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Summary: Long‐term observation of patients with ANCA‐associated vasculitis (AAV) allows the identification of different longitudinal patterns of ANCA levels during follow‐up. This study aimed to characterize these patterns and to determine their prognostic significance. All ANCA determinations performed in two university hospitals during a 2‐year period were retrospectively reviewed. Patients were included in the analysis if they had high titers of anti‐myeloperoxidase (anti‐MPO) or anti‐proteinase 3 (anti‐PR3) antibodies at least once, ≥ 5 serial ANCA determinations and AAV diagnosed by biopsy or American College of Rheumatology (ACR) classification criteria. Patients' time–course ANCA patterns were classified as monophasic, remitting, recurrent or persistent. Associations between ANCA patterns and prognostic variables (relapse rate and renal outcome) were analysed by univariate and multivariate statistics. A total of 99 patients [55 with microscopic polyangiitis (MPA), 36 with granulomatosis with polyangiitis (GPA) and eight with eosinophilic granulomatosis with polyangiitis (EGPA)] were included. Median follow‐up was 9 years. Among patients diagnosed with MPA or GPA, recurrent or persistent ANCA patterns were associated with a higher risk of clinical relapse [hazard ratio (HR) = 3·7, 95% confidence interval (CI) = 1·5–9·1 and HR = 2·9, 95% CI = 1·1–8·0, respectively], independently of clinical diagnosis or ANCA specificity. In patients with anti‐MPO antibodies, the recurrent ANCA pattern was associated with worsening renal function [odds ratio (OR) = 5·7, 95% CI = 1·2–26·0]. Recurrent or persistent ANCA patterns are associated with a higher risk of clinical relapse. A recurrent ANCA pattern was associated with worsening renal function in anti‐MPO‐associated vasculitis. [ABSTRACT FROM AUTHOR]

The objective was to evaluate whether changes in circulating soluble adhesion molecule levels reflect disease activity in patients with systemic polyarteritis nodosa (PAN). A sandwich ELISA was used to measure soluble (s) intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1 (sVCAM-1), E-selectin, L-selectin and P-selectin in sera and plasma from 22 patients with active PAN, in sera from 13 of these patients taken serially during follow-up, and in sera from 13 healthy controls. At the time of diagnosis, sICAM-1, sVCAM-1 and sE-selectin levels (488.5 +/- 201.3, 1176.5 +/- 514.1 and 60.6 +/- 27 ng/ml, respectively) were significantly higher in patients than in controls (P < 0.0001, P = 0.001 and P = 0.003, respectively). In contrast, sL-selectin levels tended to be lower in patients than in controls. Within the first 7 days after starting treatment, there was a significant increase in sICAM-1 concentrations, which fell thereafter, but did not completely reach normal levels when patients achieved clinical remission. sE-selectin also remained elevated during follow-up. Only sVCAM-1 decreased, tending to reach normal values in inactive disease. Increased levels of sICAM-1, sVCAM-1 and sE-selectin, and decreased levels of sL-selectin, in active PAN suggest immune and endothelial stimulation during disease activity. Abnormal levels of soluble adhesion molecules in clinically inactive patients might reflect persistence of immune activation and/or endothelial cell exposure to a remaining inflammatory microenvironment. [ABSTRACT FROM PUBLISHER]

Twenty consecutive patients with serologically confirmed Mediterranean spotted fever were analyzed for determination of plasma levels of tumor necrosis factor α (TNF-α) by means of an ELISA. Increased levels of TNF-α in plasma were found during the acute phase of the disease (52.3 ± 49.8 pg/mL) compared to levels in the convalescent phase (9.0 ± 9.3 pg/mL; P < .001) or in healthy controls (6.5 ± 3.2 pg/mL; P < .001). Plasma TNF-α levels were significantly higher in patients with severe Mediterranean spotted fever. Levels of TNF-α correlated significantly with serum levels of C-reactive protein and triglycerides and inversely with serum levels of sodium. [ABSTRACT FROM PUBLISHER]

