St Helier Hospital

A working party of 13 dermatologists, two family practitioners and a paediatrician was assembled, with the aim of developing a minimum list of reliable discriminators for atopic dermatitis. Each physician was asked to select 10 consecutive new cases of unequivocal mild to moderate atopic dermatitis and 10 controls with other inflammatory dermatoses. Each subject was examined by two independent observers, who were blind to the clinical diagnosis and study aim, with regard to 31 clinically useful diagnostic features for atopic dermatitis. Two hundred and twenty-four patients were studied (120 cases and 102 controls). Using the key physician's clinical diagnosis as a gold standard, the sensitivity and specificity of each of the 31 diagnostic criteria were tested. Using multiple logistic regression techniques, a minimum set of diagnostic criteria for atopic dermatitis was derived. These were: history of flexural involvement, history of a dry skin, onset under the age of 2, personal history of asthma, history of a pruritic skin condition, and visible flexural dermatitis. Adjustment for age, sex, region, social class and ethnic group did not alter the choice of final criteria. The discriminatory value of these criteria was also satisfactory when tested against a further sample of 150 patients drawn from the community, who did not have skin disease.

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

The British Journal of Haematology publishes original research papers in clinical, laboratory and experimental haematology. The Journal also features annotations, reviews, short reports, images in haematology and Letters to the Editor.

PURPOSE: Early mortality in multiple myeloma (MM) is usually attributed to combined effects of active disease and comorbid factors. We have studied early deaths in a series of large multicenter trials to assess direct causes of death, their predictability, and whether current management strategies have reduced their frequency. PATIENTS AND METHODS: A total of 3,107 newly diagnosed patients entered onto United Kingdom Medical Research Council MM trials from 1980 to 2002 were studied. Trial files, final clinical summaries, and postmortem reports were analyzed. RESULTS: Death within 60 days of trial entry occurred in 299 patients (10%). Logistic regression modeling identified beta 2-microglobulin, performance status, and age as the most important predictors of early death, but only with 61% sensitivity and 73% specificity. Forty-five percent of deaths were attributable to infection, which was often associated with bone pain (particularly thoracic pain) and delay in presenting to medical care. Neutropenia was present at diagnosis in only 11 of the 135 deaths from infection. Renal failure was present in 28% of early deaths and was linked to light-chain MM, hypercalcemia, dehydration, and nonsteroidal anti-inflammatory drugs. There was no time related reduction in the percentage or nature of early deaths in 1,550 patients older than 65 years receiving similar therapy between 1982 and 2002. CONCLUSION: A tenth of patients die within 60 days of diagnosis of MM. Infection and renal failure are the main direct causes of early mortality, which cannot be accurately predicted by presenting prognostic features. All patients should be considered at high risk of death during induction therapy.

Intravenous immunoglobulin (IVIg) is a potential alternative treatment for anti-neutrophil cytoplasm antibody (ANCA)-associated systemic vasculitis (AASV) with less toxicity than conventional immunosuppressive agents. This randomized, placebo-controlled trial aimed to investigate the efficacy of a single course of IVIg (total dose 2 g/kg) in previously-treated AASV with persistent disease activity in whom there was an intention to escalate therapy. Vasculitic activity was monitored by the Birmingham vasculitis activity score (BVAS), C-reactive protein (CRP) and ANCA levels. Treatment response was defined as a reduction in BVAS of more than 50% after 3 months, and there was an intention to keep doses of concurrent immunosuppressive drugs unchanged during this period; follow-up continued to 12 months. Seventeen patients were randomized to receive IVIg and 17 to receive placebo. Treatment responses were found in 14/17 and 6/17 of the IVIg and placebo groups, respectively (p=0.015, OR 8.56, 95%CI 1.74-42.2). Following infusion of trial medication, greater falls in CRP were seen at 2 weeks (p=0.02) and 1 month (p=0.04) in the IVIg group. No differences were observed between ANCA levels or cumulative exposure to immunosuppressive drugs, and after 3 months there were no differences in CRP levels or disease activity between the IVIg and placebo groups. Seventeen adverse effects occurred after IVIg and six after placebo: they were mostly mild, although reversible rises in serum creatinine occurred in four from the IVIg group. A single course of IVIg reduced disease activity in persistent AASV, but this effect was not maintained beyond 3 months; mild, reversible side-effects following IVIg were frequent. IVIg is an alternative treatment for AASV with persistent disease activity after standard therapy.

BACKGROUND: There is increasing evidence that lack of facilities, equipment, and expertise in district hospitals across many low- and middle-income countries constitutes a major barrier to accessing surgical care. However, what is less clear, is the extent to which people perceive barriers when trying to access surgical care. METHODS: PubMed and EMBASE were searched using key words ("access" and "surgery," "barrier" and "surgery," "barrier" and "access"), MeSH headings ("health services availability," "developing countries," "rural population"), and the subject heading "health care access." Articles were included if they were qualitative and applied to illnesses where the treatment is primarily surgical. RESULTS: Key barriers included difficulty accessing surgical services due to distance, poor roads, and lack of suitable transport; lack of local resources and expertise; direct and indirect costs related to surgical care; and fear of undergoing surgery and anesthesia. CONCLUSIONS: The significance of cultural, financial, and structural barriers pertinent to surgery and their role in wider health care issues are discussed. Immediate action to improve financial and geographic accessibility along with investment in district hospitals is likely to make a significant impact on overcoming access and barrier issues. Further research is needed to identify issues that need to be addressed to close the gap between the care needed and that provided.

Serum levels of interleukin-10 (IL-10) are elevated in a proportion of patients with untreated chronic hepatitis C, and this may compromise the host immune response to the virus. The capacity for IL-10 production varies according to the genetic composition of the IL-10 locus. We examined the inheritance of 3 biallelic polymorphisms in the IL-10 gene promoter in patients with chronic hepatitis C and their association with response to treatment with interferon alfa (IFN-alpha). After adjusting for potential confounding variables, a highly significant relationship was found between inheritance of the IL-10 promoter -592*A and -819*T alleles or the ATA haplotype and response to IFN-alpha therapy (P =.016). Response to treatment was also associated with viral genotype 3a, a low viral load, and less fibrosis on liver biopsy. Following in vitro stimulation of peripheral blood mononuclear cells, the IL-10 promoter haplotypes, GCC, ACC, and ATA, were associated with high, intermediate, and low IL-10 production, respectively. These findings indicate that heterogeneity in the promoter region of the IL-10 gene has a role in determining the initial response of chronic hepatitis C to IFN-alpha therapy. Patients who are genetically predisposed to high IL-10 production have a poor response to IFN-alpha and may benefit from additional treatment strategies designed to enhance a T-helper type 1 (Th1) response.

