Ocular involvement in adult and paediatric patients with monogenic autoinflammatory diseases: a Spanish multicentre retrospective study.

OBJECTIVES: Ophthalmologic involvement in monogenic autoinflammatory diseases has been explored mainly in paediatric patients. The aim of this study is to characterise ophthalmologic manifestations, therapeutic management and visual outcomes in a Spanish (UVESAI) cohort of adult/paediatric patients with monogenic autoinflammatory diseases. METHODS: Multicentre and retrospective study of patients with monogenic autoinflammatory diseases and ocular involvement. Eye manifestations, structural complications, treatments used and visual outcomes were analysed, and compared with previous studies. RESULTS: Forty-six patients (44/2 adults/children; 21/25 adult/paediatric-onset) with monogenic autoinflammatory diseases [cryopyrin associated periodic syndromes (n=13/28.3%), mainly Muckle-Wells syndrome (MWS) (n=11/24%); familial Mediterranean fever (FMF) (n=12/26%); TNF receptor-associated periodic syndrome (TRAPS); (n=9/20%); Blau syndrome (n=8/17%); hyperimmunoglobulin D syndrome (HIDS) (n=2/4.3%), deficiency of adenosine deaminase-2 and NLRC4-Autoinflammatory disease] (one each) were included. Conjunctivitis (n=26/56.5%) and uveitis (n=23/50%) were the most frequent ocular manifestations. Twelve (26.1%) patients developed structural complications, being cataracts (n=11/24%) and posterior synechiae (n=10/22%) the most frequent. Conjunctivitis predominated in TRAPS, FMF, MWS and HIDS (mainly in adults), and uveitis, in Blau syndrome. Seven (8%) eyes (all with uveitis) presented with impaired visual acuity. Local and systemic treatment led to good visual outcomes in most patients. Compared with previous studies mainly including paediatric patients, less severe ocular involvement was observed in our adult/paediatric cohort. CONCLUSIONS: Conjunctivitis was the most common ocular manifestation in our TRAPS, FMF, MWS and HIDS patients, and uveitis predominated in Blau syndrome. Severe eye complications and poor visual prognosis were associated with uveitis. Adults with monogenic autoinflammatory diseases seem to exhibit a less severe ophthalmologic presentation than paediatric patients.

Factors associated with serum IgM concentrations: a general adult population study.

BACKGROUND AND AIM: To investigate the influence of common factors on serum immunoglobulin M (IgM) concentrations in adults, and clinical associations with high and low values. METHODS: We measured serum IgM levels using immunonephelometry in a random sample of 1510 individuals (aged 18-91 years, 44.7% male). We obtained data defining metabolic syndrome from all participants, defined atopy by skin prick tests to aeroallergens, and assessed lifestyle factors by questionnaire. RESULTS: Women showed higher IgM concentrations than men; 95 (6.3%, mostly male) individuals showed low (<0.40 g/L) IgM values, and 64 (4.2%, mostly female) showed high (>2.30 g/L) IgM values. Individuals with abnormal IgM concentrations had no history of opportunistic infections nor a different atopy prevalence. Serum IgM concentrations decreased with age, and obesity was negatively associated with IgM concentrations. Alcohol consumption, smoking, physical activity, and metabolic syndrome had no significant influence in the multivariate analyses. CONCLUSIONS: Many adults in the general population show abnormally high or low IgM concentrations with no evidence of immunodeficiency-associated diseases. Sex and age should be considered when defining reference IgM concentrations.

Being an internist throughout the world - same name, different training curricula.

In the 79 countries revised, two fundamental internal medicine (IM) training patterns were in evidence, first, only basic training needed, requiring a 3-4-year residency period for obtaining the diploma of internist; and advanced training needed, requiring 5-7 years of study. Second, evaluation of common IM training for sub-specialists revealed the following three patterns: dual training; core training and separate training.

FXa inhibition by rivaroxaban modifies mechanisms associated with the pathogenesis of human abdominal aortic aneurysms.

