Neil Snowden

Tumour necrosis factor c2 microsatellite allele is associated with the rate of HIV disease progression

Background:The rate of immunological deterioration and progression to AIDS differs markedly between HIV-positive individuals, and may be influenced by cofactors, HIV phenotype and host T-cell response. Tumour necrosis factor (TNF)-α and lymphotoxin stimulate HIV replication and may induce apoptosis of HIV-infected and uninfected lymphocytes in vitro, thus accelerating disease progression and CD4 depletion. Variability in TNF production between individuals is to a degree genetically determined and may be predicted from polymorphisms of microsatellite regions surrounding the human TNF gene locus. Methods:We examined TNF microsatellite polymorphisms in 24 HIV-positive patients with slower disease progression (CD4 count > 400 × 106/l at ≥ 6 years), 20 HIV-positive patients with faster progression (CD4 count < 200 × 106/l within 5 years) and 109 healthy controls resident in north-west England. Typing was performed by polymerase chain reaction amplification of TNF a, b, c and d microsatellites and alleles were defined using fluorescence-based semi-automated microsatellite mapping techniques. Results:No significant differences in TNF a, b and d allele frequencies were observed between faster and slower progressors, or with healthy controls. The frequency of the TNF c2 allele was significantly different between HIV-positive slower (60.9%) and faster (15%) progressors (P = 0.002) with an odds ratio of 0.1 (95% confidence interval, 0–0.6). TNF c2 was also less frequent in faster progressors than in healthy controls (45.9%, P = 0.006) with an odds ratio of 0.2 (95% confidence interval 0–0.8). Conclusions:This is the first report demonstrating a strong association between the TNF c2 allele and the rate of HIV progression. Although it is possible that this finding may have arisen as a result of linkage disequilibrium with other alleles within the major histocompatibility complex that exert a more powerful effect upon progression, evidence is mounting to suggest that both TNF-α and lymphotoxin are closely involved in HIV disease progression and CD4 depletion. Our results serve to highlight the potential importance of genetic polymorphism, particularly of the TNF locus, in influencing the progression of HIV infection.

Brief report: Shortened telomere length in patients with systemic lupus erythematosus

OBJECTIVE Patients with systemic lupus erythematosus (SLE) have a higher rate of premature death compared to the general population, suggesting a phenotype of premature senescence in SLE. Telomere length can be used to assess overall biologic aging. This study was undertaken to address the hypothesis that patients with SLE have reduced telomere length. METHODS Telomere length was measured cross-sectionally in whole blood from SLE patients and age-matched healthy female controls, using real-time quantitative polymerase chain reaction. SLE-related and cardiovascular risk factors were assessed. RESULTS We compared telomere length in 63 SLE patients and 63 matched controls with a median age of 50.8 years (interquartile range [IQR] 37-59 years) and 49.9 years (IQR 32-60 years), respectively. The median relative telomere length in SLE patients was 0.97 (IQR 0.47-1.57), compared to 1.53 (IQR 0.82-2.29) in controls (P = 0.0008). We then extended our cohort to measure telomere length in 164 SLE patients. Shorter telomere length was associated with Ro antibodies (β ± SE -0.36 ± 0.16; P = 0.023), and longer telomere length was associated with steroid therapy (0.29 ± 0.14; P = 0.046). We also noted an association of longer telomere length with increasing body mass index (β ± SE 0.07 ± 0.01; P < 0.0001) and tobacco smoking (0.64 ± 0.26; P = 0.016), as well as with the presence of carotid plaque (0.203 ± 0.177; P = 0.032). CONCLUSION Telomere length is shortened in SLE patients compared to controls and does not appear to be a reflection of disease activity or immune cell turnover. Subsets of patients such as those positive for Ro antibodies may be particularly susceptible to premature biologic aging. The predictive value of telomere length as a biomarker of future risk of damage/mortality in SLE requires longitudinal evaluation.

Telomere length is shortened in SLE patients.

