Early progression in follicular lymphoma in the absence of histological transformation or high-risk Follicular Lymphoma International Prognostic Index still has a favourable outcome.

Although follicular lymphoma (FL) patients relapsing within 24 months after first-line treatment (POD24) have a poor prognosis, some cases show notable survival after first relapse (SF1R). We aimed to characterize the POD24 FL population and to identify the main prognostic factors at progression. We selected 162 POD24 patients (80F; median age at first relapse 59 years) from a cohort of 1067 grades 1-3a FL-treated patients. The remaining 905 patients treated with first-line immunochemotherapy and diagnosed during the same period were used to compare outcomes in terms of survival. After a median follow-up of 11.0 years, 96 patients died (10y-SF1R of 40%). Age over 60 years (p < 0.001), high lactate dehydrogenase (LDH) (p < 0.001), haemoglobin (Hb) less than 120 g/L (p < 0.001), advanced stage (p < 0.001), high-risk Follicular Lymphoma International Prognostic Index (FLIPI) (p < 0.001), histological transformation (HT) (p < 0.001) and reaching less than complete response (CR) after salvage therapy (p < 0.001), predicted poor SF1R at relapse. In multivariate analysis only high-risk FLIPI and HT maintained prognostic significance for SF1R. POD24 patients not transformed and with low/intermediate FLIPI at relapse behaved better than the remaining cases. POD24 patients showed an excess mortality of 38% compared to the general population. Although outcome of POD24 FL patients is poor, a considerable group of them (low/intermediate FLIPI and not transformed at first relapse) behave better.

A combined large-scale meta-analysis identifies COG6 as a novel shared risk locus for rheumatoid arthritis and systemic lupus erythematosus.

OBJECTIVES: During the last years, genome-wide association studies (GWASs) have identified a number of common genetic risk factors for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, the genetic overlap between these two immune-mediated diseases has not been thoroughly examined so far. The aim of the present study was to identify additional risk loci shared between RA and SLE. METHODS: We performed a large-scale meta-analysis of GWAS data from RA (3911 cases and 4083 controls) and SLE (2237 cases and 6315 controls). The top-associated polymorphisms in the discovery phase were selected for replication in additional datasets comprising 13 641 RA cases and 31 921 controls and 1957 patients with SLE and 4588 controls. RESULTS: The rs9603612 genetic variant, located nearby the COG6 gene, an established susceptibility locus for RA, reached genome-wide significance in the combined analysis including both discovery and replication sets (p value=2.95E-13). In silico expression quantitative trait locus analysis revealed that the associated polymorphism acts as a regulatory variant influencing COG6 expression. Moreover, protein-protein interaction and gene ontology enrichment analyses suggested the existence of overlap with specific biological processes, specially the type I interferon signalling pathway. Finally, genetic correlation and polygenic risk score analyses showed cross-phenotype associations between RA and SLE. CONCLUSIONS: In conclusion, we have identified a new risk locus shared between RA and SLE through a meta-analysis including GWAS datasets of both diseases. This study represents the first comprehensive large-scale analysis on the genetic overlap between these two complex disorders.

Patterns of drug therapy in newly diagnosed Spanish patients with systemic lupus erythematosus.

OBJECTIVES: This is the first Spanish multicentric inception lupus cohort, formed by SLE patients attending Spanish Internal Medicine Services since January 2009. We aimed to analyse drug therapy during the first year of follow-up according to disease severity. METHODS: 223 patients who had at least one year of follow-up were enrolled upon diagnosis of SLE. Therapy with prednisone, pulse methyl-prednisolone, hydroxychloroquine, immunosuppressives and calcium/vitamin D was analysed. RESULTS: Prednisone was given to 65% patients, at a mean (SD) daily dose of 11 (10) mg/d. 38% patients received average doses >7.5 mg/d during the first year. Patients with nephritis and with a SLEDAI ≥6 were treated with higher doses of prednisone. 81% of patients were treated with hydroxychloroquine, with higher frequency among those with a SLEDAI ≥6 (88% vs. 68%, p<0.001). The use of immunosuppressive drugs and methyl-prednisolone pulses was higher in patients with a baseline SLEDAI ≥6, however, differences were no longer significant when patients with lupus nephritis were excluded. The use of calcium/vitamin D increased with the dose of prednisone, however, 43% of patients on medium-high doses of prednisone did not take any calcium or vitamin D. CONCLUSIONS: This study gives a real-world view of the current therapeutic approach to early lupus in Spain. The generalised use of hydroxychloroquine is well consolidated. There is still a tendency to use prednisone at medium to high doses. Pulse methyl-prednisolone and immunosuppressive drugs were used in more severe cases, but not as steroid sparing agents. Vitamin D use was suboptimal.

