers, specialist medical and nursing outpatient staff and general practitioners (GPs)) working in or attending three hospitals and three primary care trusts (PCT). RESULTS: Three barriers were identified that stood in the way of seamless integrated care in RA from the perspective of patients, carers, specialists and GPs: (i) early referral (e.g. 'gate keeper's role of GPs); (ii) limitations of ongoing care for established RA (e.g. lack of consultation time in secondary care) and (iii) management of acute flares (e.g. pressure on overbooked clinics). CONCLUSION: This timely study of the multi-perspective views of recipients and providers of care was conducted during the time of publications of many important reports in the United Kingdom (UK) that highlighted key components in the provision of high quality care for adults with RA. To achieve seamless care across primary and secondary care requires organisational changes, greater personal and professional collaboration and GP education about RA.

Fibromyalgic rheumatoid arthritis and disease assessment.

OBJECTIVE: We evaluated fibromyalgic RA to determine its clinical impact, identification using core clinical assessments and influence identifying active disease using disease activity scores (DAS-28). METHODS: We examined the impact and identification using core clinical assessments (tender minus swollen joint counts) of fibromyalgic RA (> or =11 tender points) in initial (105 patients) and replicate (100 patients) cohorts. Receiver operator characteristic (ROC) curves optimized the cut-off points using tender minus swollen joint counts; their validity was confirmed in a routine practice cohort (321 patients). We evaluated whether fibromyalgic RA affected the identification of active disease using DAS-28 (> or =5.1) and the clinical disease activity index (CDAI). RESULTS: A total of 18/105 and 12/100 patients in initial and replicate cohorts, respectively, had fibromyalgic RA. This was identified by > or =7 tender minus swollen joint counts with 83% sensitivity and 80% specificity in the initial cohort (72 and 98% in replicate, respectively) and ROC area under the curve 0.80 (0.94 in replicate). 'Fibromyalgic' RA (tender point scores in initial and tender minus swollen joints in clinical practice cohorts) had higher DAS-28, pain, fatigue and HAQ scores. More fibromyalgic RA patients had active disease by DAS-28 (odds ratio 14.3; 95% CI 5.5, 37.1; and CDAI 17.2; 95% CI 6.1, 48.5); conventional assessments (three or more tender joints; three or more swollen joints; ESR > or =28 mm/h) showed no difference (1.75; 95% CI 0.72, 4.3). CONCLUSION: Fibromyalgic RA affects 12-17% of RA outpatients and results in worse functional outcomes. DAS-28 scores over-interpret active disease in fibromyalgic RA.

Inhibiting costimulatory activation of T cells : a viable treatment option for rheumatoid arthritis?

There is now good evidence that T cells play a central role in the inflammatory pathway that leads to the persistent synovitis that causes joint damage in rheumatoid arthritis (RA). T cells require two signals to become activated. The second step in the activation of T cells involves costimulatory pathways, the best described pathway being the binding of CD28 on T cells to CD80/86 on antigen-presenting cells. This observation has led to the development of a new category of biological response modifier. Abatacept is a fusion protein (cytotoxic T-lymphocyte-associated antigen-4 immunoglobulin [CTLA4Ig]); which blocks the binding of CD28 by avidly binding CD80/86. Without this costimulatory activation, the T cell becomes anergic. Abatacept has consistently been shown to improve the signs and symptoms of RA in phase II and phase III trials in patients with an inadequate response to methotrexate and anti-tumour necrosis factor (TNF) therapy. Onset of action is rapid and efficacy is maintained during the period of treatment. Recent trials have also provided evidence of improvement in quality-of-life measures and radiographic progression. The safety profile to date has also been favourable and supports the theory that targeting naive T cells early in the inflammatory pathway will lead to immunomodulation rather than immunosuppression. The evidence produced so far suggests that abatacept will be a useful addition to the available therapies for patients with RA.

Rheumatoid arthritis: non-tumor necrosis factor targets.

PURPOSE OF REVIEW: The treatment of rheumatoid arthritis has been revolutionised in recent years with the advent of biologic treatments. The purpose of this review is to outline new treatments that target the inflammatory pathway in rheumatoid arthritis other than tumor necrosis factor-alpha. RECENT FINDINGS: As the use of anti-tumor necrosis factor-alpha treatment has become more widespread, the number of patients in whom this treatment is unsuccessful has also accumulated. Contraindications such as infection and cardiac failure further add to the number of patients who need alternative treatment. A better understanding of the inflammatory pathway in rheumatoid arthritis has led to interest in other therapeutic targets. Promising treatments such as interleukin-6 antagonists (MRA), CTLA4Ig (abatacept), and anti-B cell therapy (rituximab) have already been tested in randomized controlled trials over the past year. Other cytokines have been identified and have been shown to be of benefit in animal models, including interleukin-15, interleukin-17, and interleukin-18, and clinical trials of these agents are currently under way. SUMMARY: For patients with rheumatoid arthritis that does not respond to anti-tumor necrosis factor-alpha treatment, the promising alternatives MRA, abatacept, and rituximab have been tested. It is hoped that these agents will become available shortly.