Clinical impact and prognosis of cryoglobulinemia and cryofibrinogenemia in systemic sclerosis.

INTRODUCTION: An association of systemic sclerosis (SSc) with cryoglobulin and/or cryofibrinogenemia has been described. However, clinical, biological, morphological and prognostic implications are unknown. The objective of this study was to describe the phenotype and evaluate the prognosis of cryoglobulinemia and/or cryofibrinogenemia in the progression of SSc. MATERIALS AND METHODS: Patients were included from the Systemic Scleroderma Toulouse Cohort (SSTC), between June 1, 2005 and May 31, 2018, and underwent a measurement of a cryoglobulin and/or cryofibrinogen in immunology laboratory at the Toulouse University Hospital Center. Patients with and without cryoglobulinemia >50 mg/l and patients with and without cryofibrinogenemia were compared to identified the impact of cryoprcipitate on the phenotype. Mortality based on cryoprecipitate was explored. RESULTS: 166 patients were included in the study. 43.3% and 46.6% had a cryoglobulinemia >50 mg/l and cryofibrinogenemia, respectively. Cryoglobulin >50 mg was not associated with microvascular damage. Cryoglobulin does not influence the phenotype. 5-and 10-years survival were 97.6% and 88.8% respectively in patients with cryoglobulinemia >50 mg/l versus 91.9% and 78.4% in patients without cryoglobulin>50 mg/l. 10-years survival was better for patients with cryoglobulinemia >50 mg/l (log-rank 0.0363). Cryofibrinogenemia was not associated with neoplasia, any clinical (in particular ischemic damage), biological or morphological features. Cryofibrinogenemia had no influence on the mortality of these patients. CONCLUSION: Cryoglobulinemia and cryofibrinogenemia are frequent in SSc. The presence of cryoprecipitate (cryoglobulin or cryofibrinogen) not influence the phenotype and has not associated with a poor survival.

Sine scleroderma, limited cutaneous, and diffused cutaneous systemic sclerosis survival and predictors of mortality.

BACKGROUND: Systemic sclerosis (SSc) is associated with a variability of mortality rates in the literature. OBJECTIVE: To determine the mortality and its predictors in a long-term follow-up of a bi-centric cohort of SSc patients. METHODS: A retrospective observational study by systematically analyzing the medical records of patients diagnosed with SSc in Toulouse University Hospital and Ducuing Hospital. Standardized Mortality Ratio (SMR), mortality at 1, 3, 5, 10, and 15 years of disease and causes of death were described. Predictors of mortality using Cox regression were assessed. RESULTS: Three hundred seventy-five patients were included: 63 with diffuse cutaneous SSc, 279 with limited cutaneous SSc, and 33 with sine scleroderma. The SMR ratio was 1.88 (95% CI 1.46-1.97). The overall survival rates were 97.6% at 1 year, 93.4% at 3 years, 87.1% at 5 years, 77.9% at 10 years, and 61.3% at 15 years. Sixty-nine deaths were recorded. 46.4% were SSc related deaths secondary to interstitial lung disease (ILD) (34.4%), pulmonary hypertension (31.2%), and digestive tract involvement (18.8%). 53.6% were non-related to SSc: cardiovascular disorders (37.8%) and various infections (35.1%) largely distanced those from cancer (13.5%). Four significant independent predictive factors were identified: carbon monoxide diffusing capacity (DLCO) < 70% (HR=3.01; p=0.0053), C-reactive protein (CRP) >5 mg/l (HR=2.13; p=0.0174), cardiac involvement (HR=2.86; p=0.0012), and the fact of being male (HR=3.25; p=0.0004). CONCLUSION: Long-term data confirmed high mortality of SSc. Male sex, DLCO <70%, cardiac involvement, and CRP> 5mg/l were identified as independent predictors of mortality.

Presentation and Real-World Management of Giant Cell Arteritis (Artemis Study).