By 21 March 2020 infections related to the novel coronavirus SARS-CoV-2 had affected people from 177 countries and caused 11,252 reported deaths worldwide. Little is known about risk, presentation and outcomes of SARS-CoV-2 (COVID-19) infection in kidney transplantation recipients, who may be at high-risk due to long-term immunosuppression, comorbidity and residual chronic kidney disease. Whilst COVID-19 is predominantly a respiratory disease, in severe cases it can cause kidney and multi-organ failure. It is unknown if immunocompromised hosts are at higher risk of more severe systemic disease. Therefore, we report on seven cases of COVID-19 in kidney transplant recipients (median age 54 (range 45-69), three females, from a cohort of 2082 managed transplant follow-up patients) over a six-week period in three south London hospitals. Two of seven patients presented within three months of transplantation. Overall, two were managed on an out-patient basis, but the remaining five required hospital admission, four in intensive care units. All patients displayed respiratory symptoms and fever. Other common clinical features included hypoxia, chest crepitation, lymphopenia and high C-reactive protein. Very high D dimer, ferritin and troponin levels occurred in severe cases and likely prognostic. Immunosuppression was modified in six of seven patients. Three patients with severe disease were diabetic. During a three week follow up one patient recovered, and one patient died. Thus, our findings suggest COVID-19 infection in kidney transplant patients may be severe, requiring intensive care admission. The symptoms are predominantly respiratory and associated with fever. Most patients had their immunosuppression reduced and were treated with supportive therapy.

OBJECTIVES: Eosinophilic esophagitis (EoE) represents a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. With few exceptions, 15 eosinophils per high-power field (peak value) in ≥1 biopsy specimens are considered a minimum threshold for a diagnosis of EoE. The disease is restricted to the esophagus, and other causes of esophageal eosinophilia should be excluded, specifically proton pump inhibitor-responsive esophageal eosinophilia. This position paper aims at providing practical guidelines for the management of children and adolescents with EoE. METHODS: Relevant literature from searches of PubMed, CINAHL, and recent guidelines was reviewed. In the absence of an evidence base, recommendations reflect the expert opinion of the authors. Final consensus was obtained during 3 face-to-face meetings of the Gastroenterology Committee and 1 teleconference. RESULTS: The cornerstone of treatment is an elimination diet (targeted or empiric elimination diet, amino acid-based formula) and/or swallowed, topical corticosteroids. Systemic corticosteroids are reserved for severe symptoms requiring rapid relief or where other treatments have failed. Esophageal dilatation is an option in children with EoE who have esophageal stenosis unresponsive to drug therapy. Maintenance treatment may be required in case of frequent relapse, although an optimal regimen still needs to be determined. CONCLUSIONS: EoE is a chronic, relapsing inflammatory disease with largely unquantified long-term consequences. Investigations and treatment are tailored to the individual and must not create more morbidity for the patient and family than the disease itself. Better maintenance treatment as well as biomarkers for assessing treatment response and predicting long-term complications is urgently needed.

Neutralizing injurious stimuli, proinflammatory mediator catabolism, and polymorphonuclear leukocyte (PMN) clearance are determinants of inflammatory resolution. To this, we recently added innate-type lymphocyte repopulation as being central for restoring postinflammation tissue homeostasis with a role in controlling innate immune-mediated responses to secondary infection. However, although macrophages dominate resolution, their phenotype and role in restoring tissue physiology once inflammation abates are unknown. Therefore, we isolated macrophages from the resolving phase of acute inflammation and found that compared with classically activated proinflammatory M1 cells, resolution-phase macrophages (rMs) possess weaker bactericidal properties and express an alternatively activated phenotype but with elevated markers of M1 cells including inducible cyclooxygenase (COX 2) and nitric oxide synthase (iNOS). This phenotype is controlled by cAMP, which, when inhibited, transforms rM to M1 cells. Conversely, elevating cAMP in M1 cells transforms them to rMs, with implications for cAMP in the resolution of systemic inflammation. It transpires that although rMs are dispensable for clearing PMNs during self-limiting inflammation, they are essential for signaling postresolution lymphocyte repopulation via COX 2 lipids. Thus, rM macrophages are neither classically nor alternatively activated but a hybrid of both, with a role in mediating postresolution innate-lymphocyte repopulation and restoring tissue homeostasis.

Aspirin is a unique nonsteroidal anti-inflammatory drug; at high doses (aspirin(high), 1g), it is anti-inflammatory stemming from the inhibition of cyclooxygenase and proinflammatory signaling pathways including NF-kappaB, but is cardioprotective at lower doses (aspirin(low), 75 mg). The latter arises from the inhibition of thromboxane (Tx) B(2), a prothrombotic eicosanoid also implicated in polymorphonuclear leukocyte trafficking. As a result, aspirin(low) is widely used as a primary and secondary preventative against vascular disease. Despite this and its ability to synthesize proresolution 15-epi-lipoxin A(4) it is not known whether aspirin(low) is anti-inflammatory in humans. To address this, we generated skin blisters by topically applying cantharidin on the forearm of healthy male volunteers, causing an acute inflammatory response including dermal edema formation and leukocyte trafficking. Although not affecting blister fluid volume, aspirin(low) (75 mg, oral, once daily/10 days) reduced polymorphonuclear leukocyte and macrophage accumulation independent of NF-kappaB-regulated gene expression and inhibition of conventional prostanoids. However, aspirin(low) triggered 15-epi-lipoxin A(4) synthesis and up-regulated its receptor (FPRL1, ALX). From complimentary in vitro experiments, we propose that 15-epi-lipoxin A(4) exerts its protective effects by triggering antiadhesive NO, thereby dampening leukocyte/endothelial cell interaction and subsequent extravascular leukocyte migration. Since similar findings were obtained from murine zymosan-induced peritonitis, we suggest that aspirin(low) possesses the ability to inhibit mammalian innate immune-mediated responses. This highlights 15-epi-lipoxin A(4) as a novel anti-inflammatory working through a defined receptor and suggests that mimicking its mode of action represents a new approach to treating inflammation-driven diseases.