OBJECTIVE Patients with systemic lupus erythematosus (SLE) have a higher rate of premature death compared to the general population, suggesting a phenotype of premature senescence in SLE. Telomere length can be used to assess overall biologic aging. This study was undertaken to address the hypothesis that patients with SLE have reduced telomere length. METHODS Telomere length was measured cross-sectionally in whole blood from SLE patients and age-matched healthy female controls, using real-time quantitative polymerase chain reaction. SLE-related and cardiovascular risk factors were assessed. RESULTS We compared telomere length in 63 SLE patients and 63 matched controls with a median age of 50.8 years (interquartile range [IQR] 37-59 years) and 49.9 years (IQR 32-60 years), respectively. The median relative telomere length in SLE patients was 0.97 (IQR 0.47-1.57), compared to 1.53 (IQR 0.82-2.29) in controls (P = 0.0008). We then extended our cohort to measure telomere length in 164 SLE patients. Shorter telomere length was associated with Ro antibodies (β ± SE -0.36 ± 0.16; P = 0.023), and longer telomere length was associated with steroid therapy (0.29 ± 0.14; P = 0.046). We also noted an association of longer telomere length with increasing body mass index (β ± SE 0.07 ± 0.01; P < 0.0001) and tobacco smoking (0.64 ± 0.26; P = 0.016), as well as with the presence of carotid plaque (0.203 ± 0.177; P = 0.032). CONCLUSION Telomere length is shortened in SLE patients compared to controls and does not appear to be a reflection of disease activity or immune cell turnover. Subsets of patients such as those positive for Ro antibodies may be particularly susceptible to premature biologic aging. The predictive value of telomere length as a biomarker of future risk of damage/mortality in SLE requires longitudinal evaluation.

Construct and Criterion Validity of the Short Form-6D Utility Measure in Patients with Systemic Lupus Erythematosus

Objective. Preference-based measures, such as the Short Form-6D (SF-6D), allow quality-adjusted life-years, used in cost-utility evaluations, to be calculated. We investigated the construct and criterion validity of the SF-6D in patients with systemic lupus erythematosus (SLE). Methods. Female patients with SLE were recruited from outpatient clinics at 2 timepoints, 5 years apart. Cross-sectional correlation of the SF-6D with domains of the disease-specific LupusQol health-related quality of life (HRQOL) measure, the Systemic Lupus International Collaborating Clinics Damage Index (SDI; for damage) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI; for activity) measures, and patient characteristics was tested. The ability to discriminate between groups defined by smoking status, presence/absence of carotid plaque, depression, and fatigue was tested using the t-test. Results. In total 181 patients were recruited at baseline. The SF-6D correlated moderately to strongly with all domains of the LupusQoL (0.6–0.8) apart from intimate relationships (0.42) and body image (0.34). Correlations of the SF-6D with the demographic and disease-specific measures at baseline were small for the SDI score (−0.23) and age (−0.19) and in the expected direction. The SF-6D did not correlate with disease activity (SLEDAI −0.08). The SF-6D could distinguish those who smoked, had carotid plaque, had depression, and reported fatigue from those who did not, with the largest effect size being for depression (0.75). Conclusion. The SF-6D displays construct and criterion validity for use in patients with SLE, but the low correlation with aspects of intimate relationships and body image represents a concern and reinforces the need to collect disease-specific measures of HRQOL alongside generic preference-based instruments.

