Ribosomal P antibody: 30 years on the road.

The identity of the protein antigens targeted by anti-cytoplasmic antibodies in lupus was discovered 30 years ago. These antigens are three acidic ribosomal phosphoproteins, P0, P1, and P2. Precise identification of the shared epitope on these three proteins enabled sensitive and specific immunoassays to be developed. Anti-P antibodies are highly specific for systemic lupus erythematosus (SLE) and occur in 15%-35% of patients, depending on ethnicity as well as the age of onset. Increased frequencies of detection of anti-P have been reported in childhood SLE as well as in neuropsychiatric, renal, and hepatic disease. While longitudinal studies by the Systemic Lupus International Collaborating Clinics (SLICC) consortium supported the association of anti-P with neuropsychiatric lupus, the predictive value of antibody determination remains controversial. This is likely explained by the heterogeneity of neuropsychiatric lupus as well as by the different methodologies used for assay. A number of experimental studies have suggested a direct pathogenic role for anti-P antibodies in brain disease. Findings include cross reactivity between anti-P and a neuronal surface antigen, which was detected in areas of the brain involved in memory, cognition, and emotion. Direct injection of anti-P antibodies into the brains of rodents was also associated with abnormal electrical activity and behavioral disturbances. Taken together, research over the last 30 years has established anti-P antibodies as a useful diagnostic marker of SLE and at least a subset of patients with neuropsychiatric disease. Further research is required to fine tune the association of anti-P with clinical manifestations and establish beyond high probability a pathophysiologic role for the antibodies.

Genetic testing in a cohort of young patients with HER2-amplified breast cancer.

BACKGROUND: Young age at diagnosis for breast cancer raises the question of genetic susceptibility. We explored breast cancer susceptibility genes testing on ≤40-year-old patients with HER2-amplified invasive breast cancer. PATIENTS AND METHODS: Patients were selected from a large UK cohort study. The inclusion criterion was age ≤40 at diagnosis with confirmed HER2-amplified breast cancer. The probability of finding a BRCA gene mutation was calculated based on family history. Genetic testing used was either clinical testing for BRCA1 and BRCA2, with a subset also tested for TP53 mutations, or research-based testing using a typical panel comprising 17 breast cancer susceptibility genes (CSGs) including BRCA1, BRCA2 and TP53. RESULTS: Of the 591 eligible patients, clinical testing results were available for 133 cases and an additional 263 cases had panel testing results. BRCA testing across 396 cases found 8 BRCA2 (2%) and 6 BRCA1 (2%) pathogenic mutations. Of the 304 patients tested for TP53 mutations, overall 9 (3%) had deleterious TP53 mutations. Of the 396 patients, 101 (26%) met clinical criteria for BRCA testing (≥10% probability), among whom 11% had pathogenic BRCA mutations (6 BRCA2, 5 BRCA1). Where the probability was calculated to be <10%, only 4 of 295 (1%) patients had BRCA mutations. Among the 59 patients who had TP53 testing meeting the 10% threshold, 7 had mutations (12%). Likely functionally deleterious mutations in 14 lower penetrance CSGs were present in 12 of 263 (5%) panel-tested patients. CONCLUSION: Patients aged <41 at diagnosis with HER2+ breast cancer and no family history of breast cancer can be reassured that they have a low chance of being a high-risk gene carrier. If there is a strong family history, not only BRCA but also TP53 gene testing should be considered. The clinical utility of testing lower penetrance CSGs remains unclear.

Immunomodulators in SLE: Clinical evidence and immunologic actions.

Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease. Current treatment strategies rely heavily on corticosteroids, which are in turn responsible for a significant burden of morbidity, and immunosuppressives which are limited by suboptimal efficacy, increased infections and malignancies. There are significant deficiencies in our immunosuppressive armamentarium, making immunomodulatory therapies crucial, offering the opportunity to prevent disease flare and the subsequent accrual of damage. Currently available immunomodulators include prasterone (synthetic dehydroeipandrosterone), vitamin D, hydroxychloroquine and belimumab. These therapies, acting via numerous cellular and cytokine pathways, have been shown to modify the aberrant immune responses associated with SLE without overt immunosuppression. Vitamin D is important in SLE and supplementation appears to have a positive impact on disease activity particularly proteinuria. Belimumab has specific immunomodulatory properties and is an effective therapy in those with specific serological and clinical characteristics predictive of response. Hydroxychloroquine is a crucial background medication in SLE with actions in many molecular pathways. It has disease specific effects in reducing flare, treating cutaneous disease and inflammatory arthralgias in addition to other effects such as reduced thrombosis, increased longevity, improved lipids, better glycemic control and blood pressure. Dehydroeipandrosterone is also an immunomodulator in SLE which can have positive effects on disease activity and has bone protective properties. This review outlines the immunologic actions of these drugs and the clinical evidence supporting their use.