In 2006 guidelines for the diagnosis and management of multiple myeloma were published (Smith et al, 2006). These current guidelines represent a major revision. The guideline has been split into two documents, focussing on the 'Diagnosis and management of multiple myeloma' and 'Supportive care in multiple myeloma 2011' (Snowden et al 2011). They are designed to be used together and to complement each other. The contents of 'Diagnosis and management of multiple myeloma' are listed below: Methodology, epidemiology and clinical presentation Diagnosis, prognostic factors and disease monitoring Imaging techniques Management of common medical emergencies in myeloma patients Myeloma bone disease Renal impairment Induction therapy including management of major toxicities and stem cell harvesting Management of refractory disease High dose therapy and autologous stem cell transplantation Allogeneic stem cell transplantation Maintenance therapy Management of relapsed myeloma including drugs in development Patient Information and Support The key areas that are covered comprehensively in the document entitled 'Guidelines for Supportive Care in Multiple Myeloma 2011' (Snowden et al 2011) are listed below: Anaemia Haemostasis and thrombosis issues Pain management Peripheral neuropathy Other symptom control – gastrointestinal, sedation/fatigue, mucositis Bisphosphonate-induced osteonecrosis of the jaw Complementary therapies End of life care The production of these guidelines involved the following steps: Establishment of working groups in the topic areas detailed above followed by review of key literature to 30th June 2010 including Cochrane database, Medline, internet searches and major conference reports. Development of key recommendations based on randomized, controlled trial evidence. In the absence of randomized data, recommendations were developed on the basis of literature review and a consensus of expert opinion. Involvement of patient advocacy through Myeloma UK. Review by UK Myeloma Forum (UKMF) Executive and British Committee for Standards in Haematology (BCSH) Committees. Review by a British Society for Haematology (BSH) sounding board. Levels of evidence and grades of recommendation are those of the US Agency for Healthcare Research and Quality (see Appendix I, Tables 1 and 2). In preparing these guidelines the authors have considered overall cost-effectiveness of recommended interventions as well as clinical efficacy data but formal health economic assessments have not been carried out. The annual incidence of myeloma in the UK is approximately 60–70 per million (http://info.cancerresearchuk.org/cancerstats/types/multiplemyeloma/incidence/index.htm). The overall prevalence is likely to be increasing given the recently published data demonstrating improved survival rates over the last decade (Kumar et al, 2008a; Brenner et al, 2009). The median age at presentation is approximately 70 years. Only 15% of patients are aged <60 years. Myeloma has a higher incidence in Afro-Caribbean ethnic groups than in Caucasians but there are few other distinctive epidemiological features. The majority of cases present de novo but it is now recognized that myeloma is preceded by an asymptomatic monoclonal gammopathy of undetermined significance (MGUS) phase in virtually all patients (Landgren et al, 2009). Presenting clinical features include symptoms of: Bone disease Impaired renal function Anaemia Hypercalcaemia Recurrent or persistent bacterial infection Hyperviscosity Other patients are diagnosed following the incidental detection of a raised erythrocyte sedimentation rate (ESR), plasma viscosity, serum protein or globulin. Patients with suspected myeloma require urgent specialist referral. Spinal cord compression, hypercalcaemia and renal failure are medical emergencies requiring immediate investigation and treatment. Investigation of a patient with suspected myeloma should include the screening tests indicated in Table I, followed by further tests to confirm the diagnosis. Electrophoresis of serum and concentrated urine should be performed, followed by immunofixation to confirm and type any M-protein present. Immunofixation and serum-free light chain (SFLC) assessment are indicated in patients where there is a strong suspicion of myeloma but in whom routine serum protein electrophoresis is negative (Pratt, 2008). Quantification of serum M-protein should be performed by densitometry of the monoclonal peak on electrophoresis; immunochemical measurement of total immunoglobulin (Ig) isotype level can also be used and is particularly useful for IgA and IgD M-proteins. Quantification of urinary total protein and light chain excretion can be performed directly on a 24 hour (h) urine collection or calculated on a random urine sample in relation to the urine creatinine. Quantification of SFLC levels and κ/λ ratio is an additional tool for the assessment of light chain production. The serum tests are particularly useful for diagnosis and monitoring of light chain only myeloma (Bradwell et al, 2003) and patients with oligosecretory/non-secretory disease (Drayson et al, 2001) and in requests for which urine has not been sent to the laboratory. In renal impairment the half-life, and thus serum concentration of SFLC, can increase ten-fold and there is often an increased κ/λ ratio (Hutchison et al, 2008). A diagnosis of myeloma should be confirmed by bone marrow (BM) assessment. It is recommended that an adequate trephine biopsy of at least 20 mm in length be obtained in all patients as it provides a better assessment of the extent of marrow infiltration than aspirate smears (Ng et al, 2006; Al-Quran et al, 2007). It is recommended that a diagnosis of myeloma be confirmed by the demonstration of an aberrant plasma cell phenotype and/or monoclonality. Plasma cell phenotyping may be performed by flow cytometry and/or immunohistochemistry on trephine sections. The European Myeloma Network have provided practical guidance on the optimal methods for flow cytometry (Rawstron et al, 2008) and rapid and cost effective single-tube assays have been developed (Rawstron et al, 2008). CD138 immunostaining of trephine sections can be useful to determine the extent of infiltration in selected cases (Ng et al, 2006; Al-Quran et al, 2007). All diagnoses should be made or reviewed by an appropriately constituted Multidisciplinary Team (MDT) (National Institute for Health and Clinical Excellence (NICE), 2003). Cytogenetic and radiological investigations are discussed in Sections 2.4 and 3, respectively. A diagnosis of myeloma should be made using the criteria proposed in 2003 by the International Myeloma Working Group (IMWG), which are detailed in Table II. These criteria distinguish between myeloma and MGUS principally on the basis of M-protein concentration, percentage of BM plasma cells and presence or absence of myeloma-related organ and tissue impairment (ROTI) (Table III). Other differential diagnoses in patients with M-proteins include solitary plasmacytoma and other B-cell lymphoproliferative disorders. Detailed guidance on the diagnosis and management of MGUS and solitary plasmacytoma are provided in recently published UKMF/BCSH guidelines (Bird et al, 2009; Hughes et al, 2009). IMWG diagnostic criteria should be used Investigation should be based on the tests shown in Table I including an assessment of possible myeloma-related organ and tissue impairment All diagnoses should be made or reviewed by an appropriately constituted MDT Plasma cell phenotyping by flow cytometry and/or immunohistochemistry on trephine biopsy sections is recommended in all cases Chemotherapy is indicated for the management of symptomatic myeloma defined by the presence of ROTI. Early intervention in patients with asymptomatic myeloma is not required (Hjorth et al, 1993; Riccardi et al, 2000) although chemotherapy may be considered in patients with a rising M-protein concentration in the absence of ROTI. Patients with asymptomatic myeloma require close monitoring under the supervision of a Consultant Haematologist. The overall risk of progression is 10% per year for the first 5 years but, interestingly, declines in subsequent years (Kyle et al, 2007). The SFLC ratio (≤0·125 or ≥8) appears to be predictive of outcome and a risk score incorporating BM plasma cell percentage, M-protein concentration and SFLC ratio has been proposed (Dispenzieri et al, 2008). Flow cytometry is also predictive of outcome as the risk of progression is significantly greater when aberrant phenotype plasma cells determined by flow cytometry comprise ≥95% of total BM plasma cells (Perez-Persona et al, 2007). Chemotherapy is only indicated in patients with symptomatic myeloma based on the presence of ROTI (Grade A recommendation; level of evidence Ib) Patients with asymptomatic myeloma should be monitored under the supervision of a Consultant Haematologist. These patients should be offered entry into clinical trials if available. (Grade C recommendation; level of evidence IV) Monitoring of patients with asymptomatic myeloma should include regular (typically 3-monthly) clinical assessment for the emergence of ROTI and measurement of serum and urinary M-protein (and SFLC when indicated). Repeat BM examination and skeletal imaging should be considered prior to the start of treatment (Grade C recommendation; level of evidence IV) The natural history of myeloma is heterogeneous with survival times ranging from a few weeks to >20 years. Analysis of prognostic factors is essential to compare outcomes within and between clinical trials. The Durie/Salmon staging system was published in 1975 (Durie & Salmon, 1975) but has been superseded by the International Staging System (ISS) reproduced in Table IV (Greipp et al, 2005). This defines three risk categories determined by the serum concentration of β2-microglobulin and albumin. The use of staging systems to determine choice of therapy for individual patients remains unproven. Certain cytogenetic and molecular genetic abnormalities have been shown to predict outcome in myeloma. It is generally accepted that the t(4;14), t(14;16) and deletion 17p, demonstrated by fluorescence in situ hybridization (FISH), confer an adverse outcome in myeloma. It has therefore been proposed that these abnormalities define 'high-risk' myeloma and should be specifically sought at diagnosis in all patients (Fonseca et al, 2009; Munshi et al, 2011). The prognostic significance of chromosome 13 deletions has been difficult to clarify as some studies have suggested that it is only of prognostic significance when demonstrated by conventional karyotyping, which significantly underestimates the overall incidence of the abnormality. Emerging data however suggests that the adverse effect of chromosome 13 deletion relates to its close association with high-risk abnormalities, particularly the t(4;14) and there is now consensus that conventional karyotyping has little or no added value in the routine setting (Fonseca et al, 2009). Although there are preliminary data to suggest that the adverse effect of these factors may be abrogated by newer agents (San Miguel et al, 2008a), the current international consensus is that further prospective evaluation is required before clinical decisions can be guided by genetic factors (Munshi et al, 2011). A number of groups have used gene expression profiling to define risk in both newly diagnosed and relapsed patients (Mulligan et al, 2007; Shaughnessy et al, 2007) but its role in determining treatment decisions is yet to be defined. Baseline SFLC concentration may also provide useful prognostic information (Dispenzieri et al, 2008). It is essential that new prognostic indicators continue to be evaluated in prospective clinical trials. The International Staging System based on serum albumin and β2-microglobulin should be used FISH studies are encouraged for all patients at diagnosis as they provide important prognostic information but their role in directing therapy needs further evaluation in prospective clinical trials The European Group for Blood and Bone Marrow Transplant/International Bone Marrow Transplant Registry/American Bone Marrow Transplant Registry (EBMT/IBMTR/ABMTR) criteria (Blade et al, 1998) were updated by the IMWG in 2006 (Durie et al, 2006) and further modifications were subsequently proposed (Rajkumar et al, 2011). The uniform response criteria are detailed in Table V. There are two new response categories, stringent complete response (sCR) and