AIMS: To evaluate if rivaroxaban, an oral factor Xa (FXa) inhibitor, could modify the expression in vitro of inflammatory and oxidative stress biomarkers in abdominal aortic aneurysmal (AAA) sites showing intraluminal thrombus. METHODS: AAA sites with intraluminal mural thrombus were obtained from six patients undergoing elective AAA repair. In addition, control abdominal aortic samples were obtained from six organ donors. AAA sites were incubated in the presence and absence of 50 nmol l-1 rivaroxaban. RESULTS: AAA sites showing thrombus demonstrated higher content of FXa than control. Interleukin-6 levels released from AAA [Control: median: 23.45 (interquartile range: 16.17-37.15) vs. AAA: median: 153.07 (interquartile range: 100.80-210.69) pg ml-1  mg tissue-1 , P < 0.05] and the expression levels of nitric oxide synthase 2 were significantly higher in AAA than in control. The protein expression level of NADPH oxidase subunits gp67-and gp91-phox, but did not gp47-phox, were also significantly higher in the AAA sites than in control. Addition of rivaroxaban to AAA sites explants significantly reduced the release of interleukin-6 [median: 51.61 (interquartile range: 30.87-74.03) pg ml-1  mg tissue-1 , P < 0.05 with respect to AAA alone] and the content of nitric oxide synthase 2, gp67 and gp91-phox NADPH subunits. The content of matrix metallopeptidase 9 was significantly higher in the AAA sites as compared to control. Rivaroxaban also reduced matrix metallopeptidase 9 content in AAA sites to similar levels to control. CONCLUSIONS: FXa inhibition by rivaroxaban exerted anti-inflammatory and antioxidative stress properties in human AAA sites, suggesting a role of FXa in these mechanisms associated with the pathogenesis of AAA.

Clinical and epidemiological differences between men and women with systemic sclerosis: a study in a Spanish systemic sclerosis cohort and literature review.

OBJECTIVES: The low overall prevalence of systemic sclerosis (SSc) and the low proportion of male patients have resulted in a scarcity of studies assessing sex differences in Ssc patients, and contradictory results have often been show among those studies that have been performed. METHODS: A prospective study was conducted with the Spanish RESCLE register to analyse the influence of gender on survival of SSc patients. RESULTS: In total, 1506 SSc patients (1341 women, 165 men) were recruited from 21 centres. Older age at onset (OR 1.02), shorter time from onset to diagnosis (OR 0.96), smoking (OR 2.57), interstitial lung disease (ILD) (OR 1.58), less predisposition to sicca syndrome and to antinuclear antibody positivity (OR 0.29 and 0.43, respectively), and higher compliance with the ACR 1980 criteria (OR 1.79) were independently associated with the male sex. During follow-up, 30.4% of men versus 14.6% of women died (p<0.001). Survival at 10 years from the onset of symptoms was 75.3% for men and 92.9% for women (p<0.001), and the difference remained after selecting only SSc-related deaths (85.6% vs. 96.1%, p<0.001). The mortality predictive factors were diffuse SSc (OR 2.26), ILD (OR 1.82), digital ulcers (OR 1.38), tendon friction rubs (OR 1.74), male sex (OR 1.53), increased age at onset (OR 1.13) and isolated PH (considering only deaths from diagnosis), both in the overall (OR 3.63) and female cohorts (OR 3.97). The same risk factors were observed in the male cohort, except for isolated PH and ILD. CONCLUSIONS: The present study confirms the existence of epidemiological, clinical, laboratory and prognostic gender differences in systemic sclerosis patients.

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.

Systemic involvement in primary Sjogren's syndrome evaluated by the EULAR-SS disease activity index: analysis of 921 Spanish patients (GEAS-SS Registry).

OBJECTIVE: To evaluate systemic involvement in primary SS in a large cohort of Spanish patients using the EULAR-SS disease activity index (ESSDAI) definitions. METHODS: Systemic involvement was characterized using ESSDAI definitions for the 10 clinical domains (constitutional, lymphadenopathy, glandular, articular, cutaneous, pulmonary, renal, peripheral nervous system, central nervous system and muscular). ESSDAI scores at diagnosis, during follow-up and cumulated at the last visit were calculated. RESULTS: The cohort consisted of 921 patients. After a mean follow-up of 75 months, 77 (8%) patients still had an ESSDAI score of zero at the last visit. Organ by organ, the percentage of patients who developed activity during the follow-up (ESSDAI score ≥ 1 at any time) ranged between 1.4% and 56%, with articular, pulmonary and peripheral neurological involvement being the most common. Logistic multivariate regression analysis showed the following features at diagnosis and had the closest association with systemic activity (statistically significant independent variables in at least two domains): cryoglobulinaemia in five domains; anaemia, lymphopenia and low C3 levels in three domains each and age <35 years in two domains. Sicca features, ANA and RF at diagnosis were not associated with a higher cumulated activity score in any clinical domain. CONCLUSION: Primary SS is undeniably a systemic disease, with the joints, lungs, skin and peripheral nerves being the most frequently involved organs. Cytopenias, hypocomplementaemia and cryoglobulinaemia at diagnosis strongly correlated with higher cumulated ESSDAI scores in the clinical domains. Clinically the ESSDAI provides a reliable picture of systemic involvement in primary SS.