Background: Few studies of daily practice for patients with giant cell arteritis (GCA) are available. This French study aimed to describe the characteristics and management of GCA in a real-life setting. Methods: Cross-sectional, non-interventional, multicenter study of patients ≥50 years old who consulted hospital-based specialists for GCA and were under treatment. Patient characteristics and journey, diagnostic methods and treatments were collected. Descriptive analyses were performed. Results: In total, 306 patients (67% females, mean age 74 ± 8 years old) were recruited by 69 physicians (internists: 85%, rheumatologists: 15%); 13% of patients had newly diagnosed GCA (diagnosis-to-visit interval <6 weeks). Overall median disease duration was 13 months (interquartile range 5-26). Most patients were referred by general practitioners (56%), then ophthalmologists (10%) and neurologists (7%). Most common comorbidities were hypertension (46%), psychiatric disorders (10%), dyslipidemia (12%), diabetes (9%), and osteoporosis (6%). Initial GCA presentations included cranial symptoms (89%), constitutional symptoms (74%), polymyalgia rheumatica (48%), and/or other extra-cranial manifestations (35%). Overall, 85, 31, 26, and 30% of patients underwent temporal artery biopsy, high-resolution temporal artery Doppler ultrasonography, 18FDG-PET, and aortic angio-CT, respectively. All patients received glucocorticoids, which were ongoing for 89%; 29% also received adjunct medication(s) (methotrexate: 19%, tocilizumab: 15%). A total of 40% had relapse(s); the median time to the first relapse was 10 months. Also, 37% had comorbidity(ies) related to or aggravated by glucocorticoids therapy. Conclusion: This large observational study provides insight into current medical practices for GCA. More than one third of patients had comorbidities related to glucocorticoid therapy for a median disease duration of 13 months. Methotrexate and tocilizumab were the most common adjunct medications.

USAID Associated with Myeloid Neoplasm and VEXAS Syndrome: Two Differential Diagnoses of Suspected Adult Onset Still's Disease in Elderly Patients.

BACKGROUND: Patients with solid cancers and hematopoietic malignancy can experience systemic symptoms compatible with adult-onset Still's disease (AOSD). The newly described VEXAS, associated with somatic UBA1 mutations, exhibits an overlap of clinical and/or biological pictures with auto inflammatory signs and myelodysplastic syndrome (MDS). OBJECTIVES: To describe a cohort of patients with signs of undifferentiated systemic autoinflammatory disorder (USAID) concordant with AOSD and MDS/chronic myelomonocytic leukemia (CMML) and the prevalence of VEXAS proposed management and outcome. METHODS: A French multicenter retrospective study from the MINHEMON study group also used for other published works with the support of multidisciplinary and complementary networks of physicians and a control group of 104 MDS/CMML. RESULTS: Twenty-six patients were included with a median age at first signs of USAID of 70.5 years with male predominance (4:1). Five patients met the criteria for confirmed AOSD. The most frequent subtypes were MDS with a blast excess (31%) and MDS with multilineage dysplasia (18%). Seven patients presented with acute myeloid leukemia and twelve died during a median follow-up of 2.5 years. Six out of 18 tested patients displayed a somatic UBA1 mutation concordant with VEXAS, including one woman. High-dose corticosteroids led to a response in 13/16 cases and targeted biological therapy alone or in association in 10/12 patients (anakinra, tocilizumab, and infliximab). Azacytidine resulted in complete or partial response in systemic symptoms for 10/12 (83%) patients including 3 VEXAS. CONCLUSIONS: Systemic form of VEXAS syndrome can mimic AOSD. The suspicion of USAID or AOSD in older males with atypia should prompt an evaluation of underlying MDS and assessment of somatic UBA1 mutation.

Risk factors of hospitalisation for thrombosis in adults with primary immune thrombocytopenia, including disease-specific treatments: a French nationwide cohort study.

We aimed to assess the risk factors of venous thrombosis (VT) and arterial thrombosis (AT) in adults with primary immune thrombocytopenia (ITP), particularly in relation to treatments. The population comprised all incident primary ITP adults in France between 2009 and 2017 (FAITH cohort; NCT03429660) built in the national health database. Outcomes were the first hospitalisation for VT and AT. Multivariable Cox regression models included baseline risk factors, time-varying exposure to ITP drugs, splenectomy and to cardiovascular drugs. The cohort included 10 039 patients. A higher risk of hospitalisation for VT was observed with older age, history of VT, history of cancer, splenectomy [hazard ratio (HR) 3·23, 95% confidence interval (CI) 2·26-4·61], exposure to corticosteroids (HR 3·55, 95% CI 2·74-4·58), thrombopoietin-receptor agonists (TPO-RAs; HR 2·28, 95% CI 1·59-3·26) and intravenous immunoglobulin (IVIg; HR 2·10, 95% CI 1·43-3·06). A higher risk of hospitalisation for AT was observed with older age, male sex, a history of cardiovascular disease, splenectomy (HR 1·50, 95% CI 1·12-2·03), exposure to IVIg (HR 1·85, 95% CI 1·36-2·52) and TPO-RAs (HR 1·64, 95% CI 1·26-2·13). Rituximab was not associated with an increased risk. These findings help to estimate the risk of thrombosis in adult patients with ITP and to select treatment.