Impaired humoral responses to subgenus D adenovirusenovirus infections in HIV-positive patients

HIV‐positive patients are at increased risk of developing adenovirus infection, particularly of the gastrointestinal tract and with unusual subgenus D strains. To investigate humoral immunity to these strains of adenoviruses, the humoral immune response was examined in longitudinal samples of serum against isolates collected from a prospective study of HIV‐positive patients with subgenus D adenovirus infection. Of 10 HIV‐positive patients developing adenovirus infection, 3 had chronic infection (8–>27 months) with one serotype, 3 had chronic infection (≥10 months) with changing serotypes and 4 had acute and self‐limiting adenovirus infection (<1 month). Fifty‐one sera were tested, and samples collected before adenovirus infection were available in 8 patients. Neutralising assays were performed against the patients own isolate (adenoviruses 9, 17, 19, 19/23, 19/37, 23, 26, 23/26, 43 and 46) and common circulating strains of adenovirus 1–5. Indirect immunofluorescence tests were carried out against the autologous isolate and complement‐fixation tests were undertaken using a standard assay. Immunofluorescence test antibodies were detected (titre ≥160) in all patients, and present to high titre (≥320) in 8/10 patients. Complement‐fixing antibodies were not detected in significant titre. Of particular note, there was no significant neutralising antibody response to the patients own isolate after acute infection. Neutralising antibody to adenovirus 3 (titre 20) was transiently detected in two patients. In the remaining patients neutralising antibody directed against adenoviruses 1–5 was not detected. Persistent carriage of subgenus D adenoviruses in HIV‐positive patients is probably the result of failure of cell‐mediated immune responses to clear primary infection. Nevertheless, there is marked impairment of B cell responses resulting in poor neutralising and complement‐fixing antibody production even though immunofluorescence test determined antibodies are produced in high titre. These possibly reflect impairment of effective B cell priming mechanisms within the germinal centres of lymph nodes, or the polyclonal activation of B cells driven by HIV infection. J. Med. Virol. 62:405–409, 2000.

Diagnostic yield of FDG-PET/CT in fever of unknown origin: a systematic review, meta-analysis, and Delphi exercise

AIM To perform a systematic review, meta-analysis and Delphi exercise to evaluate diagnostic yield of combined 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography and computed tomography (FDG-PET/CT) in fever of unknown origin (FUO). MATERIALS AND METHODS Four databases were searched for studies of FDG-PET/CT in FUO 1/1/2000-1/12/2015. Exclusions were non-English language, case reports, non-standard FDG radiotracer, and significant missing data. Quality was assessed by two authors independently using a standardised tool. Pooled diagnostic yield was calculated using a random-effects model. An iterative electronic and face-to-face Delphi exercise generated interspeciality consensus. RESULTS Pooled diagnostic yield was 56% (95% confidence interval [CI]: 50-61%, I2=61%) from 18 studies and 905 patients. Only five studies reported results of previous imaging, and subgroup analysis estimated diagnostic yield beyond conventional CT at 32% (95% CI: 22-44%; I2=66%). Consensus was established that FDG-PET/CT is increasingly available with an emerging role, but there is prevailing variability in practice. CONCLUSION There is insufficient evidence to support the value of FDG-PET/CT in investigative algorithms of FUO. A paradigm shift in research is needed, involving prospective studies recruiting at diagnosis of FUO, with updated case definitions and hard outcome measures. Although these studies will be a significant undertaking with multicentre collaboration, their completion is vital for balancing both radiation exposure and costs against the possible benefits of utilising FDG-PET/CT.

Achievement of NICE quality standards for patients with new presentation of inflammatory arthritis: observations from the National Clinical Audit for Rheumatoid and Early Inflammatory Arthritis

Objectives. A national audit was performed assessing the early management of suspected inflammatory arthritis by English and Welsh rheumatology units. The aim of this audit was to measure the performance of rheumatology services against National Institute for Health and Care Excellence (NICE) quality standards (QSs) for the management of early inflammatory arthritis benchmarked to regional and national comparators for the first time in the UK. Methods. All individuals >16 years of age presenting to rheumatology services in England and Wales with suspected new-onset inflammatory arthritis were included in the audit. Information was collected against six NICE QSs that pertain to early inflammatory arthritis management. Results. We present national data for the 6354 patients recruited from 1 February 2014 to 31 January 2015; 97% of trusts and health boards in England and Wales participated in this audit. Only 17% of patients were referred by their general practitioner within 3 days of first presentation. Specialist rheumatology assessment occurred within 3 weeks of referral in 38% of patients. The target of DMARD initiation within 6 weeks of referral was achieved in 53% of RA patients; 36% were treated with combination DMARDs and 82% with steroids within the first 3 months of specialist care. Fifty-nine per cent of patients received structured education on their arthritis within 1 month of diagnosis. In total, 91% of patients had a treatment target set; the agreed target was achieved within 3 months of specialist review in only 27% of patients. Access to urgent advice via a telephone helpline was reported to be available in 96% of trusts. Conclusion. The audit has highlighted gaps between NICE standards and delivery of care, as well as substantial geographic variability.

