Luis Corral-Gudino

Epidemiology of Paget's disease of bone: A systematic review and meta-analysis of secular changes

CONTEXT Several studies have suggested that the prevalence and severity of PDB have fallen in recent years. The magnitude of this trend and its globalization have not been well established. OBJECTIVE The objective of this study is to estimate the pooled magnitude of the changes in the prevalence of PDB and as a secondary objective, to make up a world atlas of PDB prevalence. METHODS A systematic review of English and non-English articles using MEDLINE (1946 to 2013) and EMBASE (1980 to 2013) was the method used. Search terms included epidemiology, incidence, prevalence, cohort studies, osteitis deformans or Pagets disease of bone. Studies with incidence and/or prevalence rate for PDB were included. Two authors independently extracted the data using predefined data fields and quality assessment. A pooled analysis based on random-effects models was carried out for secular trends. RESULTS Twenty-eight articles documented the prevalence of PDB; four articles the incidence and two articles the rate of new referrals. The prevalence of PDB varied greatly between the different countries, from 0.00028% in Japan to 5.4% in the UK. There were available data on changes in prevalence from two different surveys over two different time frames in Europe and New Zealand. In all but one city (Turin), a drop in the prevalence of PDB was recorded (pooled OR 0.64; 95% CI 0.45-0.91). CONCLUSION The incidence and prevalence rates of PDB vary widely between populations but both have decreased in most regions over recent years. The changes are heterogeneous however and within countries, the largest changes have been in areas that previously had a high prevalence. The reasons for these changes remain unclear at present but are likely to be due to an interaction between genetic factors and environmental triggers which may differ in different regions.

Overall survival, renal survival and relapse in patients with microscopic polyangiitis: a systematic review of current evidence

OBJECTIVE There are limited data on the long-term prognosis of microscopic polyangiitis (MPA). A systematic review was performed to estimate the survival, renal survival and relapse rates in patients with MPA. METHODS Articles included in MEDLINE and EMBASE databases were reviewed. Randomized or non-randomized trials, cohort, case-control and cases-series studies of patients with MPA diagnosed according to Chapel Hill Consensus Conference definitions, a high rate of biopsy-confirmed diagnosis, follow-up >1 year and follow-up losses <10%. Two independent authors using a predefined questionnaire for evaluating the quality and risk of bias for each study extracted data. RESULTS Eighteen studies for MPA prognosis (n = 940) and six for MPA outcomes after transplantation (n = 65) were included. Survival rates were 77-100% at 1 year, 46-80% at 5 years and 60-80% at 10 years. Higher mortality density occurred within the first months after diagnosis. Vasculitis was the cause of death in 32-50% of patients. Relapses were detected in 19-39% of cases (median time to relapse 15-43 months). Renal graft survival was 85-94% at 1 year and 51-87% at 5 years. Age, renal involvement and immunosuppressive treatment were related to mortality. Lower relapse rate was achieved with 12 vs 6 CYC pulses. CONCLUSION Evidence regarding MPA prognosis is weak. MPA mortality is mainly concentrated in the first months after diagnosis. Fewer than 50% of deaths are related to MPA activity. MPA long-term prognosis is less severe, although relapses are frequent. End-stage renal failure is a frequent complication of MPA, and renal transplantation could be an effective therapy in these patients. Early diagnosis, early initiation of a tailored therapy according to risk factors and a longer follow-up of the patients are needed.

Common susceptibility alleles and SQSTM1 mutations predict disease extent and severity in a multinational study of patients with Paget's disease

Pagets disease of bone (PDB) has a strong genetic component. Here, we investigated possible associations between genetic variants that predispose to PDB and disease severity. Allelic variants identified as predictors of PDB from genome‐wide association studies were analyzed in 1940 PDB patients from the United Kingdom, Italy, Western Australia, and Spain. A cumulative risk allele score was constructed by adding the variants together and relating this to markers of disease severity, alone and in combination with SQSTM1 mutations. In SQSTM1‐negative patients, risk allele scores in the highest tertile were associated with a 27% increase in disease extent compared with the lowest tertile (p < 0.00001) with intermediate values in the middle tertile (20% increase; p = 0.0007). The effects were similar for disease severity score, which was 15% (p = 0.01) and 25% (p < 0.00001) higher in the middle and upper tertiles, respectively. Risk allele score remained a significant predictor of extent and severity when SQSTM‐positive individuals were included, with an effect size approximately one‐third of that observed with SQSTM1 mutations. A genetic risk score was developed by combining information from both markers, which identified subgroups of individuals with low, medium, and high levels of severity with a specificity of 70% and sensitivity of 55%. Risk allele scores and SQSTM1 mutations both predict extent and severity of PDB. It is possible that with further refinement, genetic profiling may be of clinical value in identifying individuals at high risk of severe disease who might benefit from enhanced surveillance and early intervention.