Treatment with calcitriol, the hormonal form of vitamin D, has shown beneficial effects in experimental models of acute lung injury. In this study, we aimed to analyze the associations between calcitriol supplementation and the risk of SARS-CoV2 infection or COVID-19 mortality. Individuals ≥18 years old living in Catalonia and supplemented with calcitriol from April 2019 to February 2020 were compared with propensity score matched controls. Outcome variables were SARS-CoV2 infection, severe COVID-19 and COVID-19 mortality. Associations between calcitriol supplementation and outcome variables were analyzed using multivariable Cox proportional regression. A total of 8076 patients were identified as being on calcitriol treatment. Advanced chronic kidney disease and hypoparathyroidism were the most frequent reasons for calcitriol supplementation in our population. Calcitriol use was associated with reduced risk of SARS-CoV2 infection (HR 0.78 [CI 95% 0.64-0.94], p = 0.010), reduced risk of severe COVID-19 and reduced COVID-19 mortality (HR 0.57 (CI 95% 0.41-0.80), p = 0.001) in patients with advanced chronic kidney disease. In addition, an inverse association between mean daily calcitriol dose and COVID-19 severity or mortality was observed in treated patients, independently of renal function. Our findings point out that patients with advanced chronic kidney disease could benefit from calcitriol supplementation during the COVID-19 pandemic.

Objectives: Rituximab (RTX) is a biological treatment used off-label in patients with systemic lupus erythematosus (SLE). This survey aimed to investigate the off-label use of RTX in Europe and compare the characteristics of patients receiving RTX with those receiving conventional therapy., Methods: Data on patients with SLE receiving RTX were taken from the International Registry for Biologics in SLE retrospective registry and complemented with data on patients with SLE treated with conventional therapy. For nationwide estimates of RTX use in patients with SLE, investigators were asked to provide data through case report forms (CRFs). Countries for which no data were submitted through CRFs, published literature and/or personal communication were used, and for European countries where no data were available, estimates were made on the assumption of similarities with neighbouring countries., Results: The estimated off-label use of RTX in Europe was 0.5%-1.5% of all patients with SLE. In comparison with patients with SLE on conventional therapy, patients treated with RTX had longer disease duration, higher disease activity and were more often treated with immunosuppressives. The most frequent organ manifestations for which either RTX or conventional therapy was initiated were lupus nephritis followed by musculoskeletal and haematological. The reason for treatment was, besides disease control, corticosteroid-sparing for patients treated with conventional therapy., Conclusions: RTX use for SLE in Europe is restrictive and appears to be used as a last resort in patients for whom other reasonable options have been exhausted.

Objectives: We analyse the safety and effectiveness of self-outpatient parenteral antimicrobial therapy (s-OPAT) in older patients., Methods: We prospectively evaluated all adults admitted to our home hospitalization unit (HHU) for s-OPAT in the period 2008-12 in whom the bacteria responsible for the infection were identified. We divided patients into three age groups: <65, 65-79 and ≥80 years. s-OPAT was administered by patients or their caregivers using elastomeric infusion devices. Effectiveness was assessed by analysing readmissions to hospital for inadequate control of underlying infection. Safety was assessed by analysing adverse events, catheter-related complications and readmission to hospital for causes unrelated to inadequate control of underlying infection., Results: During the study period, 420 episodes of s-OPAT were registered in 351 patients: 139 (33.1%) in patients aged <65 years, 182 (43.3%) in those aged 65-79 years and 99 (23.6%) in those aged ≥80 years. Patients aged ≥80 years had a significantly lower Barthel index. The length of stay for s-OPAT and the complete HHU stay were similar in the three groups. Older people had similar changes in antibiotic treatment and hospital readmission rates due to poor control of underlying infection but higher readmission rates due to worsening of underlying diseases than younger adults. Adverse events and catheter-related complications were similar in the three age groups., Conclusions: s-OPAT administered by patients or their caregivers using elastomeric devices was safe and effective in the treatment of infections in older people., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

There is general agreement that the growth of the numbers of older people throughout the world has significant implications for both health and social care and for the prevention and treatment of disease and disability. The optimum use of pharmaceuticals and possibly nutraceuticals is, and will to a greater extent, therefore be of crucial importance. A snapshot of the current status of older people in relation to the issues discussed in this review is provided in an informative report published by Age UK.