Analysis of two autoimmunity genes, IRAK1 and MECP2, in giant cell arteritis.

OBJECTIVES: The Xq28 region, containing IRAK and MECP2, represent a common susceptibility locus for a high number of autoimmune diseases. Our aim in the present study was to evaluate the influence of the IRAK1 and MECP2 autoimmunity-associated genetic variants in the giant cell arteritis (GCA) susceptibility and its clinical subphenotypes. METHODS: We analysed a total of 627 female biopsy-proven GCA patients and 1,520 female healthy controls of Spanish Caucasian origin. Two polymorphisms, rs1059702 and rs17345, located at IRAK1 and MECP2, respectively, were genotyped using TaqMan® allelic discrimination assays. RESULTS: No association with any of the analysed polymorphisms was evident when genotype and allele frequencies were compared between GCA patients and controls (rs1059702: allelic p-value=0.699, OR=0.96, CI 95% 0.80-1.17; rs17435: allelic p-value=0.994, OR=1.00, CI 95% 0.84-1.19). Likewise, the subphenotype analysis yield similar negative results. CONCLUSIONS: We have assessed for the first time the possible role of IRAK1 and MECP2 autoimmune disease-associated polymorphisms in GCA. Our data suggest that IRAK1 rs1059702 and MECP2 rs17435 genetic variants do not play a significant role in GCA susceptibility or severity.

Synovial fluid eosinophilia: a case series with a long follow-up and literature review.

OBJECTIVES: To establish the frequency and describe the characteristics of a cohort of patients with SF eosinophilia (SFE) and a long clinical follow-up. A systematic review of the literature on this topic was performed. METHODS: From November 2005 to May 2010, 982 consecutive arthrocentesis procedures performed at a tertiary care hospital were reviewed. Clinical and analytical data of patients with SFE at the time of diagnosis and during follow-up until 31 January 2012, were recorded. According to the percentage of eosinophils in SF, SFE was classified as minor (<10%) or major (>10%). Also, a literature search of all publications on eosinophilic synovitis found in MEDLINE, EMBASE and Web of Science without publication date restrictions was performed. RESULTS: Eosinophils in SF were found in 10 of 982 (1.02%) patients: minor SFE was recorded in three patients, all of them with haemorrhagic fluid and without peripheral eosinophilia. Major SFE was found in seven patients, and only two of them had peripheral eosinophilia. In six patients, an underlying cause of the arthritis was found. Only one patient was classified as having idiopathic SFE. Most SFE promptly resolved with NSAIDs without relapses or new deformities. The literature search identified 56 patients with SFE; 49 of them (88%) had major SFE and 7 (12%) had minor SFE. CONCLUSIONS: Eosinophils are infrequently found in SF, and in most cases peripheral eosinophilia was not detected. Most patients with SFE had a benign course with prompt resolution and few relapses.

Efficacy of canakinumab in a patient with adult-onset glucocorticoid-resistant periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, a polygenic or multifactorial condition, is the most frequent autoinflammatory disease in children. There is increasing evidence that some patients may have a disease onset during adulthood. With regard to PFAPA syndrome treatment, single medium-to-high doses of glucocorticoids during flares constitute the therapy of choice in children and adults, colchicine may be useful in some patients, and tonsillectomy has been reported of utility mainly in paediatric patients. Interleukin-1 (IL-1) blockers have been sporadically used with good response in glucocorticoid-resistant cases. We report a patient with an adult onset of glucocorticoid-resistant PFAPA syndrome and inconsistent response to colchicine and anakinra, who later achieved a complete and sustained response to canakinumab. Although canakinumab seems to be a good therapeutic option in paediatric and adult patients with refractory PFAPA syndrome, the best anti-IL-1 agent and the sequence of administration have to be still determined in well-designed clinical trials.

Autoimmune disease-associated CD226 gene variants are not involved in giant cell arteritis susceptibility in the Spanish population.

