Effect of immunosuppressive therapies on survival of systemic lupus erythematosus: a propensity score analysis of a longitudinal cohort.

Objectives The aim of this study was to study the relationship between immunosuppressive drug treatment and survival in patients with systemic lupus erythematosus (SLE). Methods Patients who fulfilled four or more American College of Rheumatology criteria for SLE were followed longitudinally. Clinical characteristics, use of immunosuppressive agents and mortality were reviewed. Cox regression was used to study the relationship between immunosuppressive treatment and survival, adjusted for age, sex, vascular risk factors, organ damage, the anti-phospholipid antibodies and a propensity score for the indication of individual immunosuppressive agent derived from separate regression models. Results A total of 803 SLE patients were studied (92% women; age of SLE onset 33.2±14 years; follow-up time 10.8±7.7 years). The frequencies of ever use of immunosuppressive agents were: high-dose prednisolone (≥0.6 mg/kg/day for ≥4 weeks) (85%), azathioprine (63%), cyclophosphamide (25%), mycophenolate mofetil (27%), the calcineurin inhibitors (23%) and hydroxychloroquine (69%). Ninety-seven patients (12%) died and 56 (7%) patients were lost to follow-up. The causes of death were infection (44%), cerebrovascular events (12%), cardiovascular events (10%) and malignancy (8.2%). Cox regression revealed that the ever use of high-dose prednisolone, mycophenolate mofetil, calcineurin inhibitors or cyclophosphamide was not significantly associated with improved survival. However, the ever use of hydroxychloroquine (hazard ratio 0.59 (0.37-0.93); P=0.02) and azathioprine (hazard ratio 0.46 (0.28-0.75); P=0.002) was significantly associated with reduced mortality (41% and 54%, respectively) after adjustment for the propensity score and other confounding factors. A similar beneficial effect of hydroxychloroquine and azathioprine on survival was also observed in patients with lupus nephritis. Conclusions In this longitudinal cohort of Chinese SLE patients, the ever use of hydroxychloroquine and azathioprine was significantly associated with a probability of better survival. Treatment with high-dose prednisolone, cyclophosphamide, mycophenolate mofetil or the calcineurin inhibitors was not associated with long-term survival benefit.

ST13 polymorphisms and their effect on exacerbations in steroid-treated asthmatic children and young adults.

BACKGROUND: The clinical response to inhaled corticosteroids (ICS) is associated with single nucleotide polymorphisms (SNPs) in various genes. This study aimed to relate variations in genes in the steroid pathway and asthma susceptibility genes to exacerbations in children and young adults treated with ICS. METHODS: We performed a meta-analysis of three cohort studies: Pharmacogenetics of Asthma Medication in Children: Medication with Anti-Inflammatory effects (n = 357, age: 4-12 years, the Netherlands), BREATHE (n = 820, age: 3-22 years, UK) and Paediatric Asthma Gene Environment Study (n = 391, age: 2-16 years, UK). Seventeen genes were selected based on a role in the glucocorticoid signalling pathway or a reported association with asthma. Two outcome parameters were used to reflect exacerbations: hospital visits and oral corticosteroid (OCS) use in the previous year. The most significant associations were tested in three independent validation cohorts; the Childhood Asthma Management Programme (clinical trial, n = 172, age: 5-12 years, USA), the Genes- environment and Mixture in Latino Americans II- study (n = 745, age: 8-21, USA) and the Pharmacogenetics of adrenal suppression cohort (n = 391, age: 5-18, UK) to test the robustness of the findings. Finally, all results were meta-analysed. RESULTS: Two SNPs in ST13 (rs138335 and rs138337), but not in the other genes, were associated at a nominal level with an increased risk of exacerbations in asthmatics using ICS in the three cohorts studied. In a meta-analysis of all six studies, ST13 rs138335 remained associated with an increased risk of asthma-related hospital visits and OCS use in the previous year; OR = 1.22 (P = 0.013) and OR = 1.22 (P = 0.0017), respectively. CONCLUSION AND CLINICAL RELEVANCE: A novel susceptibility gene, ST13, coding for a cochaperone of the glucocorticoid receptor, is associated with exacerbations in asthmatic children and young adults despite their ICS use. Genetic variation in the glucocorticoid signalling pathway may contribute to the interindividual variability in clinical response to ICS treatment in children and young adults.