Association of a rare variant of the TNFSF13B gene with susceptibility to Rheumatoid Arthritis and Systemic Lupus Erythematosus.

A rare variant (BAFF-var) of the tumor necrosis factor superfamily 13b (TNFSF13B) gene has been recently associated with multiple sclerosis (MS) and systemic lupus erythematosus (SLE). The aim of this study was to investigate the association between TNFSF13B BAFF-var and susceptibility to rheumatoid arthritis (RA) and replicate that association in SLE. 6,218 RA patients, 2,575 SLE patients and 4,403 healthy controls from three different countries were included in the study. TNFSF13B BAFF-var was genotyped using TaqMan allelic discrimination assay. PLINK software was used for statistical analyses. TNFSF13B BAFF-var was significantly associated with RA (p = 0.015, OR = 1.21, 95% CI = 1.03-1.41) in the Spanish cohort. A trend of association was observed in the Dutch (p = 0.115) and German (p = 0.228) RA cohorts. A meta-analysis of the three RA cohorts included in this study revealed a statistically significant association (p = 0.002, OR = 1.24, 95% CI = 1.10-1.38). In addition, TNFSF13B BAFF-var was significantly associated with SLE in the Spanish (p = 0.001, OR = 1.41, 95% CI = 1.14-1.74) and the German cohorts (p = 0.030, OR = 1.86, 95% CI = 1.05-3.28), with a statistically significant p-value obtained in the meta-analysis (p = 0.0002, OR = 1.46, 95% CI = 1.09-2.32). The results obtained confirm the known association of TNFSF13B BAFF-var with SLE and, for the first time, demonstrate that this variant contributes to susceptibility to RA.

Predictors of active cancer thromboembolic outcomes. RIETE experience of the Khorana score in cancer-associated thrombosis.

Even though the Khorana risk score (KRS) has been validated to predict against the development of VTE among patients with cancer, it has a low positive predictive value. It is also unknown whether the score predicts outcomes in patients with cancer with established VTE. We selected a cohort of patients with active cancer from the RIETE (Registro Informatizado Enfermedad TromboEmbolica) registry to assess the prognostic value of the KRS at inception in predicting the likelihood of VTE recurrences, major bleeding and mortality during the course of anticoagulant therapy. We analysed 7948 consecutive patients with cancer-associated VTE. Of these, 2253 (28 %) scored 0 points, 4550 (57 %) 1-2 points and 1145 (14 %) scored ≥3 points. During the course of anticoagulation, amongst patient with low, moderate and high risk KRS, the rate of VTE recurrences was of 6.21 (95 %CI: 4.99-7.63), 11.2 (95 %CI: 9.91-12.7) and 19.4 (95 %CI: 15.4-24.1) events per 100 patient-years; the rate of major bleeding of 5.24 (95 %CI: 4.13-6.56), 10.3 (95 %CI: 9.02-11.7) and 19.4 (95 %CI: 15.4-24.1) bleeds per 100 patient-years and the mortality rate of 25.3 (95 %CI: 22.8-28.0), 58.5 (95 %CI: 55.5-61.7) and 120 (95 %CI: 110-131) deaths per 100 patient-years, respectively. The C-statistic was 0.53 (0.50-0.56) for recurrent VTE, 0.56 (95 %CI: 0.54-0.59) for major bleeding and 0.54 (95 %CI: 0.52-0.56) for death. In conclusion, most VTEs occur in patients with low or moderate risk scores. The KRS did not accurately predict VTE recurrence, major bleeding, or mortality among patients with cancer-associated thrombosis.

Outcome after discontinuing anticoagulant therapy in women with venous thromboembolism during hormonal use.

INTRODUCTION: Whether women developing venous thromboembolism (VTE) while using hormonal therapy should be classified as having "unprovoked" or "provoked" VTE is controversial. METHODS: We used the RIETE (Registro Informatizado Enfermedad TromboEmbólica) database to compare the rate of symptomatic VTE recurrences after discontinuing anticoagulation in 3 subgroups of women aged ≤50years without cancer, pregnancy or puerperium: (1) those with hormonal therapy and no additional risk factors (hormonal users only); (2) those with unprovoked VTE; and (3) those with additional risk factors, with or without hormonal therapy. RESULTS: As of March 2016, 1513 women had been followed-up for at least one month after discontinuing anticoagulation. Of these, 654 (43%) were hormonal users only, 390 (26%) had unprovoked VTE and 469 (31%) had transient risk factors with or without hormonal therapy. After discontinuing anticoagulation, the rate of VTE recurrences in women with hormonal use only (2.44 per 100 patient-years; 95% CI: 1.53-3.69) was significantly lower than in those with unprovoked VTE (6.03; 95% CI: 3.97-8.77) and similar to those with transient risk factors (2.58; 95% CI: 1.50-4.13). Interestingly, the rate of VTE recurrences presenting as pulmonary embolism in women with hormonal use only (0.55 per 100 patient-years; 95% CI: 0.18-1.29) was similar to those with transient risk factors (0.46; 95% CI: 0.09-1.33) and 4-fold lower than in women with unprovoked VTE (2.23; 95% CI: 1.07-4.10). CONCLUSIONS: After discontinuing anticoagulation, the rate of VTE recurrences in hormonal users only was significantly lower than in women with unprovoked VTE and similar to the rate in women with additional risk factors.