Patient- and clinician-reported outcomes for patients with new presentation of inflammatory arthritis: observations from the National Clinical Audit for Rheumatoid and Early Inflammatory Arthritis.

Objectives. Our aim was to conduct a national audit assessing the impact and experience of early management of inflammatory arthritis by English and Welsh rheumatology units. The audit enables rheumatology services to measure for the first time their performance, patient outcomes and experience, benchmarked to regional and national comparators. Methods. All individuals >16 years of age presenting to English and Welsh rheumatology services with suspected new-onset inflammatory arthritis were included in the audit. Clinician- and patient-derived outcome and patient-reported experience measures were collected. Results. Data are presented for the 6354 patients recruited from 1 February 2014 to 31 January 2015. Ninety-seven per cent of English and Welsh trusts participated. At the first specialist assessment, the 28-joint DAS (DAS28) was calculated for 2659 (91%) RA patients [mean DAS28 was 5.0 and mean Rheumatoid Arthritis Impact of Disease (RAID) score was 5.6]. After 3 months of specialist care, the mean DAS28 was 3.5 and slightly >60% achieved a meaningful DAS28 reduction. The average RAID score and reduction in RAID score were 3.6 and 2.4, respectively. Of the working patients ages 16–65 years providing data, 7, 5, 16 and 37% reported that they were unable to work, needed frequent time off work, occasionally and rarely needed time off work due to their arthritis, respectively; only 42% reported being asked about their work. Seventy-eight per cent of RA patients providing data agreed with the statement ‘Overall in the last 3 months I have had a good experience of care for my arthritis’; <2% disagreed. Conclusion. This audit demonstrates that most RA patients have severe disease at the time of presentation to rheumatology services and that a significant number continue to have high disease activity after 3 months of specialist care. There is a clear need for the National Health Service to develop better systems for capturing, coding and integrating information from outpatient clinics, including measures of patient experience and outcome and measures of ability to work.

Extreme elevation of ferritin and creatine kinase in primary infection with HIV-1

The diagnosis of primary HIV-1 infection can be challenging, especially in the absence of reported risks or when presenting features are unusual and uncommon. We report an atypical case of primary HIV-1 infection with HIV-1 subtype C in a 61-year old Caucasian man who presented with extreme hyperferritinaemia without iron overload and marked elevation of serum creatine kinase without rhabdomyolysis. In view of his symptomatic seroconversion and low baseline CD4+ T-lymphocyte count, the patient was treated promptly with combination antiretroviral therapy. Subsequently, he made good clinical improvement on treatment and no opportunistic infections were diagnosed at presentation or as part of a later immune reconstitution syndrome. This novel case highlights the importance of clinical suspicion of HIV and suggests that primary HIV-1 infection should be considered in patients presenting with severe hyperferritinaemia or markedly elevated creatine kinase levels. Further studies are required to explain the causative biological mechanisms underlying this rare presentation.

