Fowzia Ibrahim

A randomized placebo-controlled trial of methotrexate in psoriatic arthritis

Objective. MTX is widely used to treat synovitis in PsA without supporting trial evidence. The aim of our study was to test the value of MTX in the first large randomized placebo-controlled trial (RCT) in PsA. Methods. A 6-month double-blind RCT compared MTX (15 mg/week) with placebo in active PsA. The primary outcome was PsA response criteria (PsARC). Other outcomes included ACR20, DAS-28 and their individual components. Missing data were imputed using multiple imputation methods. Treatments were compared using logistic regression analysis (adjusted for age, sex, disease duration and, where appropriate, individual baseline scores). Results. Four hundred and sixty-two patients were screened and 221 recruited. One hundred and nine patients received MTX and 112 received placebo. Forty-four patients were lost to follow-up (21 MTX, 23 placebo). Twenty-six patients discontinued treatment (14 MTX, 12 placebo). Comparing MTX with placebo in all randomized patients at 6 months showed no significant effect on PsARC [odds ratio (OR) 1.77, 95% CI 0.97, 3.23], ACR20 (OR 2.00, 95% CI 0.65, 6.22) or DAS-28 (OR 1.70, 95% CI 0.90, 3.17). There were also no significant treatment effects on tender and swollen joint counts, ESR, CRP, HAQ and pain. The only benefits of MTX were reductions in patient and assessor global scores and skin scores at 6 months (P = 0.03, P < 0.001 and P = 0.02, respectively). There were no unexpected adverse events. Conclusions. This trial of active PsA found no evidence for MTX improving synovitis and consequently raises questions about its classification as a disease-modifying drug in PsA. Trial registration. Current Controlled Trials, www.controlled-trials.com, ISRCTN:54376151.

A randomized placebo-controlled trial of MTX in PsA

Objective. MTX is widely used to treat synovitis in PsA without supporting trial evidence. The aim of our study was to test the value of MTX in the first large randomized placebo-controlled trial (RCT) in PsA. Methods. A 6-month double-blind RCT compared MTX (15 mg/week) with placebo in active PsA. The primary outcome was PsA response criteria (PsARC). Other outcomes included ACR20, DAS-28 and their individual components. Missing data were imputed using multiple imputation methods. Treatments were compared using logistic regression analysis (adjusted for age, sex, disease duration and, where appropriate, individual baseline scores). Results. Four hundred and sixty-two patients were screened and 221 recruited. One hundred and nine patients received MTX and 112 received placebo. Forty-four patients were lost to follow-up (21 MTX, 23 placebo). Twenty-six patients discontinued treatment (14 MTX, 12 placebo). Comparing MTX with placebo in all randomized patients at 6 months showed no significant effect on PsARC [odds ratio (OR) 1.77, 95% CI 0.97, 3.23], ACR20 (OR 2.00, 95% CI 0.65, 6.22) or DAS-28 (OR 1.70, 95% CI 0.90, 3.17). There were also no significant treatment effects on tender and swollen joint counts, ESR, CRP, HAQ and pain. The only benefits of MTX were reductions in patient and assessor global scores and skin scores at 6 months (P = 0.03, P < 0.001 and P = 0.02, respectively). There were no unexpected adverse events. Conclusions. This trial of active PsA found no evidence for MTX improving synovitis and consequently raises questions about its classification as a disease-modifying drug in PsA. Trial registration. Current Controlled Trials, www.controlled-trials.com, ISRCTN:54376151.

Efavirenz is associated with severe vitamin D deficiency and increased alkaline phosphatase

Objective(s):To identify factors (including exposure to specific antiretroviral drugs) associated with severe vitamin D deficiency (VDD) in HIV-infected individuals and to explore the effects of severe VDD and antiretroviral drug exposure on serum alkaline phosphatase (ALP) as surrogate marker of bone turnover. Design:Cross-sectional survey of vitamin D status among HIV-infected patients attending for routine clinical care at a large London HIV clinic. Methods:Severe VDD was defined as 25(OH)D levels of less than 10 μg/l (<25 nmol/l). Multivariate logistic regression analysis was used to identify factors associated with severe VDD and upper quartile ALP levels. Results:Vitamin D levels were measured in 1077 patients and found to be suboptimal in 91%. One-third of patients had severe VDD. Black ethnicity, sampling in winter, nadir CD4 cell count less than 200 cells/μl, and exposure to combination antiretroviral therapy were associated with severe VDD. In analyses restricted to patients on combination antiretroviral therapy, current efavirenz use was significantly associated with severe VDD [adjusted odds ratio 2.0 (95% confidence interval 1.5–2.7)]. Current tenofovir [adjusted odds ratio 3.5 (95% confidence interval 2.3–5.2)] and efavirenz use [adjusted odds ratio 1.6 (95% confidence interval 1.02–2.4)], but not severe VDD [odds ratio 1.1 (0.8–1.5)], were associated with increased bone turnover (upper quartile ALP). Conclusion:Efavirenz was associated with severe VDD, a condition associated with multiple adverse health outcomes, and efavirenz and tenofovir with increased ALP. The clinical significance of these findings requires further investigation, given the widespread use of efavirenz and tenofovir in first-line combination antiretroviral therapy.