Background: There are no simple and validated instruments for evaluating the training of specialists., Objectives: To analyze the reliability and validity of a computerized self-assessment method to quantify the acquisition of medical competences during the Internal Medicine residency program., Methods: All residents of our department participated in the study during a period of 28 months. Twenty-two questionnaires specific for each rotation (the Computer-Book of the Internal Medicine Resident) were constructed with items (questions) corresponding to three competence domains: clinical skills competence, communication skills and teamwork. Reliability was analyzed by measuring the internal consistency of items in each competence domain using Cronbach's alpha index. Validation was performed by comparing mean scores in each competence domain between senior and junior residents. Cut-off levels of competence scores were established in order to identify the strengths and weaknesses of our training program. Finally, self-assessment values were correlated with the evaluations of the medical staff., Results: There was a high internal consistency of the items of clinical skills competences, communication skills and teamwork. Higher scores of clinical skills competence and communication skills, but not in those of teamwork were observed in senior residents than in junior residents. The Computer-Book of the Internal Medicine Resident identified the strengths and weaknesses of our training program. We did not observe any correlation between the results of the self- evaluations and the evaluations made by staff physicians., Conclusions: The items of Computer-Book of the Internal Medicine Resident showed high internal consistency and made it possible to measure the acquisition of medical competences in a team of Internal Medicine residents. This self-assessment method should be complemented with other evaluation methods in order to assess the acquisition of medical competences by an individual resident., (Copyright © 2012 Elsevier España, S.L. All rights reserved.)

Background: There has been concern about under-representation of older people in clinical trials. The PREDICT study reported that older people and those with co-morbidity continue to be excluded unjustifiably from clinical trials. However, there is no information about differences of opinion on these issues between EU countries. The results of a survey of health-related professionals from nine EU countries that participated in the PREDICT study are presented in this study., Objective: The aim of the study was to identify and examine any differences of opinion between EU countries on the inclusion of older patients in clinical trials., Methods: A questionnaire using a Likert scale and free text was completed by 521 general practitioners, geriatricians, clinical researchers, ethicists, nurses and industry pharmacologists/pharmacists. The questions explored the impact of the present situation, possible reasons for under-representation and potential methods of improving participation. Countries participating were the Czech Republic, Israel, Italy, Lithuania, the Netherlands, Poland, Romania, Spain and the UK., Results: There was agreement that exclusion from clinical trials on age grounds alone was unjustified (87%) and that under-representation of older people in trials caused difficulties for prescribers (79%) and patients (73%). There were national differences between professionals. All but the Lithuanians believed that older people were disadvantaged because of under-representation. The Czech, Lithuanian and Romanian professionals felt that it was justified to have age limits based on co-morbidity (61-83%) and polypharmacy (63-85%). Romanians also thought that having age limits on trial participation was justified because of reduced life expectancy (62%) and physical disability (58%) in older people. All but the Romanian professionals felt that the present arrangements for clinical trials were satisfactory (62%). All but the Israelis (56%) and Lithuanians (70%) agreed that regulation of clinical trials needed alteration., Conclusions: Although respondent selection bias cannot be excluded, the differences that emerged between countries may be the result of the political and healthcare-system differences between older and newer members of the EU. These differences may influence decision making about clinical trial regulations and practice in older people.

Introduction: The purpose of this observational study was to analyze the rates, characteristics and associated risk factors of severe infections in patients with systemic autoimmune diseases (SAD) who were treated off-label with biological agents in daily practice., Methods: The BIOGEAS registry is an ongoing Spanish prospective cohort study investigating the long-term safety and efficacy of the off-label use of biological agents in adult patients with severe, refractory SAD. Severe infections were defined according to previous studies as those that required intravenous treatment or that led to hospitalization or death. Patients contributed person-years of follow-up for the period in which they were treated with biological agents., Results: A total of 344 patients with SAD treated with biological agents off-label were included in the Registry until July 2010. The first biological therapies included rituximab in 264 (77%) patients, infliximab in 37 (11%), etanercept in 21 (6%), adalimumab in 19 (5%), and 'other' agents in 3 (1%). Forty-five severe infections occurred in 37 patients after a mean follow-up of 26.76 months. These infections resulted in four deaths. The crude rate of severe infections was 90.9 events/1000 person-years (112.5 for rituximab, 76.9 for infliximab, 66.9 for adalimumab and 30.5 for etanercept respectively). In patients treated with more than two courses of rituximab, the crude rate of severe infection was 226.4 events/1000 person-years. A pathogen was identified in 24 (53%) severe infections. The most common sites of severe infection were the lower respiratory tract (39%), bacteremia/sepsis (20%) and the urinary tract (16%). There were no significant differences relating to gender, SAD, agent, other previous therapies, number of previous immunosuppressive agents received or other therapies administered concomitantly. Cox regression analysis showed that age (P = 0.015) was independently associated with an increased risk of severe infection. Survival curves showed a lower survival rate in patients with severe infections (log-rank and Breslow tests < 0.001)., Conclusions: The rates of severe infections in SAD patients with severe, refractory disease treated depended on the biological agent used, with the highest rates being observed for rituximab and the lowest for etanercept. The rate of infection was especially high in patients receiving three or more courses of rituximab. In patients with severe infections, survival was significantly reduced. Older age was the only significant predictive factor of severe infection.