very good partial response (VGPR). The criteria now incorporate changes in the SFLC assay to support the uniform reporting of clinical trials. In routine clinical practice there is a clear rationale for utilising the SFLC assay to assess response in light chain only disease, irrespective of the extent of light chain excretion in the urine (Pratt, 2008). The response category 'sCR' (for use in the reporting of clinical trials) has been refined recently to incorporate the use of flow cytometry to detect minimal residual disease on the basis of the presence of an aberrant immunophenotype (Rajkumar et al, 2011). Low levels of residual disease may also be demonstrated using allele-specific polymerase chain reaction (PCR) and a further new category of molecular CR is proposed, which is defined as the absence of disease by sequence specific PCR methods with a sensitivity of 10−5. Delayed achievement of complete remission (CR) is seen in a significant proportion of patients following high-dose therapy (Davies et al, 2001). The majority of such patients will have IgG M-proteins which have a half-life of approximately 23 d, significantly longer than that of IgA (6 d) and free light chains (4 h) (Mead et al, 2004). Repeat BM aspirate assessment is required to confirm CR (repeat trephine biopsy is not required under the response criteria but may be needed for accurate assessment; Durie et al, 2006) and should be performed in all patients at Day 100 following high-dose therapy in accordance with EBMT standards. Flow cytometric assessment of minimal residual disease at this time point also provides prognostic information (Paiva et al, 2008) and may in the future be used to guide maintenance/consolidation therapies. The definitions of progressive disease and relapse have also been revised by the IMWG (Table VI) and include a new category of clinical relapse, which reflects the fact that progressive disease (PD) as defined does not necessarily indicate a need for further therapy. Response to therapy should be defined using the IMWG uniform response criteria The response category sCR is recommended only for use in the clinical trial setting The SFLC assay should be used to assess response in all patients with light chain only, non secretory and oligo-secretory disease The rare myelomas comprise up to 7% of all myelomas and consist of plasma cell leukaemia, IgD, IgE, IgM and non-secretory myeloma. Plasma cell leukaemia. Plasma cell leukaemia (PCL) may be primary or secondary to multiple myeloma and is characterized by the presence of ≥20% circulating plasma cells and/or an absolute level of >2·0 × 109/l (Kyle et al, 1974). IgD, E and M Myelomas. IgD myeloma may comprise up to 1·8% of all myelomas (Blade & Kyle, 1994; Wechalekar et al, 2005). Diagnosis may be difficult because some patients may present with a very small or no visible monoclonal spike on serum electrophoresis. Care must be exercised to avoid a false diagnosis of non-secretory or light chain only myeloma (Sinclair, 2002). The clinical features are similar to that of other myelomas but Bence-Jones proteinuria, extramedullary involvement, lytic lesions and amyloidosis seem to be more frequent (Jancelewicz et al, 1975). Relatively few cases of IgE myeloma have been reported in the literature (Endo et al, 1981; Kairemo et al, 1999Morris et al, 2010). There may be clinical similarities with IgD myeloma and in both conditions the prognosis appears to be poor (Morris et al, 2010). With the increased use of BM trephine biopsies and improved immunohistomorphology (Konduri et al, 2005; Feyler et al, 2008), IgM myelomas are being recognized more frequently and may comprise up to 0·3% of all myelomas (Morris et al, 2010). It is important that such cases are distinguished from other IgM secreting disorders, particularly Waldenstrom macroglobulinaemia (Avet-Loiseau et al, 2003a). There is a high incidence of the t(11;14) and prognosis appears to be poor (Avet-Loiseau et al, 2003b; Feyler et al, 2008; Morris et al, 2010). Non-secretory myeloma. Non-secretory myeloma poses particular diagnostic difficulties as there is no serum M-protein and no urinary Bence-Jones protein excretion. The SFLC assay is informative in approximately two thirds of patients (Drayson et al, 2001). While the clinical presentation is essentially similar to standard myeloma, anaemia and lytic lesions may be seen more frequently while renal failure is uncommon (Morris et al, 2010). Significant advances in available imaging technologies have paralleled developments in therapy for myeloma and may play a more prominent role in determining prognosis in the future (Durie, 2006). A detailed guideline for the use of imaging in myeloma has been published (D'Sa et al, 2007). Key recommendations are summarized below. The skeletal survey remains the screening technique of choice at diagnosis The skeletal survey should include a postero-anterior (PA) view of the chest, antero-posterior (AP) and lateral views of the cervical spine, thoracic spine, lumbar spine, humeri and femora, AP and lateral view of the skull and AP view of the pelvis; other symptomatic areas should be specifically visualized with appropriate views Computerized tomography (CT) scanning or magnetic resonance imaging (MRI) should be used to clarify the significance of ambiguous plain radiographic findings, such as equivocal lytic lesions, especially in parts of the skeleton that are difficult to visualize on plain radiographs, such as ribs, sternum and scapulae Urgent MRI is the diagnostic procedure of choice to assess suspected cord compression in myeloma patients with or without vertebral collapse (Grade B recommendation; level IIB evidence). Urgent CT scanning is an alternative, when MRI is unavailable, intolerable or contraindicated (Grade B recommendation; level III evidence) CT or MRI is indicated to delineate the nature and extent of soft tissue masses and where appropriate, tissue biopsy may be guided by CT scanning (Grade B recommendation; level IIB evidence) There is insufficient evidence to recommend the routine use of positron-emission tomography (PET) or 99mTechnetium sestamibi (MIBI) imaging. Either technique may be useful in selected cases for clarification of previous imaging findings preferably within the context of a clinical trial Bone scintigraphy has no place in the routine staging of myeloma Routine assessment of bone mineral density cannot be recommended, owing to the methodological difficulties of the technique and the universal use of bisphosphonates in symptomatic myeloma patients Hyperviscosity syndrome may develop in patients with high serum paraprotein levels, particularly those of IgA and IgG3 type. Symptoms include blurred vision, headaches, mucosal bleeding and dyspnoea due to heart failure. All patients with high protein levels should undergo fundoscopy, which may demonstrate retinal vein distension, haemorrhages and papilloedema. Patients usually have raised plasma viscosity and symptoms commonly appear when it exceeds 4 or 5 mPa. This usually corresponds to a serum IgM level of at least 30 g/l, an IgA level of 40 g/l and an IgG level of 60 g/l (Mehta & Singhal, 2003). Plasma viscosity results should not be used to determine the need for plasma exchange as this may result in delay but testing should be carried out both before and after the procedure. Symptomatic patients should be with plasma may be useful if plasma exchange are not available. is exchange should be The need for further over the few should be determined by symptoms and for of protein levels is and treatment should be Symptomatic should be with plasma exchange with is not available but symptoms are with as a treatment of the disease should be as as possible to of myeloma patients present with hypercalcaemia in the context of hypercalcaemia can present with system and of the on and renal of hypercalcaemia should be considered of the disease should be as as possible with treatment of hypercalcaemia to renal The of treatment are and hypercalcaemia may be with and/or to hypercalcaemia with urine should be and use of such as should be considered to avoid and heart failure and urinary excretion. All patients with to hypercalcaemia should a A randomized controlled trial in patients with hypercalcaemia of has shown that is to et al, 2001). the remains high after a further dose of may be modifications are required in renal impairment and dose may be more appropriate in patients with renal impairment (see Appendix Patients with refractory hypercalcaemia may require and In hypercalcaemia with and/or In to hypercalcaemia with and if required is the of choice in the treatment of hypercalcaemia A level I of the cord from extramedullary of disease in of patients with myeloma the of their disease (Kyle et al, 2003). Clinical features on the nature of the cord compression to or to soft tissue the extent of disease and the rate of development of cord compression, but commonly include and This is a medical requiring rapid diagnosis and treatment. clinical suspicion of cord compression, 40 for 4 should be and MRI obtained as as MRI is or due to patient or an urgent CT should be The between soft tissue and cord compression is essential and should be discussed with on if there is any the need for is usually for in the setting of compression and/or to the and is usually by soft tissue disease is the treatment of choice and should be preferably within 24 of the diagnosis of cord There are no randomized controlled trials to guidance on optimal dose and but a of myeloma patients has been published and demonstrated a better overall outcome in of in function for patients with at least 30 et al, 2006). Urgent MRI should be performed and or obtained is the treatment of choice for lesions and should be as as is preferably within 24 of diagnosis. A dose of 30 in is recommended (Grade B recommendation; level evidence) is recommended for in the setting of compression and/or to the cord compression is a it is important to a rapid diagnosis and to therapy as as possible Myeloma is with an increased incidence of This is to in both and and poor which are all with both the disease and its treatment. It has been reported that up to 10% of patients of within 60 of diagnosis et al, 2005). is not usually a in infection et al, 2005). There is increasing evidence that high dose in the or in patients with poor may be with increased and a higher rate in the and should be given to the use of in this et al, et al, 2009; et al, 2010). Patient as well as to specialist and treatment is in and infection in myeloma. and management of infection in myeloma patients is discussed in more in the care guideline (Snowden et al 2011). There must be to specialist for the patient and/or primary care myeloma patient should be with are required for infection or should be if possible There is insufficient evidence to recommend the routine use of Bone disease in of myeloma The development of bone disease, or can result in cord compression and hypercalcaemia & & and of life & et al, et al, 2007) and increase overall treatment bone require and subsequent is useful to control and may also of the a lytic may skeletal an should be sought and considered in selected clinical interventions for with including and are discussed in the care guideline (Snowden et al, 2011). is for a dose of is recommended bone require and subsequent a dose of is recommended A Cochrane Review of the use of bisphosphonates in myeloma et al, data from trials of or and from a preliminary of a trial of on a of trial data at that the was that bisphosphonates to the treatment of myeloma vertebral and but does not The evidence also suggested a in both patients with and without bone disease at trials with and in myeloma patients have now been published in et al, 2009). has been shown to be in myeloma and may et al, There are as yet no published randomized studies of or while to any effect on rates or survival et al, 2002). The trials of et al, et al, 2001) demonstrated for up to years in patients chemotherapy for the first including patients with no lytic using the bisphosphonates have been in patients with more and have demonstrated their in the of skeletal in this setting et al, et al, 2003). and appear with to although there has been no randomized and no of treatment is however with greater in skeletal and of of type 1 in some studies et al, 2001). The Research Myeloma trial has recently reported with a median up of years and demonstrated significant of