Incidence of severe reproductive tract complications associated with diagnosed genital chlamydial infection: the Uppsala Women's Cohort Study

Objective: To estimate the cumulative incidence of severe complications associated with genital chlamydia infection in the general female population. Methods: The Uppsala Women’s Cohort Study was a retrospective population based cohort study in Sweden, linking laboratory, hospital, and population registers. We estimated the cumulative incidence of hospital diagnosed pelvic inflammatory disease, ectopic pregnancy, and infertility, and used multivariable regression models to estimate hazard ratios according to screening status. Results: We analysed complete data from 43 715 women in Uppsala aged 15–24 years between January 1985 and December 1989. Follow up until the end of 1999 included 709 000 woman years and 3025 events. The cumulative incidence of pelvic inflammatory disease by age 35 years was 3.9% (95% CI 3.7% to 4.0%) overall: 5.6% (4.7% to 6.7%) in women who ever tested positive for chlamydia, 4.0% (3.7% to 4.4%) in those with negative tests, and 2.9% (2.7% to 3.2%) in those who were never screened. The corresponding figures were: for ectopic pregnancy, 2.3% (2.2% to 2.5%) overall, 2.7% (2.1% to 3.5%), 2.0% (1.8% to 2.3%), and 1.9% (1.7% to 2.1%); and for infertility, 4.1% (3.9% to 4.3%) overall, 6.7% (5.7% to 7.9%), 4.7% (4.4% to 5.1%), and 3.1% (2.8% to 3.3%). Low educational attainment was strongly associated with the development of all outcomes. Conclusions: The incidence of severe chlamydia associated complications estimated from ours, and other population based studies, was lower than expected. Studies that incorporate data about pelvic inflammatory disease diagnosed in primary care and behavioural risk factors would further improve our understanding of the natural history of chlamydia. Our results provide reassurance for patients, but mean that the benefits of chlamydia screening programmes might have been overestimated.

Investigating Black-White differences in prostate cancer prognosis: A systematic review and meta-analysis

The case‐fatality rate following a diagnosis of prostate cancer is higher for Black men compared to White men. How this elevated rate arises is uncertain, with differences in disease biology, presentation, treatment and comorbidity having been suggested. A systematic search was conducted for articles that reported ethnic differences in overall‐survival, prostate cancer specific survival (PSS) or biochemical recurrence. 48 articles met the inclusion criteria. Black men had worse overall survival (risk ratio 1.35, 95% CI 1.23–1.48) but this was not due to comorbidity alone as PSS and risk of biochemical recurrence were also elevated (1.29, 95% CI 1.13–1.47 and 1.34, 95% CI 1.23–1.46, respectively). Studies adjusting for clinical predictors and socioeconomic variables no longer supported a difference in overall survival (1.01, 95% CI 0.88–1.16), but continued to find an increased risk amongst Black men for PSS (1.13, 95% CI 1.00–1.27) and biochemical recurrence (1.25, 95% CI 1.11–1.41). Similar results were seen for studies from the pre‐PSA era and free‐health care settings. In contrast to others, studies of metastatic cancer did not find evidence of Black‐White differences (p for interaction = 0.01). In conclusion, Black men had a poorer prognosis which was not fully explained by comorbidity, PSA screening, or access to free health care, although few studies measure these factors well. Either management differences for local disease and/or biological differences may be behind Black‐White differences in prostate cancer prognosis.

