Laurent Sailler

Hydroxychloroquine in systemic lupus erythematosus: results of a French multicentre controlled trial (PLUS Study).

Introduction Hydroxychloroquine (HCQ) is an important medication for treating systemic lupus erythematosus (SLE). Its blood concentration ([HCQ]) varies widely between patients and is a marker and predictor of SLE flares. This prospective randomised, double-blind, placebo-controlled, multicentre study sought to compare standard and adjusted HCQ dosing schedules that target [HCQ] ≥1000 ng/ml to reduce SLE flares. Patients and methods [HCQ] was measured in 573 patients with SLE (stable disease and SELENA-SLEDAI≤12) treated with HCQ for at least 6 months. Patients with [HCQ] from 100 to 750 ng/ml were randomised to one of two treatment groups: no daily dose change (group 1) or increased HCQ dose to achieve the target [HCQ] (group 2). The primary end point was the number of patients with flares during 7 months of follow-up. Results Overall, mean [HCQ] was 918±451 ng/ml. Active SLE was less prevalent in patients with higher [HCQ]. A total of 171 patients were randomised and followed for 7 months. SLE flare rates were similar in the two groups (25% in group 1 vs 27.6% in group 2; p=0.7), but a significant spontaneous increase in [HCQ] in both groups between inclusion and randomisation strongly suggested improved treatment adherence. Patients at the therapeutic target throughout follow-up tended to have fewer flares than those with low [HCQ] (20.5% vs 35.1%, p=0.12). Conclusions Although low [HCQ] is associated with higher SLE activity, adapting the HCQ dose did not reduce SLE flares over a 7-month follow-up. ClinicalTrials.gov NCT00413361

Epidemiology of incident immune thrombocytopenia: a nationwide population-based study in France.

The epidemiology of immune thrombocytopenia (ITP) is not well known. The purpose of this study was to assess ITP incidence at a nationwide level (France) with recent data (mid-2009 to mid-2011; 129 248 543 person-years). The data source is the French health insurance database. We selected cases with diagnosis codes for in-hospital stays and long-term disease attributions, thus restricting our search to ITPs necessitating health care. We studied incidence by age, gender, calendar month, regions, and proportion of secondary ITPs, of ITPs becoming persistent or chronic, and of severe bleeding at disease onset. We identified 3771 incident ITP patients. Incidence was 2.9/100,000 person-years, with peaks among children and in those >60 years of age. ITP was more frequent among males in these subgroups. The incidence was lower in overseas Caribbean French departments, suggesting a lower incidence among Afro-American people. There was a north-south gradient in mainland France and seasonal variations (peak in winter and nadir in summer). Persistence or chronicity occurred in 36% of children compared with 67% of adults. Among adults, 18% of ITPs were secondary. Malignancy was the main cause (10.9%). Myelodysplastic syndromes were not rare (2.3%). Severe gastrointestinal or central nervous system bleeding at ITP onset was rare (<1%).

Cancer Risk of Anti-TNF-α at Recommended Doses in Adult Rheumatoid Arthritis: A Meta-Analysis with Intention to Treat and per Protocol Analyses

Background The risk of malignancies on TNF-α antagonists is controversial. The aim of this survey was to assess cancer risk on TNF-α antagonists in adult rheumatoid arthritis patients, including the five marketed drugs (infliximab, etanercept, adalimumab, golimumab and certolizumab) used in line with the New Drug Application. Furthermore, the relative interest of modified intention to treat or per protocol analyses to assess such sparse events remains unknown. Methodology/Principal Findings Data sources were MEDLINE, CENTRAL, ISI Web of Science, ACR and EULAR meeting abstracts, scientific evaluation of the drugs leading to their marketing approval, and clinicaltrials.gov, until 31 December 2012.We selected double-blind randomized controlled trials in adult rheumatoid arthritis patients, including at least one treatment arm in line with New Drug Application. We performed random effect meta-analysis, with modified intention to treat and per protocol analyses. Thirty-three trials were included. There was no excess risk of malignancies on anti-TNF-α administered in line with New Drug Application in the per protocol model (OR, 0.93 95%CI[0.59–1.44]), as well as in the modified intention to treat model (OR, 1.27 95%CI[0.82–1.98]). There was a non-significant tendency for an excess non-melanoma skin cancer risk in both models (respectively, 1.37 [0.71–2.66] and 1.90 [0.98–3.67]). With fixed effect Peto model restricting to trials during at least 52 weeks, the overall cancer risk was respectively 1.60 [0.97–2.64] and 1.22 [0.72–2.08]. Whatever the model, modified intention to treat analysis led to higher estimations than per protocol analysis. The later may underestimate the treatment effect when assessing very sparse events and when many patients dropped out in placebo arms. In metaregression, there was no differential risk among the five drugs. Conclusions/Significance This study did not find any evidence for an excess cancer risk on TNF-α antagonists in adult rheumatoid arthritis patients, but an excess cancer risk after several years of exposure cannot be ruled out. Both modified intention to treat and per protocol analyses should be presented in such safety analyses.