Pulmonary mucormycosis following autologous hematopoietic stem cell transplantation for rapidly progressive diffuse cutaneous systemic sclerosis: A case report.

RATIONALE: The use of autologous hematopoietic stem cell transplantation (AHSCT) for autoimmune diseases has become the first indication for transplant in nonmalignant disease. Mucormycosis is a rare invasive infection with increasing incidence in patients treated with AHSCT. We report the first case of pulmonary mucormycosis following AHSCT for systemic sclerosis (SSc). PATIENT CONCERNS: A 24-year-old woman with rapidly progressive diffuse cutaneous SSc presented with an acute respiratory distress syndrome 6 days after AHSCT. DIAGNOSES: The results of clinical and computed tomography scan were consistent with pulmonary mucormycosis and the diagnosis was confirmed by a positive Mucorales Polymerase Chain Reaction on a peripheral blood sample. INTERVENTIONS AND OUTCOMES: Early antifungal therapy by intravenous amphotericin B provided rapid improvement within 4 days and sustained recovery after 2 years of follow-up. LESSONS: With the progressively increasing use of AHSCT and other stem cell therapy for treatment of severe SSc and other autoimmune diseases, the potential onset of rare post-transplant fungal infections, such as mucormycosis, requires careful patient monitoring and better awareness of early initiation of adequate therapy.

Impact of risk factors on the occurrence of arterial thrombosis and venous thromboembolism in adults with primary immune thrombocytopenia - Results from two nationwide cohorts.

BACKGROUND: Previous studies have found that patients with Immune thrombocytopenia (ITP) have an increased risk of arterial thrombosis (AT) and venous thromboembolism (VTE). However, risk factors for thrombosis in adults with primary ITP remain unassessed in large cohorts. Aim To assess the occurrence and impact of risk factors for AT and VTE in patients with primary ITP in France and Sweden. METHODS: Both countries have national health databases, including hospital diagnoses and drug dispensing data. Adults with incident primary ITP identified using algorithms between the years 2009-2015 in France, and 2009-2016 in Sweden were included. Cumulative incidence rates (IR) of AT and VTE were calculated by risk factors and multivariable Cox models were used to estimate associations. RESULTS: The study included 7225 patients from France and 2490 from Sweden. The IR of AT were 15.0 (95% CI: 13.4-16.7) and 14.7 (95% CI: 12.4-17.5) per 1000 person-years, respectively. The incidences of VTE were 6.9 (95% CI: 5.9-8.1) and 6.5 (95% CI: 5.1-8.4), respectively. Increasing age, male sex and a previous AT were associated with AT in both countries and so were exposure to antiplatelet drugs in France and a history of VTE and chronic kidney disease in Sweden. Increasing age and a history of VTE were associated with VTE in both countries, in France also cancer. CONCLUSION: The IR of AT and VTE were similar in France. Age and male sex remained the most important risk factors for AT, age for VTE.

Efficacy and safety of biologics in relapsing polychondritis: a French national multicentre study.

OBJECTIVES: To assess the efficacy and the safety of biologics in a cohort of patients with relapsing polychondritis (RP). METHODS: We conducted a French multicentre retrospective cohort study including patients treated with biologics for RP. Efficacy outcomes were clinical response (partial or complete) and complete response during the first 6 months of exposure, plus daily corticosteroid dose at 6 months. Other outcomes were adverse drug reactions (ADRs), persistence of biologics and factors associated with a response. RESULTS: This study included 41 patients exposed to 105 biologics (tumour-necrosis factor (TNF) inhibitors, n=60; tocilizumab, n=17; anakinra, n=15; rituximab, n=7; abatacept, n=6). Overall response rate during the first 6 months of exposure was 62.9%. Complete response rate was 19.0%. Reduced corticosteroid doses were highly variable among patients. ADRs were mostly infections (n=42). Reasons for biologic withdrawal (73.3%) were insufficient efficacy (34.3%; ranging from 23.5% for tocilizumab to 72.7% for etanercept), loss of efficacy (18.1%) and ADRs (20.9%; mostly for anakinra: 46.7%). Persistence was comparable among biologic classes. Among TNF inhibitors, the highest persistence was observed with adalimumab. Differences in clinical response rates were observed depending on biologics and organ involvement. There were trends towards a lower response rate in cases with associated myelodysplastic syndrome and for a higher response rate for nasal/auricular chondritis, sternal chondritis and concomitant exposure to non-biologic disease-modifying antirheumatic drugs. CONCLUSIONS: This study describes the efficacy of biologics for refractory RP. However, the number of complete responses was low and there were concerns about the risk of ADRs, particularly infections.