OBJECTIVE: Previous in vitro and animal studies have suggested that vitamin D, in particular, its metabolite 25-hydroxyvitamin D (25[OH]D), may have immunomodulatory effects. To study further the potential immunomodulatory effects of vitamin D in humans, we explored the hypothesis that serum vitamin D metabolites may be inversely associated with current disease activity, severity, and functional disability in patients with early inflammatory polyarthritis (IP). METHODS: We studied 206 consecutive patients with IP who were enrolled in the Norfolk Arthritis Register between January 2000 and November 2003 inclusive. Patients were studied within 6 months of symptom onset. None of the patients was taking steroids, and all had received <6 weeks of disease-modifying therapy. Associations between serum levels of 25(OH)D and 1,25-dihydroxyvitamin D (1,25[OH](2)D) at baseline and the swollen and tender joint counts, Health Assessment Questionnaire (HAQ) scores, C-reactive protein (CRP) levels, and the Disease Activity Score 28-joint assessment (DAS28) scores at baseline and 1 year were assessed. RESULTS: The median age at symptom onset was 59 years (range 20-88 years), with a median disease duration of 4 months. At baseline, there was an inverse relationship between 25(OH)D levels and the tender joint count, DAS28 score, and HAQ score. The only inverse relationship with 1,25(OH)(2)D was with the HAQ score. Each 10-ng/ml increase in the level of 25(OH)D was associated with a decrease in the DAS28 score of 0.3 and in the CRP level of approximately 25%. At 1 year, the only significant result was an inverse association between baseline vitamin D metabolite levels and the HAQ score; that is, those with higher metabolite levels had lower HAQ scores. CONCLUSION: These data provide further support that vitamin D plays an immunomodulatory role in inflammatory arthritis. This association needs to be examined in other cohorts of patients with early IP, as well as in longitudinal studies. If confirmed, the clinical response to vitamin D supplementation should be examined in early IP.