Use of noninvasive ventilation on internal wards for elderly patients with limitations to respiratory care: a cohort study

Eur J Clin Invest 2010; 41 (1): 59–69

Polymorphisms in Autophagy Genes Are Associated with Paget Disease of Bone

Paget disease of bone (PDB) is a focal bone disorder affecting the skeleton segmentally. The main alteration resides in osteoclasts that increase in size, number and activity. Many osteoclasts have cytoplasmic inclusions that have been associated with protein aggregates, increasing the evidences of a possible deregulation of autophagy in the development of the PDB. Autophagy starts with encapsulation of the target into a double-membrane-bound structure called an “autophagosome.” It has been reported that at least 18 ATG genes (autophagy-related genes) are involved in autophagosome formation. We have studied the distribution of genotypes of the ATG2B rs3759601, ATG16L1 rs2241880, ATG10 rs1864183 and ATG5 rs2245214 polymorphisms in a Spanish cohort of subjects with PDB and compared with healthy subjects. Our results show that being a carrier of the C allele of the ATG16L1 rs2241880 and the G allele of ATG5 rs2245214 polymorphisms were associated with an increased risk of developing PDB, whereas being a carrier of the T allele of ATG10 rs1864183 polymorphism decreased the risk of suffering the disease in our series. This is the first report that shows an association between autophagy and Paget Disease of Bone and requires further confirmation in other series.

Paget’s disease of bone is not associated with common polymorphisms in interleukin-6, interleukin-8 and tumor necrosis factor alpha genes

BACKGROUND Cytokines, specially interleukin (IL)-6, play an important role in the differentiation and activation of osteoclasts and might be involved in osteoblast stimulation in Pagets disease of bone (PDB). OBJECTIVES The aim of this study was to investigate the association of polymorphisms in IL-6, IL-8 and tumor necrosis factors-alpha (TNFA) genes among Spanish patients with PDB. METHODS We studied four single nucleotide polymorphisms (-174 G>C IL-6, -251 T>A IL-8, -238 G>A TNFA and -308 G>A TNFA) in 172 PDB patients and 150 healthy controls. Distribution of alleles and pro-inflammatory genotypes were studied for association with the presence of the disease and with clinical and laboratory data, as well as the response to bisphosphonate treatment in PDB patients. RESULTS We found no statistically significant association between genotype and allele distribution of any of the cytokines polymorphism studied and PDB. No association between the clinical and therapeutic characteristics of PDB and the investigated polymorphism were found. CONCLUSIONS This study does not support the hypothesis that the analyzed IL6, IL8 and TNFA polymorphism are associated with PDB.

Collagen type 1 (COL1A1) Sp1 binding site polymorphism is associated with osteoporotic fractures but not with bone density in post-menopausal women from the Canary Islands: a preliminary study

Background and aims: An association between the polymorphism for transcription factor Sp1 in the gene COL1A1 and low bone density (BMD) and osteoporotic fractures has been described but not confirmed for all races and ages. The aim of this preliminary work was to ascertain whether this association is present in women from the Canary Islands. Methods: Polymerase chain reaction RFLP was used to determine COL1A1 polymorphism Sp1 in 199 consecutive outpatient post-menopausal Caucasian women from the Canary Islands, aged 50–70 years. BMD was measured at lumbar spine and hip by DXA and at third lumbar vertebrae by QCT. Prevalent vertebral fractures were recorded on standard lateral X-ray film. Non-vertebral osteoporotic fractures were registered by medical record and self-reported history. Biochemical markers (serum osteocalcin, tartrate-resis-tant acid phosphatase), blood calcium and phosphate were also assessed. Results: Distribution genotypes were 113 (50.8%) GG homozygotes, 73 (36.7%) Ss heterozygotes and 7 (3.5%) TT homozygotes. All patients with osteoporotic fractures carried the GG allele more frequently than TT homozygotic women. The odds ratio was 3.01 (95% CI 1.6–5.7) for prevalent vertebral fractures (n=62) and 2.33 (95% CI 1.2–4.4) for all osteoporotic fractures (n=65) for the T-carrying allele vs TT homozygotic women. There was no difference in BMD measured by DXA or QCT, nor in bone markers, blood calcium or phosphate. Conclusions: This preliminary study confirmed that the presence of at least one copy of the T allele is associated with osteoporotic fractures, but not with low BMD, in women from the Canary Islands.