Long-term outcome of anti-tumor necrosis factor alpha blockade in the treatment of juvenile spondyloarthritis.

OBJECTIVES: A significant proportion of patients with juvenile spondyloarthritis (JSpA) are refractory to treatment with established medications. The objective of this study was to assess long-term efficacy of treatment with anti-TNF agents in patients with JSpA. METHODS: An observational study of 16 patients with JSpA from 3 centres treated with infliximab (n=10) and etanercept (n=6) was performed, with a median follow-up period of 7.2 years. Prospective data was collected according to a standardized protocol. Outcomes examined were TEC, TAJC, markers of inflammation (ESR, CRP), functional assessments (C-HAQ, BASDAI, BASFI), and ongoing requirement for anti-TNF treatment. RESULTS: 13/16 patients (83%) had achieved clinical remission 6 months into the treatment. Improvement was sustained over time, with a median TAJC and TEC of 0 at any time point after 6 weeks. 6/16 patients (38%) showed a flare of arthritis after a median of 3.5 years. Two patients with hip disease prior to treatment required an arthroplasty 3 and 8 years post anti-TNF initiation. Patients showed progression of sacroiliitis with median modified New York score of 1 (range 0-3) at time of diagnosis and 3 (range 0-4) at last follow-up (p=0.002). Median BASDAI at last follow up was 1.6, median BASFI 3.1. Two patients developed transient reactions (one generalised, one local); no patient developed other adverse effects during the study. CONCLUSIONS: Anti-TNF treatment in JSpA refractory to standard treatment results in good long-term disease control except for pre-existing hip disease. However, radiographic evidence suggests inferior efficacy for control of sacroiliac joint disease.

The pharmacogenetics and pharmacogenomics of asthma therapy.

Despite the availability of several classes of asthma medications and their overall effectiveness, a significant portion of patients fail to respond to these therapeutic agents. Evidence suggests that genetic factors may partly mediate the heterogeneity in asthma treatment response. This review discusses important findings in asthma pharmacogenetic and pharmacogenomic studies conducted to date, examines limitations of these studies and, finally, proposes future research directions in this field. The focus will be on the three major classes of asthma medications: ß-adrenergic receptor agonists, inhaled corticosteroids and leukotriene modifiers. Although many studies are limited by small sample sizes and replication of the findings is needed, several candidate genes have been identified. High-throughput technologies are also allowing for large-scale genetic investigations. Thus, the future is promising for a personalized treatment of asthma, which will improve therapeutic outcomes, minimize side effects and lead to a more cost-effective care.

Comparison of clinical and radiographic severity of juvenile-onset versus adult-onset ankylosing spondylitis.

OBJECTIVES: An important unresolved issue in the pathogenesis and clinical course of ankylosing spondylitis (AS) is whether juvenile-onset AS (JoAS) is a clinical entity in its own right or just an earlier onset variant of adult-onset AS (AoAS). A study was undertaken to address this issue. METHODS: All patients with AS were extracted from the database of a large spondylitis clinic. Those with symptom onset at < or =16 years were compared with those with symptom onset at > or =17 years. Odds ratios (OR) were calculated and adjusted for disease duration and current age. RESULTS: 267 patients with AS were identified; 84 met the criteria for JoAS and 183 met the criteria for AoAS. There were no differences in gender ratio (male: JoAS 81%, AoAS 79%) or in HLA-B27 status (positive: JoAS 75%, AoAS 81%). The axial/peripheral pattern of disease at presentation differed; an exclusively peripheral pattern was seen in 26% with JoAS but in only 4.6% of those with AoAS (p<0.001). There were no differences in disease activity between the two groups. When adjusted for disease duration, axial features were more prominent in AoAS than JoAS as represented by neck pain (OR 2.93 (95% CI 1.54 to 5.55)), neck stiffness (OR 3.39 (95% CI 1.80 to 6.39)), back pain (OR 2.96 (95% CI 1.43 to 6.11)) or back stiffness (OR 3.30 (95% CI 1.50 to 7.28)). AoAS was associated with worse functional and quality of life measures and higher fatigue scores when adjusted for disease duration. CONCLUSIONS: JoAS follows a distinctive clinical course from AoAS. These clinical features are dictated by factors other than male gender and HLA-B27 and warrant further investigation.