Hematopoietic prostaglandin D(2) synthase (hPGD(2)S) metabolizes cyclooxygenase (COX)-derived PGH(2) to PGD(2) and 15-deoxyDelta(12-14) PGJ(2) (15d-PGJ(2)). Unlike COX, the role of hPGD(2)S in host defense is ambiguous. PGD(2) can be either pro- or antiinflammatory depending on disease etiology, whereas the existence of 15d-PGJ(2) and its relevance to pathophysiology remain controversial. Herein, studies on hPGD(2)S KO mice reveal that 15d-PGJ(2) is synthesized in a self-resolving peritonitis, detected by using liquid chromatography-tandem MS. Together with PGD(2) working on its DP1 receptor, 15d-PGJ(2) controls the balance of pro- vs. antiinflammatory cytokines that regulate leukocyte influx and monocyte-derived macrophage efflux from the inflamed peritoneal cavity to draining lymph nodes leading to resolution. Specifically, inflammation in hPGD(2)S KOs is more severe during the onset phase arising from a substantial cytokine imbalance resulting in enhanced polymorphonuclear leukocyte and monocyte trafficking. Moreover, resolution is impaired, characterized by macrophage and surprisingly lymphocyte accumulation. Data from this work place hPGD(2)S at the center of controlling the onset and the resolution of acute inflammation where it acts as a crucial checkpoint controller of cytokine/chemokine synthesis as well as leukocyte influx and efflux. Here, we provide definitive proof that 15d-PGJ(2) is synthesized during mammalian inflammatory responses, and we highlight DP1 receptor activation as a potential antiinflammatory strategy.