Long-term follow-up of microscopic polyangiitis, 17-year experience at a single center

BACKGROUND Long-term prognoses of Wegener granulomatosis (WG) and Churg-Strauss syndrome (CSS) are known; however, few data exist on long-term prognoses for microscopic polyangiitis (MPA). Our aim was to analyse the prognoses of MPA. METHODS Cohort study with retrospective selection of patients. Twenty-two patients admitted to our Hospital (1990-2006) with biopsy-proven MPA were studied. The start date for entry into the study was the date of diagnosis. Statistical analysis was performed to look for prognostic factors for survival. RESULTS MPA patients were followed-up for a median of 78 (5-131) months. MPA patients were treated with cyclophosphamide (Cy) plus corticosteroid (Cs) (59%) or Cs alone (41%). Seven MPA patients died. Cumulative MPA patient survival at 1, 5, and 10 years were 85% (75-95%), 85% (75-95%), and 74% (60-88%) in those treated with Cy plus Cs and 50% (32-68%), 36% (14-58%), and 0% (0-30%) in those treated with Cs alone, respectively (P=0.04). Disease extent index <5 (P=0.02) and age <65 years (P=0.02) were associated with improved survival rates in MPA patients treated with Cy. Five MPA (23%) patients relapsed after a median of 54 months (35-93). No variables were related to relapses. Despite treatment, 11MPA (50%) patients developed end-stage renal disease after a median of 9 months (0-53). CONCLUSIONS Most MPA patients had life-threatening renal or lung involvement at diagnosis. Patients not treated with immunosuppressants had a poorer prognosis. The long-term prognosis of MPA patients who survived 6 months post diagnosis was good, although renal survival rates are low.

VAV3 Gene Polymorphism Is Associated with Paget's Disease of Bone

BACKGROUND AND AIMS Pagets disease of bone (PDB) is a focal bone disorder affecting the skeleton segmentally. The disease affects osteoclasts which increase in size, number, and activity. One of the etiopathogenic hypotheses is that the disease is genetic. It has been reported that Rho GEF Vav3 is an essential factor in the regulation of osteoclast function, and alteration of the VAV3 gene could influence the development of the disease. The aim of our study was to perform an association study between variants of the VAV3 gene and the risk of developing Pagets disease of bone. PATIENTS AND METHODS The genotypic and allelic distribution of the VAV3 c.892A>T/p.T298S (rs7528153) polymorphism was compared between a cohort of 238 Spanish subjects with PDB and a cohort of 253 healthy subjects. RESULTS Our results indicated that individuals carrying the VAV3 rs7528153 TT genotype were at a significantly increased risk of developing PDB (p < 0.001, odds ratio [OR] = 3.15, 95% confidence interval [95% CI] = 1.77-5.61). CONCLUSIONS These results suggest that inheriting the VAV3 rs7528153 polymorphism is a likely susceptibility factor for developing Pagets disease of bone.

Polymorphisms in genes implicated in base excision repair (BER) pathway are associated with susceptibility to Paget's disease of bone

Pagets disease of bone (PDB) is a chronic bone metabolic disorder. Currently, PDB is the second most frequent bone disorder. PDB is a focal disorder affecting the skeleton segmentally but the cause of which is unknown. It has been hypothesised that somatic mutations could be responsible for the mosaicism described in PDB patients. Therefore, our hypothesis is that defective response to DNA damage may lead to somatic mutations favouring an increased risk of PDB. So that we have analysed polymorphisms in DNA repair genes involved in the BER, NER and DSBR pathways in order to evaluate the role of these variants in modulating PDB risk. We found statistically significant differences in genotypic and allelic distribution for polymorphisms in genes implicated in the BER pathway. Our results showed that carrying the allele T of XRCC1 rs1799782 polymorphism and the allele G of APEX rs1130409 polymorphism increased the risk of developing PDB. These polymorphisms could cause a lower DNA repair efficiency and this might lead to local somatic mutations favouring bone metabolic alterations characteristic of PDB. This is the first report showing an association between polymorphism in genes implicated in the BER pathway with PDB.