Platelet Count and Major Bleeding in Patients Receiving Vitamin K Antagonists for Acute Venous Thromboembolism, Findings From Real World Clinical Practice.

The outcome of patients with acute venous thromboembolism (VTE) and abnormal platelet count (PlC) at baseline has not been consistently studied. In real-world clinical practice, a number of patients with abnormal PlC receive vitamin K antagonists (VKAs) to treat acute VTE despite their higher risk of bleeding.We used the Registro Informatizado de Enfermedad TromboEmbólica registry database to compare the rate of major bleeding in patients receiving VKA for long-term therapy of acute VTE according to PlC levels at baseline. Patients were categorized as having very low (<100,000/µL), low (100,000-150,000/µL), normal (150,000-300,000/µL), high (300,000-450,000/µL), or very high (>450,000/µL) PlC at baseline.Of 55,369 patients recruited as of January 2015, 37,000 (67%) received long-term therapy with VKA. Of these, 611 patients (1.6%) had very low PlC, 4006 (10.8%) had low PlC, 25,598 (69%) had normal PlC, 5801 (15.6%) had high PlC, and 984 (2.6%) had very high PlC at baseline. During the course of VKA therapy (mean, 192 days), there were no differences in the duration or intensity (as measured by international normalized ratio levels) of treatment between subgroups. The rate of major bleeding was 3.6%, 2.1%, 1.9%, 2.1%, and 3.7%, respectively, and the rate of fatal bleeding was 0.98%, 0.17%, 0.29%, 0.34%, and 0.50%, respectively. Patients with very low or very high PlC levels were more likely to have severe comorbidities.We found a nonlinear "U-shaped" relationship between PlC at baseline and major bleeding during therapy with VKA for VTE. Consistent alteration of PlC values at baseline suggested a greater frailty.

Discharge against medical advice at a general hospital in Catalonia.

Some studies on discharge against medical advice (AMA) in general hospitals report a prevalence between 0.7-7% with 11-42% of this population identified as psychiatric patients. To study the sociodemographic and psychopathological features of patients who leave AMA, we performed a retrospective case-control comparison study of length of hospitalization and presence of psychiatric disturbances on patients who left AMA from the University General Hospital in Catalan Spain over a two-year period. An analysis of the hospital epidemiological discharge register and retrospective chart review for presence of psychiatric disturbances found that AMA prevalence was 0.34%, the total discharge number in the 2-year period being 41,648. AMA rates by medical department were 0.44% for the internal medicine department; 0.24% for surgery; 0.26% for orthopedic surgery, 0.32% for obstetrics-gynecology and 0.93% for rehabilitation. The mean age for AMA patients was 38.63 years, with a higher number of men (59.9%). A total of 45.8% AMA discharges were from the internal medicine department. No significant differences were found in the average length of hospitalization between the AMA and control groups. The presence of psychiatric pathology was significantly higher among the AMA group (P<.05). The prevalence of AMA at our hospital was low in comparison to the rates reported in the literature. The patient at high risk for AMA discharge is a young man with a history of psychiatric pathology, mainly narcotic dependence.

Early- versus late-onset systemic sclerosis: differences in clinical presentation and outcome in 1037 patients.

Peak age at onset of systemic sclerosis (SSc) is between 20 and 50 years, although SSc is also described in both young and elderly patients. We conducted the present study to determine if age at disease onset modulates the clinical characteristics and outcome of SSc patients. The Spanish Scleroderma Study Group recruited 1037 patients with a mean follow-up of 5.2 ± 6.8 years. Based on the mean ± 1 standard deviation (SD) of age at disease onset (45 ± 15 yr) of the whole series, patients were classified into 3 groups: age ≤ 30 years (early onset), age between 31 and 59 years (standard onset), and age ≥ 60 years (late onset). We compared initial and cumulative manifestations, immunologic features, and death rates. The early-onset group included 195 patients; standard-onset group, 651; and late-onset, 191 patients. The early-onset group had a higher prevalence of esophageal involvement (72% in early-onset compared with 67% in standard-onset and 56% in late-onset; p = 0.004), and myositis (11%, 7.2%, and 2.9%, respectively; p = 0.009), but a lower prevalence of centromere antibodies (33%, 46%, and 47%, respectively; p = 0.007). In contrast, late-onset SSc was characterized by a lower prevalence of digital ulcers (54%, 41%, and 34%, respectively; p < 0.001) but higher rates of heart conduction system abnormalities (9%, 13%, and 21%, respectively; p = 0.004). Pulmonary hypertension was found in 25% of elderly patients and in 12% of the youngest patients (p = 0.010). After correction for the population effects of age and sex, standardized mortality ratio was shown to be higher in younger patients. The results of the present study confirm that age at disease onset is associated with differences in clinical presentation and outcome in SSc patients.