Validation of an algorithm identifying incident primary immune thrombocytopenia in the French national health insurance database.

OBJECTIVES: To evaluate the accuracy of an algorithm identifying newly diagnosed immune thrombocytopenia (ITP) patients in the French national health insurance database (SNIIRAM). METHODS: The source of data was the SNIIRAM of Midi-Pyrenees region (southwest of France, three million inhabitants). Data of patients with at least one ITP code (D69.3 code of the International Classification of Disease, version 10) were extracted between January 1, 2012, and December 31, 2014. We used an algorithm that identifies newly diagnosed primary ITPs. Medical charts of incident ITPs were reviewed. Positive predictive values (PPVs) of identification of true, incident, and primary ITP cases were estimated. RESULTS: Of the 168 patients selected, 161 were true ITP cases yielding a PPV of 95.8% (95% confidence interval-95% CI: 92.8-98.8). Among them, 128 were truly incident according to symptom onset date and 134 according to the diagnosis date yielding PPVs of 79.5% (95% CI: 73.2-85.7) and 83.2% (95% CI: 77.4-89.0), respectively. Median time between estimated diagnosis date by the algorithm and true diagnosis date was 0 days (interquartile range: 0 to 15). CONCLUSIONS: This study showed a very good PPV of this algorithm identifying incident primary ITP patients in the SNIIRAM.

Adding Azathioprine to Remission-Induction Glucocorticoids for Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss), Microscopic Polyangiitis, or Polyarteritis Nodosa Without Poor Prognosis Factors: A Randomized, Controlled Trial.

OBJECTIVE: In most patients with nonsevere systemic necrotizing vasculitides (SNVs), remission is achieved with glucocorticoids alone, but one-third experience a relapse within 2 years. This study was undertaken to determine whether the addition of azathioprine (AZA) to glucocorticoids could achieve a higher sustained remission rate of newly diagnosed nonsevere eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA), microscopic polyangiitis (MPA), or polyarteritis nodosa (PAN). METHODS: All patients included in this double-blind trial received glucocorticoids, gradually tapered over 12 months, and were randomized to receive AZA or placebo for 12 months, with stratification according to SNV (EGPA or MPA/PAN). The primary end point was the combined rate of remission induction failures and minor or major relapses at month 24. RESULTS: Ninety-five patients (51 with EGPA, 25 with MPA, and 19 with PAN) met the inclusion criteria, were randomized, and received at least 1 dose of AZA (n = 46) or placebo (n = 49). At month 24, 47.8% of the patients receiving AZA versus 49% of the patients receiving placebo had remission induction failures or relapses (P = 0.86). Secondary end points were comparable between the AZA and placebo arms. These included initial remission rate (95.7% versus 87.8%), total relapse rate (44.2% versus 40.5%), and glucocorticoid use. Two patients in the placebo arm died; 22 patients in the AZA arm (47.8%) and 23 patients in the placebo arm (46.9%) experienced ≥1 severe adverse event. For EGPA patients, the primary end point (48% in the AZA arm versus 46.2% in the placebo arm) and the percent of patients who experienced asthma/rhinosinusitis exacerbations (24% in the AZA arm versus 19.2% in the placebo arm) were comparable between treatment arms. CONCLUSION: Addition of AZA to glucocorticoids for the induction of remission of nonsevere SNVs does not improve remission rates, lower relapse risk, spare steroids, or diminish the EGPA asthma/rhinosinusitis exacerbation rate.

Cryofibrinogenemia: a marker of severity of cryoglobulinemic vasculitis.