Increased exposure to statins in patients developing chronic muscle diseases: a 2-year retrospective study

Objective: Case reports have suggested that lipid-lowering drugs (LLDs), especially statins, could induce or reveal chronic muscle diseases. We conducted a study to evaluate the association between chronic muscle diseases and prior exposure to LLDs. Method: This was a retrospective study of chronic primary muscle disease cases newly diagnosed at the Toulouse University Hospitals between January 2003 and December 2004 among patients living in the Midi-Pyrénées area, France. All patients remained symptomatic for more than 1 year after drug withdrawal, or required drugs for inflammatory myopathy. Data on the patient’s exposure to LLDs and to other drugs were compared with that of matched controls (5/1) selected through the Midi-Pyrénées Health Insurance System database. Results: A total of 37 patients were included in the study. Of those, 21 (56.8%) suffered from dermatomyositis (DM) or polymyositis (PM), 12 (32.4%) from genetic myopathy, and 4 (10.8%) from an unclassified disease. The prevalence of exposure to statins was 40.5% in patients and 20% in controls (odds ratio (OR) 2.73, 95% confidence interval (CI) 1.21–6.14; p<0.01). There was a significant positive interaction between statins and proton pump inhibitors exposure (weighted OR 3.3, 95% CI 1.37–7.54; p = 0.02). Statin exposure rate was 47.6% among patients with DM/PM (OR 3.86, 95% CI 1.30–11.57; p<0.01). There was no difference between patients and controls for exposure to fibrates. Conclusion: Patients who developed chronic muscle diseases after the age of 50, including DM/PM, had a higher than expected frequency of prior exposure to statins. Further studies are needed to confirm this association and the role of proton pump inhibitors.

Pulmonary involvement in Sweet's syndrome: a case report and review of the literature.

Pulmonary involvement in Sweets syndrome (SS) is rare. We report a case of SS with severe respiratory involvement responding to corticosteroid therapy. A 82‐year‐old man presented fever of 39 °C associated with cough and dyspnea, and crackles in the left lung. The infection work‐up was negative. Chest X‐ray showed cardiomegaly and left lower lobe pulmonary infiltrates. Pulmonary signs did not improve on treatment with antibiotics, and after 1 week maculopapular lesions appeared, localized on the knees, the periombilical area and the back. The antibiotics were changed without improvement. A skin biopsy revealed infiltration by neutrophilic granulocytes and marked edema in the dermis, consistent with SS. The patients condition progressively worsened, requiring high oxygenotherapy, and he was transferred to an intensive care unit. Chest X‐ray revealed an important alveolar and interstitial syndrome. Bronchoalveolar lavage found 170 leukocytes with 30% neutrophils (N < 5%), 7% lymphocytes and 63% macrophages. A search for bacteria, viruses or parasites in bronchoalveolar lavage was negative. The patient was treated with antibiotics, a high dose of furosemide and steroids for 4 days. Because the patient improved dramatically within 5 days, with a negative infection work‐up and a dramatic decrease of C‐reactive protein, the antibiotics were stopped. Steroids were secondarily tapered very slowly. A chest computed tomography (CT) scan showed a substantial improvement of pulmonary lesions. We also review the 22 cases of pulmonary involvement of SS reported in the literature.

Abdominal Infectious Aortitis Caused by Streptococcus pneumoniae: A Case Report and Literature Review

We report a case of a 75-year-old man who had been complaining of fever and pelvic pain for 3 weeks. First angio-computed tomography (CT) characteristics and blood culture led to suspicion of a pneumococcal-infected aortic aneurysm, which however was not confirmed by the surgeon. The abdominal infectious aortitis caused by Streptococcus pneumoniae was affirmed by a second angio-CT performed 7 days later. Without further delay, the patient underwent surgery for resection of mycotic aneurysm and in situ reconstruction with aortobiiliac homograft, in association with antibiotics. He died 10 days after the surgery as a result of severe sepsis in a polyvalent intensive care unit. This case report highlights the severity of this pathology. We reviewed the relevant literature related to Streptococcal pneumoniae mycotic aneurysm located in the abdominal aorta, including 29 more cases. Various microorganisms have already been associated with mycotic aneurysms, including S pneumoniae. Infectious aortitis remains a rare disease. It is extremely important to establish an early diagnosis but it may be delayed because clinical manifestations are usually nonspecific. However, if left untreated it is always lethal. Antibiotic in combination with complete surgical excision of the infected aorta is the treatment of reference. This therapeutic association dramatically improved patient survival.