T he overall aim of the NHS R&D Health Technology Assessment (HTA) programme is to ensure that high-quality research information on the costs, effectiveness and broader impact of health technologies is produced in the most efficient way for those who use, manage and work in the NHS. Research is undertaken in those areas where the evidence will lead to the greatest benefits to patients, either through improved patient outcomes or the most efficient use of NHS resources.

BACKGROUND: Health-related quality of life (QOL) is an important outcome for older people who are often on dialysis for life. Little is, however, known about differences in QOL on haemodialysis (HD) and peritoneal dialysis (PD) in older age groups. Randomising patients to either modality to assess outcomes is not feasible. METHODS: In this cross-sectional, multi-centred study we conducted QOL assessments (Short Form-12 Mental and Physical Component Summary scales, Hospital Anxiety and Depression Scale and Illness Intrusiveness Ratings Scale) in 140 people (aged 65 years or older) on PD and HD. RESULTS: The groups were similar in age, gender, time on dialysis, ethnicity, Index of Deprivation (based on postcode), dialysis adequacy, cognitive function (Mini-Mental State Exam and Trail-Making Test B), nutritional status (Subjective Global Assessment) and social networks. There was a higher comorbidity score in the HD group. Regression analyses were undertaken to ascertain which variables significantly influence each QOL assessment. All were influenced by symptom count highlighting that the patient's perception of their symptoms is a critical determinant of their mental and physical well being. Modality was found to be an independent predictor of illness intrusion with greater intrusion felt in those on HD. CONCLUSIONS: Overall, in two closely matched demographic groups of older dialysis patients, QOL was similar, if not better, in those on PD. This study strongly supports offering PD to all suitable older people.

Clinical biochemists have long known the analytical and clinical limitations of creatinine and creatinine clearance measurement in the assessment of glomerular filtration rate (GFR). This background is reviewed in the article before assessing the utility of cystatin C, the most promising replacement biochemical marker yet identified. Cystatin C has been used in clinical research studies for more than 20 years and yet has been introduced into clinical practice in very few centres, firstly in Lund in Sweden and now Carshalton in the UK. Why is this? The review compares our ability to measure creatinine and cystatin C and their relative sensitivity and specificity for changes in GFR. Comparison is made of cystatin C with creatinine as screening tests for early renal dysfunction and for monitoring its progression where issues of reference ranges and within-individual variation are important. The superiority of cystatin C as a screening test is probably accepted but there are still concerns about non-renal influences upon its circulating concentration, particularly steroid therapy, insufficient data on the influence of malignancy and a general lack of prospective clinical studies confirming the prognostic significance of cystatin C.

BACKGROUND: Pulmonary sarcoidosis is a common condition with an unpredictable course. Oral (OCS) or inhaled steroids (ICS) are widely used in its treatment, but there is no consensus about when and in whom therapy should be initiated, what dose should be given and for how long. Corticosteroids given for several months have deleterious side-effects so it is important to know whether they have any maintained benefit in pulmonary sarcoidosis. OBJECTIVES: To determine the randomised controlled trial (RCT) evidence for the benefit of corticosteroids (oral or inhaled) in the treatment of pulmonary sarcoidosis. SEARCH STRATEGY: MEDLINE, EMBASE and CENTRAL were searched using predefined terms. Bibliographies of retrieved RCTs and reviews were searched for additional RCTs. Pharmaceutical companies and authors of identified RCTs were contacted for other published and unpublished studies. Searches are current as of May 2004. SELECTION CRITERIA: Two reviewers independently assessed full text articles for inclusion based upon the following criteria: the study had to be a RCT or controlled clinical trial in adults with histological evidence of pulmonary sarcoidosis, treated with OCS (oral steroids) or ICS (oral steroids), compared with a control. DATA COLLECTION AND ANALYSIS: Study quality was assessed and data extracted independently by two reviewers. The primary outcome was CXR (chest x-ray). Outcomes were analysed as continuous and dichotomous outcomes, using standard statistical techniques. Heterogeneity was explored where it was identified. MAIN RESULTS: Twelve RCTs of variable quality involving 1051 participants met the inclusion criteria of the review. The oral steroid dose was equivalent to prednisolone 4-40 mg/day. OCS: there was an improvement in CXR over 3-24 months (Relative Risk (RR): 1.46 [1.01 to 2.09], 3 studies), but this finding requires cautious interpretation. No other significant differences were identified on secondary outcomes. ICS: Data were inadequate to perform meaningful analysis of data on CXR. Two studies showed no improvement in lung function, In one study there was an improvement in diffusing capacity in the treated group. There were no data on side-effects. In one study symptoms improved at the end of six months of treatment. AUTHORS' CONCLUSIONS: Oral steroids improved the chest X-ray and a global score of CXR, symptoms and spirometry over 3-24 months. However, there is little evidence of an improvement in lung function. There are limited data beyond two years to indicate whether oral steroids have any modifying effect on long-term disease progression. Oral steroids may be of benefit for patients with Stage 2 and 3 disease with moderate to severe or progressive symptoms or CXR changes.