Background: Much clinical research of relevance to elderly patients examines individuals who are younger than those who have the disease in question. A good example is heart failure. Therefore, we investigated the extent of exclusion of older individuals in ongoing clinical trials regarding heart failure., Methods: In the context of the Increasing the PaRticipation of the ElDerly in Clinical Trials (PREDICT) study, data from ongoing clinical trials regarding heart failure were extracted from the World Health Organization Clinical Trials Registry Platform on December 1, 2008. Main outcome measures were the proportion of trials excluding patients by an arbitrary upper age limit or by other exclusion criteria that might indirectly cause limited recruitment of older individuals. We classified exclusion criteria into 2 categories: justified or poorly justified., Results: Among 251 trials investigating treatments for heart failure, 64 (25.5%) excluded patients by an arbitrary upper age limit. Such exclusion was significantly more common in trials conducted in the European Union than in the United States (31/96 [32.3%] vs 17/105 [16.2%]; P = .007) and in drug trials sponsored by public institutions vs those by private entities (21/59 [35.6%] vs 5/36 [13.9%]; P = .02). Overall, 109 trials (43.4%) on heart failure had 1 or more poorly justified exclusion criteria that could limit the inclusion of older individuals. A similar proportion of clinical trials with poorly justified exclusion criteria was found in pharmacologic and nonpharmacologic trials., Conclusion: Despite the recommendations of national and international regulatory agencies, exclusion of older individuals from ongoing trials regarding heart failure continues to be widespread.

Objectives: To analyse the safety and efficacy of the off-label use of rituximab in patients with severe, refractory systemic autoimmune diseases., Methods: In 2006, the Study Group on Autoimmune Diseases of the Spanish Society of Internal Medicine created the BIOGEAS project, a multicenter study devoted to collecting data on the use of biological agents in adult patients with systemic autoimmune diseases refractory to standard therapies (failure of at least two immunosuppressive agents)., Results: One hundred and ninety-six patients with systemic autoimmune diseases treated with rituximab have been included in the Registry (158 women and 38 men, mean age 43 years). Systemic autoimmune diseases included systemic lupus erythematosus (107 cases), inflammatory myopathies (20 cases), ANCA-related vasculitides (19 cases), Sjögren's syndrome (15 cases) and other diseases (35 cases). A therapeutic response was evaluable in 194 cases: 99 (51%) achieved a complete response, 51 (26%) a partial response and 44 (23%) were classified as non-responders. After a mean follow-up of 27.56+/-1.32 months, 44 (29%) out of the 150 responders patients relapsed. There were 40 adverse events reported in 33 (16%) of the 196 patients. The most frequent adverse events were infections, with 24 episodes being described in 19 patients. Thirteen (7%) patients died, mainly due to disease progression (7 cases) and infection (3 cases)., Conclusions: Although not yet licensed for this use, rituximab is currently used to treat severe, refractory systemic autoimmune diseases, with the most favourable results being observed in Sjögren's syndrome, inflammatory myopathies, systemic lupus erythematosus and cryoglobulinemia.

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.

Unlabelled: Recently a number of studies have implicated C virus as a major cause of mixed cryoglobulinemia. Several authors described that up to 95% of "essential" mixed cryoglobulinemia could be attributed to this viral infection. Nevertheless, its prevalence and clinical significance are not well known. We review our experience in relation with the clinical, biological and evolutive characteristics of patients diagnosed of type II mixed cryoglobulinemia., Methods: Descriptive and protocolized study of all cases found to have type II mixed cryoglobulinemia over a period of 8 years. Secondary cryoglobulinemic nephropathy was defined in a restrictive way: a plasma creatinine > 1.5 mg/dl and/or proteinuria > 500 mg/24 h and/or hematuria (> 15 red blood cells) need to be present in the absence of any other pathological conditions that could justify these alterations. Furthermore, the information obtained from available kidney biopsies was considered., Results: 62 patients have been detected. C virus infection was demonstrated in 44 (72%). 52% had clinical symptoms related with cryoglobulinemia. 56% had alteration of renal tests, and 17 (27%) fulfil the conditions for the diagnosis of cryoglobulinemic nephropathy (nearly all with persistent microhematuria, median proteinuria 4.2 +/- 3.9 g/24 h; median plasma creatinine 2.8 +/- 1.8 mg/dl). Nine patients had been histologically examined, showing 6 cases a membranoproliferative glomerulonephritis pattern, one with associated extraglomerular vasculitis; two with mesangial proliferative pattern and one with membranous glomerulonephritis. The most striking differences between cryoglobulinemic nephropathy patients and the rest has been: higher amount of cryoglobulins (49 +/- 28 vs 20 +/- 22); more frequent hypocomplementemia, especially C4 (93% vs 59%) and recurrent purpura (75% vs 32%). No differences in the presence of C virus infection could be observed (75% vs 71%)., In Conclusion: 72% of patients with type II mixed cryoglobulinemia are infected by C virus (so 28% in our serie are "essential"); 52% have symptoms related with the presence of cryoglobulins, half of them with cryoglobulinemic nephropathy.