Lower vitamin D levels are associated with higher systemic lupus erythematosus activity, but not predictive of disease flare-up

Objectives Growing evidence suggests that vitamin D plays a key role in the pathogenesis and progression of autoimmune diseases, including systemic lupus erythematosus (SLE). Recent studies have found an association between lower serum 25-hydroxyvitamin D (25(OH)D) levels and higher SLE activity. We studied the relationship between 25(OH)D levels and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, and we assessed for the first time the role of vitamin D in predicting SLE flare-ups. Methods Serum 25(OH)D levels were measured in 170 patients with SLE who were prospectively followed up for 6 months (Plaquenil LUpus Systemic study, ClinicalTrials.gov number NCT00413361). Results The mean SLEDAI score was 2.03±2.43 and 12.3% patients had active disease (SLEDAI ≥6). The mean 25(OH)D level was 20.6±9.8 ng/mL. Deficiency (25(OH)D <10 ng/mL) was observed in 27 (15.9%), insufficiency (10≤25(OH)D<30) in 112 (65.9%) and optimal vitamin D status (25(OH)D≥30) in 31 (18.2%) patients. In multivariate analysis, female gender (p=0.018), absence of defined antiphospholipid syndrome (p=0.002) and higher creatinine clearance (p=0.004) were predictive of lower 25(OH)D levels. In multivariate analysis, lower 25(OH)D levels were associated with high SLE activity (p=0.02). Relapse-free survival rate was not statistically different according to the vitamin D status during the 6-month follow-up (p=0.22). Conclusions We found a low vitamin D status in the majority of patients with SLE, and a modest association between lower 25(OH)D levels and high disease activity. There was no association between baseline 25(OH)D levels and relapse-free survival rate.

Rituximab versus splenectomy in persistent or chronic adult primary immune thrombocytopenia: an adjusted comparison of mortality and morbidity

Splenectomy and rituximab are both recommended as second‐line treatment in immune thrombocytopenia (ITP), but they have never been directly compared. We compared their efficacy and serious adverse outcomes in a retrospective cohort of 105 adult primary ITP patients exposed to one or other of these treatments. Primary outcome was composite: death from hemorrhage or from infection and hospitalization for bleeding or for infection. Secondary outcomes were overall mortality, hospitalization for bleeding, hospitalization for infection, as well as response and complete response (international definitions). Analyses were adjusted on a propensity score. Patients treated with rituximab (n = 43) were older and had more comorbidities than the splenectomized patients (n = 62). Mean follow‐up was, respectively, 3 and 8.4 years. After adjustment on the propensity score, there was no difference between the two groups regarding the primary and other clinical outcomes. In the multivariate analysis, only a history of mucosal bleeding (HR 3.2 95% CI [1.2–8.5]) and a Charlson score ≥1 (HR 4.2 95% CI [1.8–9.6]) were associated with the primary outcome. These two factors were also associated with hospitalization for bleeding. As expected, response, complete response and maintenance rates were higher in the splenectomy group. Splenectomy compared with rituximab was independently associated with a response at 12 months (OR 4.4, 95% CI [1.7–11.8]). Then, adjusted analyses in this real‐life cohort confirmed the better results of splenectomy compared with rituximab. Am. J. Hematol. 89:41–46, 2014.

Determinants of Hydroxychloroquine Blood Concentration Variations in Systemic Lupus Erythematosus

Blood concentrations of hydroxychloroquine (HCQ) vary widely among patients with systemic lupus erythematosus (SLE). A pharmacokinetic/pharmacodynamic relationship has been found in different situations, and a very low blood concentration of HCQ is a simple marker of nonadherence to treatment. Therefore, interest in blood HCQ concentration measurement has increased, but little is known about factors that influence blood HCQ concentration variability. This study was undertaken to analyze determinants of blood HCQ concentrations.

Statin-Induced Lupus: a Case/non-Case Study in a Nationwide Pharmacovigilance Database

Statin use has been advocated to prevent atheromatous complications in lupus patients and may be widely prescribed for these patients in future. Statin-induced lupus has also been described, though the risk is not confirmed. The goal of this study was to detect a safety signal regarding statin-induced lupus. We conducted a case/non-case study in the French PharmacoVigilance Database from January 2000 until December 2010. Cases were drug-induced lupus reports. Non-cases were all reports of other adverse drug reactions (ADRs). Exposure to statins at the time of ADR was screened in each report. Among 235,147 ADR reports, 232 were drug-induced lupus. Exposure to statins was present in 17 (7.3%) cases and in 10,601 (4.7%) non-cases. Reporting odds ratio (ROR) for statin exposure associated with lupus erythematosus was 1.67 (95% confidence interval 1.02–2.74). The ROR was > 1 for each statin but fluvastatin. This pharmacoepidemiological study suggests a link between statin exposure and lupus induction. The benefit-to-risk ratio of statin therapy in lupus patients should be evaluated through randomized controlled trials.