OBJECTIVES: CD226 genetic variants have been associated with a number of autoimmune diseases. The aim of this study was to investigate the potential implication of the CD226 loci in the susceptibility to and main clinical manifestations of giant cell arteritis (GCA). METHODS: A Spanish Caucasian cohort of 455 patients diagnosed with biopsy-proven GCA and 1414 healthy controls were included in the study. Three CD226 polymorphisms, rs727088, rs34794968 and rs763361, were genotyped using the TaqMan® allelic discrimination technology. PLINK software was used for the statistical analyses. RESULTS: No significant association between the CD226 polymorphisms and susceptibility to GCA was found (rs727088: p=0.92, OR=1.01, CI 95% 0.86-1.18; rs34794968: p=0.61, OR=1.04, CI 95% 0.89-1.22; rs763361: p=0.88, OR=0.99, CI 95% 0.84-1.16). Similarly, when patients were stratified according to the specific clinical features of GCA such as polymyalgia rheumatica, visual ischaemic manifestations or irreversible occlusive disease, no association was observed either between the case subgroups and the control set or between GCA patients with and without the specific features of the disease. Furthermore, the haplotype analysis revealed no significant association with the clinical manifestations of the disease. CONCLUSIONS: Our results show that the three CD226 polymorphisms analysed do not play a relevant role in the susceptibility to GCA and clinical manifestations of this vasculitis.

C-Reactive Protein versus Erythrocyte Sedimentation Rate: Implications Among Patients with No Known Inflammatory Conditions.

BACKGROUND: Measurements of C-reactive protein (CRP) concentration and erythrocyte sedimentation rate (ESR) are frequently ordered jointly in clinical practice. AIM: To investigate the factors associated with discordances between CRP concentration and ESR in adults. METHODS: We conducted a cross-sectional study of 1472 adults with no known inflammatory disorders (44.5% male; median age, 52 years; range, 18-91 years), randomly selected from a municipality in Spain. The participants underwent simultaneous measurements of ESR, serum CRP, and interleukin-6 concentrations. Alcohol consumption, smoking, and physical activity were evaluated by questionnaire. Body mass index (BMI) measurement and metabolic syndrome criteria were available for all participants. RESULTS: Most (n = 1123, 74.9%) of the participants showed normal CRP and ESR values. Sixty-nine (4.6%) participants showed high CRP and ESR values. Seventy-two (4.8%) participants showed a discordant pattern of high ESR and normal CRP values, which was associated with age after adjusting for sex, alcohol consumption, physical activity, BMI, and the presence of metabolic syndrome (odds ratio [OR], 1.052; 95% CI, 1.034-1.071; P < .001). A total of 208 (13.8%) participants showed a discordant pattern of high CRP and normal ESR values, which was associated with BMI after adjusting for covariates (OR, 1.099; 95% CI, 1.064-1.136; P < .001). BMI appeared to be the main determinant of serum CRP concentrations in this population. Serum interleukin-6 concentrations were positively associated with the discordant pattern of high CRP and normal ESR values. CONCLUSION: In this general adult population with no overt inflammatory disease, the discordant pattern of high ESR and normal CRP was associated with greater age, whereas the pattern of high CRP and normal ESR was associated with higher BMI.

[Asymptomatic osteonecrosis of the hip in HIV-infected patients]. / Osteonecrosis asintomática de la cadera en los pacientes infectados por el virus de inmunodeficiencia humana.

BACKGROUND: Osteonecrosis (ON) of the hip in human immunodeficiency virus (HIV)-infected patients has been related to corticosteroid use, dyslipidemia, alcoholism, lipodystrophy, antiretroviral drug use, and HIV infection, itself. The aim of this study was to evaluate the prevalence of silent ON of the hip in HIV-infected patients and its association with several risk factors. METHODS: From a total of 1200 patients followed up at the HIV clinic of Xeral-Cies Hospital in Vigo (Spain), we selected those diagnosed with HIV infection before January 2006, aged 20-70 years, who came to the clinic during the period of March to May 2008. Patients with a diagnosis of ON of the hip and those with current symptoms were excluded. A magnetic resonance imaging (MRI) study of the hips was performed. RESULTS: Ninety-seven Caucasian patients (68 men) with a median age of 44 years were included. ON of the hip was detected in 4 patients (4.1%), with bilateral involvement in 2 patients. All 4 patients were men, with a median age of 44.5 years. Several risk factors for ON of the hip were recorded in each patient. CD4 lymphocyte nadir (P=0.034), percentage of patients with CDC stage C (P=0.039), and number of patients with previous corticosteroid treatment (P=0.042) were significantly different between patients with ON of the hip and those with normal MRI findings. CONCLUSIONS: The prevalence of asymptomatic ON of the hip in HIV-infected patients was 4.1%. The most important risk factors for developing this condition were corticosteroid treatment, lower CD4 lymphocyte nadir, and AIDS-defining disease. Antiretroviral treatment was not associated with osteonecrosis.