Objective: To identify clinical and biochemical parameters that have good predictive value for identifying giant cell (temporal) arteritis (GCA) patients who are at high or low risk of developing cranial ischemic events., Methods: In this multicenter study, records of patients at 3 university hospitals in Barcelona were reviewed retrospectively. Two hundred consecutive patients with biopsy-proven GCA were studied., Results: Thirty-two patients developed irreversible cranial ischemic complications. The duration of clinical symptoms before diagnosis was similar in patients with and those without ischemic events. Patients with ischemic complications less frequently had fever (18.8% versus 56.9%) and weight loss (21.9% versus 62%) and more frequently had amaurosis fugax (32.3% versus 6%) and transient diplopia (15.6% versus 3.6%). Patients with ischemic events had lower erythrocyte sedimentation rates (ESR) (82.7 mm/hour versus 104.4 mm/hour) and higher concentrations of hemoglobin (12.2 gm/dl versus 10.9 gm/dl) and albumin (37.4 gm/liter versus 32.7 gm/liter). Clinical inflammatory status and biologic inflammatory status were defined empirically (clinical: fever and weight loss; biologic: ESR > or =85 mm/hour and hemoglobin < 11.0 gm/dl). Patients not showing a clinical and biologic inflammatory response were at high risk of developing ischemic events (odds ratio [OR] 5, 95% confidence interval [95% CI] 2.05-12.2). The risk was greatly reduced among patients with either a clinical (OR 0.177, 95% CI 0.052-0.605) or a biologic (OR 0.226, 95% CI 0.076-0.675) inflammatory reaction. No patient with both a clinical and a biologic response developed ischemic events., Conclusion: The presence of a strong acute-phase response defines a subgroup of patients at very low risk of developing cranial ischemic complications. Our findings provide a rationale for testing less aggressive treatment schedules in these individuals. Conversely, a low inflammatory response and the presence of transient cranial ischemic events provide a high risk of developing irreversible ischemic complications and require a prompt therapeutic intervention.

Renal involvement is unusual in giant cell (temporal) arteritis (GCA). Microscopic hematuria and minimal proteinuria responsive to steroid therapy have been described as the most frequent renal alterations. The nephrotic syndrome in GCA has been rarely reported. We describe 2 cases of GCA with nephrotic syndrome, one at the time of diagnosis, the other 2 years after treatment. Percutaneous renal biopsy in both cases disclosed secondary renal amyloidosis confirmed by permanganate sensitivity and immunohistochemical analysis. To our knowledge, cases of GCA and secondary amyloidosis have not been reported.

Tumor necrosis factor alpha (TNF) is a key cytokine in the defense against many intracellular pathogens, including Rickettsia conorii, the causative agent of Mediterranean spotted fever (MSF). The levels of two soluble TNF receptors (sTNFR-p55 and sTNFR-p75), the extracellular domains of the two cell surface receptors for TNF, were elevated in the acute-stage plasma samples from 20 patients with serologically confirmed MSF. The median values were 3.1 and 7.8 ng/ml for sTNFR-p55 and sTNFR-p75, respectively. sTNFR values correlated significantly with plasma TNF concentrations. Patients with severe MSF had higher values for both receptor fragments than patients with nonsevere disease. The differences were statistically significant for sTNFR-p55 (median, 5.8 versus 2.0 ng/ml; P = 0.008). Given the proportionately higher values for both TNF and sTNFR-p55 in patients with severe MSF, the sTNFR-p55/TNF ratios for the two patient subgroups did not differ (P = 0.5), while the sTNFR-p75/TNF ratios were significantly different (P = 0.01), with disproportionately lower values in patients with severe disease.