Pre-implant evaluation of speech and hearing.

This paper describes an approach taken to predict, in advance of invasive surgery, whether a permanent cochlear prosthesis will serve as an aid to hearing in postlingually deaf adults. Nine subjects were implanted transtympanically with a temporary single-channel round window electrode. Over the course of one week a number of tests were conducted, including (1) the measurement of current thresholds over a range of frequencies for sine, square and biphasic pulse waveforms and minimum detectable gap between a pair of short bursts; (2) the discrimination of elementary speech features of live voice such as interruption, intonation, and stress placement; (3) the recognition of consonants, and (4) speech tracking. Eight subjects were able to appreciate changes in loudness, pitch, duration and temporal gap for frequencies below 1 kHz. All showed significant improvements over listening with high-power hearing aids in discriminating a variety of changes in elementary speech features. It was found that the recognition of consonants and speech tracking was heavily dependent on lipreading.

The nucleus implant: rehabilitation and results.

Improvements in hearing and speech perception were studied in three postlingually deaf adults who had received a Nucleus multi-channel intracochlear implant. Over the course of one year the repeated testing of hearing and speech perception were interspersed with sessions of speech processor adjustment, rehabilitation and video recording of performance. The data indicated that, while subjects were able to discriminate simple changes in acoustic patterns (e.g., noise versus voice), they were unable to recognize words taken from an open set. Learning effects were as high as 20-30%. Psychophysical experiments indicated a wide range of performance across individuals, in some instances close to values observed for individuals with normal hearing.

The use of a temporary extracochlear electrode in preoperative testing of permanent implant candidates.

This paper describes hearing and speech perception in 9 post-lingually deaf adults fitted with a temporary single electrode, surgically positioned close to the round window niche. After baseline testing, unaided and aided binaurally with the high-power Phonic Ear PE 845, each subject was admitted to hospital for a period of 7 days. During each test session, stimuli were presented directly to the electrode lead by means of an isolation unit. Current thresholds, upper tolerable limits and gap detection were measured for various acoustical waveforms and stimulus frequencies. A laryngograph was used to test the discrimination of prelinguistic and suprasegmental speech features. The results indicated that the prosthesis could provide acoustic sensations of loudness, pitch and duration that changed with stimulus waveform, level of current and frequency, and a gap threshold less than 50 msec. Lipreading appeared to be a necessary adjunct for consonant discrimination.

Lymphoedema care of breast cancer patients in a breast care clinic: a survey of knowledge and health practice.

Lymphoedema, an accumulation of protein-rich fluid in interstitial tissue, is a well-recognised life-altering result of breast cancer treatment. With the goal of studying the prevalence and management of lymphoedema after breast cancer therapy, 171 patients were invited to complete a self-administered questionnaire following completion of treatment for breast cancer. The survey revealed that 82.5% of patients knew they were at-risk of developing lymphoedema. However, the level of knowledge about preventive care in lymphoedema was inadequate, with a mean score of 4.07 out of a full mark of 10 (SD=2.35, mode=2). A substantial proportion (45.6%; n=78) of respondents reported that they had experienced lymphoedema and subsequently developed multiple sites of lymphoedema, but only 34.7% (n=26) had been referred for physiotherapy. The study also revealed that patients who had received the combined regimen of mastectomy, lymph node dissection, radiotherapy and chemotherapy were at a higher risk of developing lymphoedema (chi2=6.305, P=0.043). Interestingly, it was found that nurses were the most frequently cited resource for information, but the least consulted professionals for discussion on treatment. It is apparent from our patient survey that there is a lack of knowledge on lymphoedema care amongst breast cancer patients. In order to improve patients' level of knowledge and their awareness of lymphoedema care, the provision for systematic and comprehensive patient education, including management protocols for lymphoedema, needs to be addressed. Education and training, will be essential components of efforts to ensure appropriate care for lymphoedema patients.