HIV Care and the Incidence of Acute Renal Failure

BACKGROUND The clinical epidemiology of acute renal failure (ARF) in human immunodeficiency virus (HIV)-infected patients remains poorly defined. METHODS We conducted a retrospective analysis of patients who developed ARF while attending Kings College Hospital (London, United Kingdom) during January 1998-December 2005. Serum creatinine level and estimated glomerular filtration rate were used to identify ARF. ARF episodes were classified as early onset if they occurred <3 months after initiation of HIV care and as late onset if they occurred > or =3 months after initiation of HIV care. RESULTS During the study period, 130 (5.7%) of 2274 patients developed 144 episodes of ARF. The incidences of early-onset and late-onset ARF were 19.3 episodes per 100 person-years (95% confidence interval [CI], 15.4-24.1 episodes per 100 person-years) and 1.1 episodes per 100 person-years (95% CI, 0.83-1.49 episodes per 100 person-years), respectively (rate ratio, 17.4; P<0.001). In multivariate analysis, nadir CD4 T cell count <100 x 10(9) cells/L (odds ratio [OR], 6.7; 95% CI, 2.5-18.3) and acquired immunodeficiency syndrome (OR, 6.7; 95% CI, 3.4-13.3) were associated with early-onset ARF, whereas injection drug use (OR, 4.8; 95% CI, 1.3-17.7), hepatitis C virus coinfection (OR, 3.4; 95% CI, 1.3-8.6), and nadir CD4 T cell count <100 x 10(9) cells/L (OR, 5.8; 95% CI, 2.5-13.4) were associated with late-onset ARF. CONCLUSIONS ARF was common and was associated with advanced immunodeficiency. The incidence of ARF decreased >10-fold in patients who had received HIV care for > or =3 months.

Sexual behaviour of people living with HIV in London: implications for HIV transmission.

Objective:To examine the sexual behaviour of gay men as well as black African heterosexual men and women living with diagnosed HIV in London, and to consider the implications for HIV transmission. Methods:People living with HIV receiving treatment and care in outpatient clinics in north east London were asked to complete a confidential, self-administered questionnaire in 2004–2005. Respondents were asked about unprotected anal or vaginal intercourse in the previous 3 months, and the type (main or casual) and HIV status of their partner(s). Results:A total of 1687 people with diagnosed HIV returned a completed questionnaire (response rate 73% of eligible clinic attenders) including 480 black African heterosexual women, 224 black African heterosexual men and 758 gay/bisexual men (464 white, 112 ethnic minority). One in five gay men with HIV (20.1%, 144/715) reported unprotected anal intercourse with a partner of unknown or discordant HIV status (usually a casual partner). This presents a risk of HIV transmission. By comparison, one in 20 (5.1%, 32/623) black African heterosexual men and women with HIV reported unprotected vaginal intercourse that presented a risk of HIV transmission; odds ratio (gay men versus black African men and women combined) 5.28, 95% confidence interval 3.52, 7.91, P < 0.001. Neither viral load nor being on HAART were significantly associated with unprotected intercourse among gay men or black African heterosexual men and women (P > 0.05). Conclusion:Behavioural research among people with diagnosed HIV in London shows that gay men are more likely than black African heterosexual men and women to engage in sexual behaviour that presents a risk of HIV transmission.

Sub-optimal CD4 reconstitution despite viral suppression in an urban cohort on Antiretroviral Therapy (ART) in sub-Saharan Africa: Frequency and clinical significance

BackgroundA proportion of individuals who start antiretroviral therapy (ART) fail to achieve adequate CD4 cell reconstitution despite sustained viral suppression. We determined the frequency and clinical significance of suboptimal CD4 reconstitution despite viral suppression (SO-CD4) in an urban HIV research cohort in Kampala, UgandaMethodsWe analyzed data from a prospective research cohort of 559 patients initiating ART between 04/04–04/05. We described the patterns of SO-CD4 both in terms of:- I) magnitude of CD4 cell increase (a CD4 count increase < 50 CD4 cells/μl at 6 months, <100 cells/μl at 12 months; and <200 cells/μl at 24 months of ART) and II) failure to achieve a CD4 cell count above 200 cells/μl at 6,12 and 24 months of ART. Using criteria I) we used logistic regression to determine the predictors of SO-CD4. We compared the cumulative risk of clinical events (death and/or recurrent or new AIDS-defining illnesses) among patients with and without SO-CD4.ResultsOf 559 patients initiating ART, 386 (69%) were female. Median (IQR) age and baseline CD4 counts were 38 yrs (33–44) and 98 cells/μl (21–163) respectively; 414 (74%) started a d4T-based regimen (D4T+3TC+NVP) and 145 (26%) a ZDV-based regimen (ZDV+3TC+EFV). After 6, 12 and 24 months of ART, 380 (68%), 339 (61%) and 309 (55%) had attained and sustained HIV-RNA viral suppression. Of these, 78 (21%), 151 (45%) and 166 (54%) respectively had SO-CD4 based on criteria I), and 165(43%), 143(42%) and 58(19%) respectively based on criteria II). With both criteria combined, 56 (15%) and 129 (38%) had SO-CD4 at 6 and 12 months respectively. A high proportion (82% and 58%) of those that had SO-CD4 at 6 months (using criteria I) maintained SO-CD4 at 12 and 24 months respectively. There were no statistically significant differences in the incidence of clinical events among patients with [19/100PYO (12–29)] and without SO-CD4 [23/100PYO (19–28)].ConclusionUsing criteria I), the frequency of SO-CD4 was 21% at 6 months. Majority of patients with SO-CD4 at 6 months maintained SO-CD4 up to 2 years. We recommend studies of CD4 T-cell functional recovery among patients with SO-CD4.