Why targeted therapies are necessary for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) continues to have important morbidity and accelerated mortality despite therapeutic advances. Targeted therapies offer the possibility of improved efficacy with fewer side effects. Current management strategies rely heavily on nonspecific immunosuppressive agents. Prednisone, in particular, is responsible for a considerable burden of later organ damage. There are a multitude of diverse mechanisms of disease activity, immunogenic abnormalities and clinical manifestations to take into consideration in SLE. Many targeted agents with robust mechanistic preclinical data and promising early phase studies have ultimately been disappointing in phase III, randomized, controlled studies. Recent efforts have focused on B-cell therapies, in particular given the success of belimumab in clinical trials, with limited success. We remain optimistic regarding other specific therapies being evaluated, including interferon-alpha blockade. It is likely that in SLE, given the heterogeneity of the population involved, precision medicine is needed, rather than expecting that any single biologic will be universally effective.

An evaluation of the prognostic model PREDICT using the POSH cohort of women aged ⩽40 years at breast cancer diagnosis.

BACKGROUND: Breast cancer is the most common cancer in younger women (aged ⩽40 years) in the United Kingdom. PREDICT (http://www.predict.nhs.uk) is an online prognostic tool developed to help determine the best available treatment and outcome for early breast cancer. This study was conducted to establish how well PREDICT performs in estimating survival in a large cohort of younger women recruited to the UK POSH study. METHODS: The POSH cohort includes data from 3000 women aged ⩽40 years at breast cancer diagnosis. Study end points were overall and breast cancer-specific survival at 5, 8, and 10 years. Evaluation of PREDICT included model discrimination and comparison of the number of predicted versus observed events. RESULTS: PREDICT provided accurate long-term (8- and 10-year) survival estimates for younger women. Five-year estimates were less accurate, with the tool overestimating survival by 25% overall, and by 56% for patients with oestrogen receptor (ER)-positive tumours. PREDICT underestimated survival at 5 years among patients with ER-negative tumours. CONCLUSIONS: PREDICT is a useful tool for providing reliable long-term (10-year) survival estimates for younger patients. However, for more accurate short-term estimates, the model requires further calibration using more data from young onset cases. Short-term prediction may be most relevant for the increasing number of women considering risk-reducing bilateral mastectomy.

Obesity and the outcome of young breast cancer patients in the UK: the POSH study.

BACKGROUND: Obese breast cancer patients have a poorer prognosis than non-obese patients. We examined data from a large prospective cohort study to explore the associations of obesity with tumour pathology, treatment and outcome in young British breast cancer patients receiving modern oncological treatments. PATIENTS AND METHODS: A total of 2956 patients aged ≤40 at breast cancer diagnosis were recruited from 126 UK hospitals from 2001 to 2007. Height and weight were measured at registration. Tumour pathology and treatment details were collected. Follow-up data were collected at 6, 12 months, and annually. RESULTS: A total of 2843 eligible patients (96.2%) had a body mass index (BMI) recorded: 1526 (53.7%) were under/healthy-weight (U/H, BMI <25 kg/m(2)), 784 (27.6%) were overweight (ov, BMI ≥25 to <30), and 533 (18.7%) were obese (ob, BMI ≥30). The median tumour size was significantly higher in obese and overweight patients than U/H patients (Ob 26 mm versus U/H 20 mm, P < 0.001; Ov 24 mm versus U/H 20 mm, P < 0.001). Obese and overweight patients had significantly more grade 3 tumours (63.9% versus 59.0%, P = 0.048; Ov 63.6% versus U/H 59.0% P = 0.034) and node-positive tumours (Ob 54.6% versus U/H 49.0%, P = 0.027; Ov 54.2% versus U/H 49%, P = 0.019) than U/H patients. Obese patients had more ER/PR/HER2-negative tumours than healthy-weight patients (25.0% versus 18.3%, P = 0.001). Eight-year overall survival (OS) and distant disease-free interval (DDFI) were significantly lower in obese patients than healthy-weight patients [OS: hazard ratio (HR) 1.65, P < 0.001; DDFI: HR 1.44, P < 0.001]. Multivariable analyses adjusting for tumour grade, size, nodal, and HER2 status indicated that obesity was a significant independent predictor of OS and DDFI in patients with ER-positive disease. CONCLUSIONS: Young obese breast cancer patients present with adverse tumour characteristics. Despite adjustment for this, obesity still independently predicts DDFI and OS.