Varicella vaccination in the immunocompromised

Primary varicella zoster virus (VZV) infection or chickenpox is typically a benign illness in immunocompetent individuals. Reactivation of latent VZV, herpes zoster (HZ), usually manifests as shingles in a restricted dermatomal distribution. However, the risk of life-threatening complications, such as disseminated VZV, is greater in immunosuppressed individuals, with significant rates of mortality. In these patients, skin lesions may be minimal, or even absent, leading to delayed diagnosis and intervention [1]. Up to 8% of patients hospitalized with VZV infection are receiving immunosuppressive therapies [2]. The case fatality rate is 10% in severely immunocompromised individuals, compared with 0.009% for all cases [3]. The British Society for Rheumatology Biologics Register revealed that the incidence of shingles is 1.6 per 100 patient-years (2% per year) in RA patients receiving antiTNF-a therapy [4]. Data for less potent immunosuppression are more uncertain [1]. VZV vaccines are safe and efficacious at reducing varicella-related morbidity and mortality in immunocompetent individuals. In the UK, VZV vaccines for primary prevention are not administered on the childhood immunization schedule. The HZ vaccine has recently been introduced for people aged 70 for shingles prevention, with a catchup programme at 79 years of age [5]. Vaccine effectiveness decreases substantially for those 580 years of age, and although the vaccine is licensed for those >50 years of age, due to limited vaccine supply, the above schedule is recommended for cost-effectiveness [5]. Patients with autoimmune disease are at increased risk of VZV from both the underlying disease process itself and the use of immunomodulation. While these patients may benefit most from vaccination, varicella and zoster vaccines are live attenuated therapies, which increase the risk of vaccine-related complications in patients receiving immunomodulatory agents. This raises a number of issues regarding the clinical utility of vaccinating such patients. Depending upon the degree of underlying immunosuppression, the immunogenic response to vaccination may be diminished and efficacy may be variable [6]. The safety of live attenuated vaccines in immunosuppression is uncertain and uncontrolled replication of the vaccine strain may occur. Furthermore, the varicella virus vaccine summary of product characteristics (SPC) contains reports of vaccine virus transmission to immunocompromised household contacts, sometimes without a breakthrough rash. Reassuringly, the vaccine strains are sensitive to acyclovir. In primary care, HZ vaccine is usually administered alongside the flu vaccine. The safety and efficacy of giving multiple vaccinations in the immunocompromised state is unknown. Vaccinated patients should therefore be counselled regarding these uncertainties, advised to avoid chickenpox exposure and be monitored for signs of VZV infection should exposure occur. Current guidance is variable and is summarized in Table 1. The UK Department of Health (DoH) generally precludes the use of live attenuated vaccines in immunosuppressed individuals with the exception of HZ vaccine [5]. The Centers for Disease Control and Prevention [7] in the USA maintains that live vaccines should be avoided only in severely immunocompromised individuals. The European League Against Rheumatism guidance [8] recommends avoidance of live attenuated vaccines in immunocompromised patients whenever possible, but VZV vaccines are considered an exception and may be considered in mildly immunosuppressed patients on a caseby-case basis. The level of immunosuppression potentially contributing to direct harm from live attenuated vaccines is unknown. This is further complicated by the use of combination immunosuppressive therapies. Additionally, the SPC for the various immunomodulatory agents also varies. The picture is further complicated by the significant variation in guidance between different specialties such as rheumatology, gastroenterology, dermatology and paediatrics. Definitive evidence on the clinical utility of live vaccinations is limited, however, in our practice we take the following approach to varicella vaccination. Primary varicella vaccination is not necessary for adults born and raised in the UK, as 90% have varicella immunity from chickenpox contracted in childhood. A detailed history can elicit this information. For uncertain cases, IgG serology can be performed within 24 h, costing less than £10 in most laboratories. For non-immune patients, administering VZV vaccination would necessitate a delay of at least 2 weeks before commencing immunosuppressive therapy. This potential delay may be unacceptable in a minority of patients with severe organ-threatening autoimmune disease, with the majority of patients gaining potential long-term benefits from this proactive approach. The risks of developing infection with the VZV vaccine strain in immunosuppressed patients who are serologically naive are high. Therefore, in keeping with the DoH recommendations [5], we would not recommend VZV or HZ vaccination in those without previous chickenpox exposure who are already immunosuppressed. However, we would re-emphasize the importance of taking a careful