Comparison of CKD-EPI and MDRD to estimate baseline renal function in HIV-positive patients

BACKGROUND Renal dysfunction is common in HIV-positive patients, and guidelines suggest regular monitoring of renal function with estimated glomerular filtration rate (eGFR) and urinalysis. It is unknown whether Chronic Kidney Disease Epidemiological Collaboration (CKD-EPI) or Modification of Diet in Renal Disease (MDRD) provide better estimates of glomerular filtration rate (GFR) in this population. METHODS We compared the CKD-EPI and MDRD equations to estimate GFR at baseline in 20,132 HIV-positive individuals in the UK CHIC cohort. Kappa statistics and Bland-Altman plots were used to assess agreement between the two estimates and Kaplan-Meier plots and Cox regression analysis to describe mortality patterns. RESULTS At baseline, median eGFR was 100 (87, 112) (CKD-EPI) and 94 (83, 108) (MDRD) (mL/min/1.73 m(2)). Good overall agreement between CKD-EPI- and MDRD-defined eGFR bands was observed (Kappa = 0.71, 95% confidence interval: 0.70-0.72). Of the 367 patients with eGFR MDRD 30-59, 57 (15.5%) were categorized as eGFR 60-89 by CKD-EPI. After adjustment for covariates, eGFR <60 (CKD-EPI), eGFR <30 (MDRD) and eGFR ≥105 (both formulae) were significantly associated with an increased risk of death. Mortality in patients classified as having eGFR 60-89 by CKD-EPI and eGFR 30-59 by MDRD more closely resembled mortality of patients who had eGFR 60-89 by both formulae. CONCLUSIONS MDRD and CKD-EPI equations showed a high degree of agreement in stratifying patients by baseline eGFR. CKD-EPI estimates of GFR <60 at baseline are more strongly associated with mortality than MDRD estimates of GFR <60, supporting the concept that MDRD may have overestimated the severity of renal impairment in these patients. Our findings support the use of CKD-EPI in HIV-positive individuals.

Tumour necrosis factor inhibitors versus combination intensive therapy with conventional disease modifying anti-rheumatic drugs in established rheumatoid arthritis: TACIT non-inferiority randomised controlled trial

Objective To determine whether intensive combinations of synthetic disease modifying drugs can achieve similar clinical benefits at lower costs to high cost biologics such as tumour necrosis factor inhibitors in patients with active rheumatoid arthritis resistant to initial methotrexate and other synthetic disease modifying drugs. Design Open label pragmatic randomised multicentre two arm non-inferiority trial over 12 months. Setting 24 rheumatology clinics in England. Participants Patients with rheumatoid arthritis who were eligible for treatment with tumour necrosis factor inhibitors according to current English guidance were randomised to either the tumour necrosis factor inhibitor strategy or the combined disease modifying drug strategy. Interventions Biologic strategy: start tumour necrosis factor inhibitor; second biologic in six month for non-responders. Alternative strategy: start combination of disease modifying drugs; start tumour necrosis factor inhibitors after six months in non-responders. Main outcome measure Primary outcome: reduction in disability at 12 months measured with patient recorded heath assessment questionnaire (range 0.00-3.00) with a 0.22 non-inferiority margin for combination treatment versus the biologic strategy. Secondary outcomes: quality of life, joint damage, disease activity, adverse events, and costs. Intention to treat analysis used multiple imputation methods for missing data. Results 432 patients were screened: 107 were randomised to tumour necrosis factor inhibitors and 101 started taking; 107 were randomised to the combined drug strategy and 104 started taking the drugs. Initial assessments were similar; 16 patients were lost to follow-up (seven with the tumour necrosis factor inhibitor strategy, nine with the combined drug strategy); 42 discontinued the intervention but were followed-up (19 and 23, respectively). The primary outcome showed mean falls in scores on the health assessment questionnaire of −0.30 with the tumour necrosis factor inhibitor strategy and −0.45 with the alternative combined drug strategy. The difference between groups in unadjusted linear regression analysis favoured the alternative strategy of combined drugs. The mean difference was −0.14, and the 95% confidence interval (−0.29 to 0.01) was below the prespecified non-inferiority boundary of 0.22. Improvements at 12 months in secondary outcomes, including quality of life and erosive progression, were similar with both strategies. Initial reductions in disease activity were greater with the biologic strategy, but these differences did not persist beyond six months. Remission was seen in 72 patients (44 with biologic strategy; 36 with alternative strategy); 28 patients had serious adverse events (18 and 10, respectively); six and 10 patients, respectively, stopped treatment because of toxicity. The alternative strategy reduced health and social care costs per patient by £3615 (€4930,