Family history and outcome of young patients with breast cancer in the UK (POSH study).

BACKGROUND: Young patients presenting to surgical clinics with breast cancer are usually aware of their family history and frequently believe that a positive family history may adversely affect their prognosis. Tumour pathology and outcomes were compared in young British patients with breast cancer with and without a family history of breast cancer. METHODS: Prospective Outcomes in Sporadic versus Hereditary breast cancer (POSH) is a large prospective cohort study of women aged less than 41 years with breast cancer diagnosed and treated in the UK using modern oncological management. Personal characteristics, tumour pathology, treatment and family history of breast/ovarian cancer were recorded. Follow-up data were collected annually. RESULTS: Family history data were available for 2850 patients. No family history was reported by 65·9 per cent, and 34·1 per cent reported breast/ovarian cancer in at least one first- or second-degree relative. Patients with a family history were more likely to have grade 3 tumours (63·3 versus 58·9 per cent) and less likely to have human epidermal growth factor receptor 2-positive tumours (24·7 versus 28·8 per cent) than those with no family history. In multivariable analyses, there were no significant differences in distant disease-free intervals for patients with versus those without a family history, either for the whole cohort (hazard ratio (HR) 0·89, 95 per cent c.i. 0·76 to 1·03; P = 0·120) or when stratified by oestrogen receptor (ER) status (ER-negative: HR 0·80, 0·62 to 1·04, P = 0·101; ER-positive: HR 0·95, 0·78 to 1·15, P = 0·589). CONCLUSION: Young British patients presenting to breast surgical clinics with a positive family history can be reassured that this is not a significant independent risk factor for breast cancer outcome.

Ethnicity and outcome of young breast cancer patients in the United Kingdom: the POSH study.

BACKGROUND: Black ethnic groups have a higher breast cancer mortality than Whites. American studies have identified variations in tumour biology and unequal health-care access as causative factors. We compared tumour pathology, treatment and outcomes in three ethnic groups in young breast cancer patients treated in the United Kingdom. METHODS: Women aged ≤ 40 years at breast cancer diagnosis were recruited to the POSH national cohort study (MREC: 00/06/69). Personal characteristics, tumour pathology and treatment data were collected at diagnosis. Follow-up data were collected annually. Overall survival (OS) and distant relapse-free survival (DRFS) were assessed using Kaplan-Meier curves, and multivariate analyses were performed using Cox regression. RESULTS: Ethnicity data were available for 2915 patients including 2690 (91.0%) Whites, 118 (4.0%) Blacks and 87 (2.9%) Asians. Median tumour diameter at presentation was greater in Blacks than Whites (26.0 mm vs 22.0 mm, P=0.0103), and multifocal tumours were more frequent in both Blacks (43.4%) and Asians (37.0%) than Whites (28.9%). ER/PR/HER2-negative tumours were significantly more frequent in Blacks (26.1%) than Whites (18.6%, P=0.043). Use of chemotherapy was similarly high in all ethnic groups (89% B vs 88.6% W vs 89.7% A). A 5-year DRFS was significantly lower in Blacks than Asians (62.8% B vs 77.0% A, P=0.0473) or Whites (62.8 B% vs 77.0% W, P=0.0053) and a 5-year OS for Black patients, 71.1% (95% CI: 61.0-79.1%), was significantly lower than that of Whites (82.4%, 95% CI: 80.8-83.9%, W vs B: P=0.0160). In multivariate analysis, Black ethnicity had an effect on DRFS in oestrogen receptor (ER)-positive patients that is independent of body mass index, tumour size, grade or nodal status, HR: 1.60 (95% CI: 1.03-2.47, P=0.035). CONCLUSION: Despite equal access to health care, young Black women in the United Kingdom have a significantly poorer outcome than White patients. Black ethnicity is an independent risk factor for reduced DRFS particularly in ER-positive patients.

Fracture liaison service in a non-regional orthopaedic clinic--a cost-effective service.