BACKGROUND: Cryofibrinogenemia is frequently associated with cryoglobulinemia. The aim of this study was to determine the characteristics associated with the presence of cryofibrinogenemia in patients with cryoglobulinemic vasculitis. METHODS: This was a single-center retrospective study that included patients with cryoglobulinemic vasculitis who were tested for cryofibrinogen at a tertiary referral center between January 1, 2011 and December 31, 2012. Twenty-nine patients fulfilled the CryoVas (cryoglobulinemic vasculitis) Survey criteria for cryoglobulinemic vasculitis. Eighteen patients had a detectable cryofibrinogen (CF-positive) and 11 had no detectable cryofibrinogen (CF-negative). Median cryoglobulin levels were 89 ± 129 mg/L in the CF-positive group and 68 ± 82 mg/L in the CF-negative group (P = .32). Median cryofibrinogen level was 70 ± 174 mg/L. Clinical manifestations were similar in both groups. Cancers and hematological disorders were more frequent among CF-positive patients (39% vs 0%, P = .026). Levels of alpha-1 and alpha-2 globulinemia were higher in the CF-positive group. Cryofibrinogenemia ≥ 100 mg/L was associated with cryoglobulinemic vasculitis (odds ratio [OR] 2.86; 95% confidence interval [CI], 1.06-7.73) in cryoglobulinemic patients. Presence of cryofibrinogenemia was associated with use of corticosteroids, immunosuppressants, or plasmapheresis in cryoglobulinemic vasculitis patients (OR 22.7; 95% CI, 2.02-256.44). CONCLUSIONS: Our results strongly suggest that presence of cryofibrinogenemia is associated with a more severe phenotype among patients with cryoglobulinemic vasculitis.

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%).

Are adverse drug reaction patterns different between romiplostim and eltrombopag? 2009-2013 French PharmacoVigilance assessment.

BACKGROUND: Romiplostim and eltrombopag, the two marketed thrombopoietin receptor agonists (TPO-RAs), have distinct binding sites and might have distinct pharmacodynamic mechanisms. The aim of this study was to compare their adverse drug reaction (ADR) patterns. METHODS: We selected in the French PharmacoVigilance Database all ADRs associated with TPO-RAs from TPO-RA marketing until the 31st of December 2013. Medical charts were reviewed. We conducted disproportionality analyses comparing romiplostim exposure in the reports of a given ADR pattern (thrombosis, neurological, cutaneous, gastrointestinal or hematological) to romiplostim exposure in all other TPO-RA-related ADR reports. Reporting Odds Ratios (RORs) were adjusted for age and gender. We also compared the number of reports of a given ADR pattern per million daily defined doses (DDDs) dispensed in France during the study period. RESULTS: We described 45 reports (53 ADRs) with romiplostim and 26 reports (37 ADRs) with eltrombopag. There were 19 venous thromboses. At least one other risk factor was present in 83.3% of the cases. Ten (55.6%) patients had been splenectomized previously. There were eight arterial thromboses. Another risk factor was noticed in all cases. There was no signal for an excess risk of thrombosis with romiplostim versus eltrombopag (ROR: 1.45, 95% CI [0.48-4.45]). There was a signal for a higher risk of gastrointestinal ADRs with eltrombopag (ROR: 30.28, 95% CI [3.23-383.86]) and of hematological ADRs with romiplostim (ROR: 14.36, 95% CI [1.73-119.08]). Dispensing data-adjusted comparisons led to similar results. CONCLUSIONS: This study suggests different ADR patterns between romiplostim and eltrombopag.

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.

Biologics in relapsing polychondritis: a case series.

OBJECTIVES: To describe the effects of biologics in an unbiased series of relapsing polychondritis cases. METHODS: We extracted all the cases encoded 'polychondritis' from the computerized medical files of our department. The relapsing polychondritis diagnosis was confirmed using Damiani's criteria. Patients treated with biologics were evaluated for efficacy and adverse drugs reactions until October 2012. RESULTS: Nine patients were exposed to 22 biologics as corticosteroid-sparing drugs. Biologics were used at the same doses as in rheumatoid arthritis. Mean duration of exposure to biologics was 28 months. A TNF-antagonist was most frequently used as first-line biologic therapy (7/9), leading to partial or complete efficacy in six cases (85.7%). Loss of efficacy occurred in 5 cases. Abatacept (n=3) and tocilizumab (n=2) were effective as second-line biologic therapy while anakinra (n=2) and certolizumab (n=1) were not. Seven serious adverse drug reactions occurred, including 5 infections. CONCLUSIONS: TNF-α antagonists may be proposed earlier in relapsing polychondritis to spare corticosteroids. Switching to another biologic can be proposed in case of loss of efficacy. Tocilizumab or abatacept can be proposed as third-line therapy. The benefit-to-risk ratio of biologics in relapsing polychondritis should be evaluated prospectively.

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.

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.