Comparison of the Birmingham Vasculitis Activity Score and the Five-Factor Score to Assess Survival in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Study of 550 Patients From Spain (REVAS Registry).

OBJECTIVE: To compare the accuracy of the Birmingham Vasculitis Activity Score (BVAS), version 3, and the Five Factor Score (FFS), version 1996 and version 2009, to assess survival in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: A total of 550 patients with AAV (41.1% with granulomatosis with polyangiitis, 37.3% with microscopic polyangiitis, and 21.6% with eosinophilic granulomatosis with polyangiitis), diagnosed between 1990 and 2016, were analyzed. Receiver operating characteristic (ROC) curves and multivariable Cox analysis were used to assess the relationships between the outcome and the different scores. RESULTS: Overall mortality was 33.1%. The mean ± SD BVAS at diagnosis was 17.96 ± 7.82 and was significantly higher in nonsurvivors than in survivors (mean ± SD 20.0 ± 8.14 versus 16.95 ± 7.47, respectively; P < 0.001). The mean ± SD 1996 FFS and 2009 FFS were 0.81 ± 0.94 and 1.47 ± 1.16, respectively, and were significantly higher in nonsurvivors than in survivors (mean ± SD 1996 FFS 1.17 ± 1.07 versus 0.63 ± 0.81 [P < 0.001] and 2009 FFS 2.13 ± 1.09 versus 1.15 ± 1.05 [P < 0.001], respectively). Mortality rates increased according to the different 1996 FFS and 2009 FFS categories. In multivariate analysis, BVAS, 1996 FFS, and 2009 FFS were significantly related to death (P = 0.007, P = 0.020, P < 0.001, respectively), but the stronger predictor was the 2009 FFS (hazard ratio 2.9 [95% confidence interval 2.4-3.6]). When the accuracy of BVAS, 1996 FFS, and 2009 FFS to predict survival was compared in the global cohort, ROC analysis yielded area under the curve values of 0.60, 0.65, and 0.74, respectively, indicating that 2009 FFS had the best performance. Similar results were obtained when comparing these scores in patients diagnosed before and after 2001 and when assessing the 1-year, 5-year, and long-term mortality. Correlation among BVAS and 1996 FFS was modest (r = 0.49; P < 0.001) but higher than between BVAS and the 2009 FFS (r = 0.28; P < 0.001). CONCLUSION: BVAS and FFS are useful to predict survival in AAV, but the 2009 FFS has the best prognostic accuracy at any point of the disease course.

Factors influencing erythrocyte sedimentation rate in adults: New evidence for an old test.

The erythrocyte sedimentation rate (ESR) is a routine test for inflammation. Few studies have investigated the potential influence of lifestyle factors and common metabolic abnormalities on the ESR. This study investigates the influence of demographic factors, alcohol consumption, smoking, physical activity, obesity, and metabolic syndrome on the ESR in adults.This cross-sectional study covered 1472 individuals (44.5% males; age range, 18-91 years) randomly selected from the population of a Spanish municipality. The ESR was measured using a standardized method. We assessed habitual alcohol consumption in standard drinking units, along with tobacco smoking, regular physical exercise (by questionnaire), body mass index, and variables defining metabolic syndrome. Multivariate analyses were performed, including mean corpuscular volume and hemoglobin concentration in the models.The ESR was higher in females than in males, and increased steadily with age. Median ESR of females was 2-fold higher than that of males, and median ESR of individuals aged >65 years was 2-fold higher than that of individuals in the youngest category (ages 18-35 years). Body mass index, presence of metabolic syndrome, and smoking were independently and positively associated with higher ESR values. Light alcohol drinkers and individuals with high regular physical activity displayed lower ESR values than did alcohol abstainers and individuals with low physical activity, respectively.ESR varies greatly with age and sex, and corresponding reference values are proposed. Lifestyle factors (physical activity, smoking, and alcohol consumption) and common metabolic abnormalities (obesity and related metabolic syndrome) may also influence ESR values.