Fracture liaison services (FLS) aim to provide cost-effective targeting of secondary fracture prevention. It is proposed that a dedicated FLS be available in any hospital to which a patient presents with a fracture. An existing orthopaedic clinic nurse was retrained to deliver a FLS. Proformas were used so that different nurses could assume the fracture liaison nurse (FLN) role, as required. Screening consisted of fracture risk estimation, phlebotomy and DXA scanning. 124 (11%) of all patients attending the orthopaedic fracture clinic were reviewed in the FLS. Upper limb fractures accounted for the majority of fragility fractures screened n=69 (55.6%). Two-thirds of patients (n=69) had reduced bone mineral density (BMD). An evidence based approach to both non-pharmacological and pharmacotherapy was used and most patients (76.6%) receiving pharmacotherapy received an oral bisphosphonate (n=46). The FLS has proven to be an effective way of delivering secondary prevention for osteoporotic fracture in a non-regional fracture clinic, without increasing staff costs.

The clinical and serological associations of hypocomplementemia in a longitudinal sle cohort.

BACKGROUND: In SLE, low complement is an important serological manifestation. Recent classification criteria include hypocomplementemia and one gives additional weight if both C3 and C4 are low. We evaluated patients with a history of, and those with persistently, low complement. As complement activation occurs in the antiphospholipid antibody syndrome, an analysis was also performed on those with positive antiphospholipid antibodies to evaluate thrombotic outcomes. METHODS: In a longitudinal SLE cohort, organ manifestations, damage, C3, C4 and antiphospholipid antibodies were assessed quarterly. Using univariate and multivariate methods we compared those with and without a history of low C3, low C4 and both. We evaluated those who had a history of low complement at any time point, and those who had persistent hypocomplementemia. Further analysis considered thrombotic outcomes in patients with positive antiphospholipid antibodies and a history of low complement. RESULTS: 2399 patients were evaluated. Fifty-five percent had a history of low C3 and 47% low C4; 83 (4%) had persistently low C3 and 65 (3.2%) had persistently low C4. Hematological, renal and serological abnormalities associated with a history of low C3 but not low C4. With anticardiolipin antibodies, a history of hypocomplementemia (both C3 and C4 low) associated with stroke and deep venous thrombosis. CONCLUSION: Low C4 was a weak marker in terms of the associated clinical and serological manifestations. Low C3 associated with renal involvement and poor renal outcomes. A history of both low C3 and C4 associated with stroke in the presence of lupus anticoagulant or anticardiolipin antibodies, and low C4 with digital gangrene (with lupus anticoagulant).

Chronic inflammatory demyelinating polyneuropathy (CIDP) in diabetics.

Seven diabetic patients developed a progressive, moderately severe, motor rather than sensory neuropathy predominantly affecting the legs. This met clinical and electrophysiological criteria for chronic inflammatory demyelinating polyneuropathy (CIDP). Nerve biopsies showed a variety of abnormalities, none of which clearly distinguished between diabetic polyneuropathy and CIDP. The patients were treated with combinations of corticosteroids, azathioprine, plasmapheresis and intravenous immune globulin; all improved substantially. We believe that CIDP may masquerade as unusually severe and progressive diabetic distal symmetric polyneuropathy. It is important to recognize CIDP in diabetics because, unlike diabetic polyneuropathy, CIDP is treatable.

The prevalence of patellar tendinopathy in elite academy rugby: a clinical and imaging study.

OBJECTIVES: Patellar tendinopathy (PT) is a challenging condition with variable outcomes. It is not commonly reported in rugby. This study was undertaken to evaluate the prevalence of PT in elite academy rugby. DESIGN: Cross-sectional study. METHODS: Members of the rugby academies in Ireland were evaluated using blinded, standardised clinical examination, self reported questionnaires and ultrasound. Anthropometrics were examined, body mass and fat% were measured by bio-impedance. The Cincinnati Sports Activity Scale, established activity levels. The VISA-P scale evaluated symptoms. Ultrasound examination established tendon thickness, echogenicity and homogeneity including focal areas of tendinopathy in both transverse and longitudinal planes. Studies were reviewed and graded by two musculoskeletal radiologists. Statistical analysis was performed using PASW 18 and CIA software. Significance was set at p<.05. RESULTS: Thirty individuals (36.1%) had US abnormalities identified with 38 abnormal tendons. The abnormalities seen were microcalculi (44.7%; N=17), thickened tendons ± large areas of cystic degenerative change (26.3%) and macrocalculi or large hypoechoic areas (28.9%; N=11). Eleven individuals (13.3%) fulfilled the clinical diagnosis of PT based on clinical examination. Combining both US and clinical the prevalence of PT in this cohort was 9.6% (N=8). There was a statistically significant difference between the prevalence of patellar tendinopathy based upon US findings (p=.027) and the combination of both clinical examination and US (p=.044) in different training academies. CONCLUSIONS: This work shows that PT is a relatively common injury in elite academy rugby players and that training practices may contribute to its development.