OBJECTIVES: To determine whether microalbuminuria is an independent prognostic factor for the development of diabetic complications and whether improved glycaemic or blood pressure control has a greater influence on the development of diabetic complications in those with microalbuminuria than in those with normoalbuminuria. DATA SOURCES: Electronic databases up until January 2002. REVIEW METHODS: A protocol for peer review by an external expert panel was prepared that included selection criteria for data extraction and required two independent reviewers to undertake article selection and review. Completeness was assessed using hand-searching of major journals. Random effects meta-analysis was used to obtain combined estimates of relative risk (RR). Funnel plots, trim and fill methods and meta-regression were used to assess publication bias and sources of heterogeneity. RESULTS: In patients with type 1 or type 2 DM and microalbuminuria there is a RR of all-cause mortality of 1.8 [95% confidence interval (CI) 1.5 to 2.1] and 1.9 (95% CI 1.7 to 2.1) respectively. Similar RRs were found for other mortality end-points, with age of cohort being inversely related to the RR in type 2 DM. In patients with type 1 DM, there is evidence that microalbuminuria or raised albumin excretion rate has only weak, if any, independent prognostic significance for the incidence of retinopathy and no evidence that it predicts progression of retinopathy, although strong evidence exists for the independent prognostic significance of microalbuminuria or raised albumin excretion rate for the development of proliferative retinopathy (crude RR of 4.1, 95% CI 1.8 to 9.4). For type 2 DM, there is no evidence of any independent prognostic significance for the incidence of retinopathy and little, if any, prognostic relationship between microalbuminuria and the progression of retinopathy or development of proliferative retinopathy. In patients with type 1 DM and microalbuminuria there is an RR of developing end-stage renal disease (ESRD) of 4.8 (95% CI 3.0 to 7.5) and a higher RR (7.5, 95% CI 5.4 to 10.5) of developing clinical proteinuria, with a significantly greater fall in glomerular filtration rate (GFR) in patients with microalbuminuria. In patients with type 2 DM, similar RRs were observed: 3.6 (95% CI 1.6 to 8.4) for developing ESRD and 7.5 (95% CI 5.2 to 10.9) for developing clinical proteinuria, with a significantly greater decline in GFR in the microalbuminuria group of 1.7 (95% CI 0.1 to 3.2) ml per minute per year compared with those who were normoalbuminuric. In adults with type 1 or type 2 DM and microalbuminuria at baseline, the numbers progressing to clinical proteinuria (19% and 24%, respectively) and those regressing to normoalbuminuria (26% and 18%, respectively) did not differ significantly. In children with type 1 DM, regression (44%) was significantly more frequent than progression (15%). In patients with type 1 or type 2 DM and microalbuminuria, there is scarce evidence as to whether improved glycaemic control has any effect on the incidence of cardiovascular disease (CVD), the incidence or progression of retinopathy, or the development of renal complications. However, among patients not stratified by albuminuria, improved glycaemic control benefits retinal and renal complications and may benefit CVD. In the effects of angiotensin-converting enzyme (ACE) inhibitors on GFR in normotensive microalbuminuric patients with type 1 DM, there was no evidence of a consistent treatment effect. There is strong evidence from 11 trials in normotensive type 1 patients with microalbuminuria of a beneficial effect of ACE inhibitor treatment on the risk of developing clinical proteinuria and on the risk of regression to normoalbuminuria. Patients with type 2 DM and microalbuminuria, whether hypertensive or not, may obtain additional cardiovascular benefit from an ACE inhibitor and there may be a beneficial effect on the development of retinopathy in normotensive patients irrespective of albuminuria. There is limited evidence that treatment of hypertensive microalbuminuric type 2 diabetic patients with blockers of the renin--angiotensin system is associated with preserved GFR, but also evidence of no differences in GFR in comparisons with other antihypertensive agents. The data on GFR in normotensive cohorts are inconclusive. In normotensive type 2 patients with microalbuminuria there is evidence from three trials (all enalapril) of a reduction in risk of developing clinical proteinuria; in hypertensive patients there is evidence from one placebo-controlled trial (irbesartan) of a reduction in this risk. Intensive compared with moderate blood pressure control did not affect the rate of progression of microalbuminuria to clinical proteinuria in the one available study. There is inconclusive evidence from four trials of any difference in the proportions of hypertensive patients progressing from microalbuminuria to clinical proteinuria when ACE inhibitors are compared with other antihypertensive agents, and in one trial regression was two-fold higher with lisinopril than with nifedipine. CONCLUSIONS: The most pronounced benefits of glycaemic control identified in this review are on retinal and renal complications in both normoalbuminuric and microalbuminuric patients considered together, with little or no evidence of any greater benefit in those with microalbuminuria. Hence, microalbuminuric status may be a false boundary when considering the benefits of glycaemic control. Classification of a person as normoalbuminuric must not serve to suggest that they will derive less benefit from optimal glycaemic control than a person who is microalbuminuric. All hypertensive patients benefit from blood pressure lowering and there is little evidence of additional benefit in those with microalbuminuria. Antihypertensive therapy with an ACE inhibitor in normotensive patients with microalbuminuria is beneficial. Monitoring microalbuminuria does not have a proven role in modulating antihypertensive therapy while the patient remains hypertensive. Recommendations for microalbuminuria research include: determining rate and predictors of development and factors involved in regression; carrying out economic evaluations of different screening strategies; investigating the effects of screening on patients; standardising screening tests to enable use of common reference ranges; evaluating the effects of lipid-lowering therapy; and using to modulate antihypertensive therapy.

The National Osteoporosis Society (NOS) published its document, Vitamin D and Bone Health: A Practical Clinical Guideline for Patient Management, in 2013 as a practical clinical guideline on the management of vitamin D deficiency in adult patients with, or at risk of developing, bone disease. There has been no clear consensus in the UK on vitamin D deficiency its assessment and treatment, and clinical practice is inconsistent. This guideline is aimed at clinicians, including doctors, nurses and dieticians. It recommends the measurement of serum 25 (OH) vitamin D (25OHD) to estimate vitamin D status in the following clinical scenarios: bone diseases that may be improved with vitamin D treatment; bone diseases, prior to specific treatment where correcting vitamin D deficiency is appropriate; musculoskeletal symptoms that could be attributed to vitamin D deficiency. The guideline also states that routine vitamin D testing is unnecessary where vitamin D supplementation with an oral antiresorptive treatment is already planned and sets the following serum 25OHD thresholds: <30 nmol/l is deficient; 30-50 nmol/l may be inadequate in some people; >50 nmol/l is sufficient for almost the whole population. For treatment, oral vitamin D3 is recommended with fixed loading doses of oral vitamin D3 followed by regular maintenance therapy when rapid correction of vitamin D deficiency is required, although loading doses are not necessary where correction of deficiency is less urgent or when co-prescribing with an oral antiresorptive agent. For monitoring, serum calcium (adjusted for albumin) should be checked 1 month after completing a loading regimen, or after starting vitamin D supplementation, in case primary hyperparathyroidism has been unmasked. However, routine monitoring of serum 25OHD is generally unnecessary but may be appropriate in patients with symptomatic vitamin D deficiency or malabsorption and where poor compliance with medication is suspected. The guideline focuses on bone health as, although there are numerous putative effects of vitamin D on immunity modulation, cancer prevention and the risks of cardiovascular disease and multiple sclerosis, there remains considerable debate about the evaluation of extraskeletal factors and optimal vitamin D status in these circumstances.