Analysis of ancestral and functionally relevant CD5 variants in systemic lupus erythematosus patients.

OBJECTIVE: CD5 plays a crucial role in autoimmunity and is a well-established genetic risk factor of developing RA. Recently, evidence of positive selection has been provided for the CD5 Pro224-Val471 haplotype in East Asian populations. The aim of the present work was to further analyze the functional relevance of non-synonymous CD5 polymorphisms conforming the ancestral and the newly derived haplotypes (Pro224-Ala471 and Pro224-Val471, respectively) as well as to investigate the potential role of CD5 on the development of SLE and/or SLE nephritis. METHODS: The CD5 SNPs rs2241002 (C/T; Pro224Leu) and rs2229177 (C/T; Ala471Val) were genotyped using TaqMan allelic discrimination assays in a total of 1,324 controls and 681 SLE patients of Spanish origin. In vitro analysis of CD3-mediated T cell proliferative and cytokine response profiles of healthy volunteers homozygous for the above mentioned CD5 haplotypes were also analyzed. RESULTS: T-cell proliferation and cytokine release were significantly increased showing a bias towards to a Th2 profile after CD3 cross-linking of peripheral mononuclear cells from healthy individuals homozygous for the ancestral Pro224-Ala471 (CC) haplotype, compared to the more recently derived Pro224-Val471 (CT). The same allelic combination was statistically associated with Lupus nephritis. CONCLUSION: The ancestral Ala471 CD5 allele confers lymphocyte hyper-responsiveness to TCR/CD3 cross-linking and is associated with nephritis in SLE patients.

Effectiveness of rituximab in severe Wegener's granulomatosis: report of two cases and review of the literature.

We hereby describe the satisfactory evolution of rituximab treatment in two patients with Wegener's granulomatosis (WG). Rituximab was indicated for refractoriness to standard treatment in one case and life-threatening myelotoxicity due to alkylating agents in the other. A brief review of previous experience with the use of rituximab in the treatment of WG is presented.

Association of HLA class II genes with systemic sclerosis in Spanish patients.

OBJECTIVE: To examine the role of HLA-DRB1 and HLA-DQB1 alleles in the susceptibility to systemic sclerosis (SSc) and its clinical expression in a Spanish population. METHODS: One hundred Spanish Caucasian patients with SSc and 130 controls were studied. Molecular HLA-DRB1 and HLA-DQB1 typing was performed by polymerase chain reaction (PCR) sequence-based typing and PCR sequence-specific oligonucleotide. RESULTS: HLA-DRB1*11 was associated with genetic susceptibility to SSc, whereas HLA-DRB1*07 (HLA-DRB1*0701) showed a protective effect. A significant increase in the frequency of the DRB1*1104 allele was observed in patients with anti-topoisomerase I autoantibodies (anti-Topo I) while HLA-DRB1*01 and HLA-DQB1*05 alleles were significantly increased in patients with anti-centromere antibodies (ACA). The HLA-DRB1*11 allele was more frequent in patients with pulmonary fibrosis; however, no significant association with any HLA-DRB1 or DQB1 alleles was identified in patients with pulmonary arterial hypertension. CONCLUSION: HLA alleles play a role in genetic susceptibility to SSc in Spanish patients. Some alleles are more prevalent in patients with pulmonary fibrosis and in patients with certain SSc-specific autoantibodies (anti-Topo I and ACA).

Deep vein thrombosis and pulmonary embolism: the same disease?

The clinical characteristics and 3-month clinical outcome of 7,664 patients with acute deep vein thrombosis(DVT), 3,968 patients with pulmonary embolism(PE), and 2,287 with signs of both DVT and PE were compared. As compared to patients with DVT signs, PE patients were more commonly females, older and had less often cancer, prior VTE or recent surgery. By contrast, they had more often chronic lung disease,chronic heart failure or renal insufficiency. Patients with both DVT and PE signs were also more commonly females and older than those with only DVT signs, but they had more often a prior episode VTE, cancer, chronic lung disease, chronic heart failure or renal insufficiency. As for the 3-month clinical outcome,patients with PE signs had a significantly higher incidence of major bleeding, recurrent PE, fatal PE and overall death than those with only DVT signs,but a lower incidence of recurrent DVT. Besides, patients with DVT and PE signs had an even worse clinical outcome.