Severe osteomalacia with multiple insufficiency fractures secondary to intravenous iron therapy in a patient with Rendu-Osler-Weber syndrome

This case report describes a 65-year-old man with a Rendu-Osler-Weber syndrome with secondary chronic anaemia, who received multiple intravenous (IV) iron infusions and sustained diffuse bone pain secondary to multiple insufficiency fractures. Laboratory study confirmed fibroblast growth factor 23 (FGF-23)-mediated hypophosphatemia as the main cause of a severe osteomalacia induced by ferric carboxymaltose (FCM). After 3 months or oral phosphate replacement and switching to iron sucrose, serum phosphate levels were normalized and patient improved clinically. Some drugs can induce asymptomatic hypophosphatemia, which if sustained, can lead to a severe osteomalacia with multiple skeletal fractures. This complication has also been described with IV iron therapy. This case report describes a patient with Rendu-Osler-Weber syndrome with chronic iron deficiency anaemia, recurrently treated with FCM, who developed a severe osteomalacia with multiple skeletal fractures. Laboratory study showed hypophosphatemia, with high ALP and high FGF-23. Images studies confirmed bone mass loss and multiple insufficiency fractures. A Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG PET/CT) did not show hidden tumor, so a diagnosis of FCM-induced hypophosphatemic osteomalacia was performed. Phosphate replacement improved clinical symptoms of the patient. Intravenous iron therapy, mainly FCM form, can cause hypophosphatemia, and in some cases induce a severe osteomalacia with multiple fractures, so it seems advisable to monitor serum phosphate levels in high risk patients, as those who receive repeated dose

High sensitivity and negative predictive value of the DETECT algorithm for an early diagnosis of pulmonary arterial hypertension in systemic sclerosis : application in a single center

Pulmonary arterial hypertension (PAH) is one of the most relevant causes of death in systemic sclerosis. The aims of this study were to analyse the recently published DETECT algorithm comparing it with European Society of Cardiology/European Respiratory Society (ESC/ERS) 2009 guidelines: as screening of PAH; (2) identifying median pulmonary arterial pressure (mPAP) ≥21 mmHg; and (3) determining any group of pulmonary hypertension (PH). Eighty-three patients fulfilling LeRoy's systemic sclerosis diagnostic criteria with at least right heart catheterization were studied retrospectively. Clinical data, serological biomarkers, echocardiographic and hemodynamic features were collected. SPSS 20.0 was used for statistical analysis. According to right heart catheterization findings, 35 patients with PAH and 28 with no PH met the standards for DETECT algorithm analysis: 27.0% of patients presented with functional class III/IV. Applying DETECT, the sensitivity was 100%, specificity 42.9%, the positive predictive value 68.6% and the negative predictive value 100%, whereas employing the ESC/ERS guidelines these were 91.4%, 85.7%, 88.9% and 89.3%, respectively. There were no missed diagnoses of PAH using DETECT compared with three patients missed (8.5%) using ESC/ERS guidelines. The DETECT algorithm also showed greater sensitivity and negative predictive value to identify patients with mPAP ≥21 mmHg or with any type of PH. The DETECT algorithm is confirmed as an excellent screening method due to its high sensitivity and negative predictive value, minimizing missed diagnosis of PAH. DETECT would be accurate either for early diagnosis of borderline mPAP or any group of PH

Standardized incidence ratios and risk factors for cancer in patients with systemic sclerosis: Data from the Spanish Scleroderma Registry (RESCLE)

Aim: Patients with systemic sclerosis (SSc) are at increased risk of cancer, a growing cause of non-SSc-related death among these patients. We analyzed the increased cancer risk among Spanish patients with SSc using standardized incidence ratios (SIRs) and identified independent cancer risk factors in this population. Material and methods: Spanish Scleroderma Registry data were analyzed to determine the demographic characteristics of patients with SSc, and logistic regression was used to identify cancer risk factors. SIRs with 95% confidence intervals (CIs) relative to the general Spanish population were calculated. Results: Of 1930 patients with SSc, 206 had cancer, most commonly breast, lung, hematological, and colorectal cancers. Patients with SSc had increased risks of overall cancer (SIR 1.48, 95% CI 1.36-1.60; P < 0.001), and of lung (SIR 2.22, 95% CI 1.77-2.73; P < 0.001), breast (SIR 1.31, 95% CI 1.10-1.54; P = 0.003), and hematological (SIR 2.03, 95% CI 1.52-2.62; P < 0.001) cancers. Cancer was associated with older age at SSc onset (odds ratio [OR] 1.22, 95% CI 1.01-1.03; P < 0.001), the presence of primary biliary cholangitis (OR 2.35, 95% CI 1.18-4.68; P = 0.015) and forced vital capacity <70% (OR 1.8, 95% CI 1.24-2.70; P = 0.002). The presence of anticentromere antibodies lowered the risk of cancer (OR 0.66, 95% CI 0.45-0.97; P = 0.036). Conclusions: Spanish patients with SSc had an increased cancer risk compared with the general population. Some characteristics, including specific autoantibodies, may be related to this increased risk

Impact of interstitial lung disease on the survival of systemic sclerosis with pulmonary arterial hypertension

To assess severity markers and outcomes of patients with systemic sclerosis (SSc) with or without pulmonary arterial hypertension (PAH-SSc/non-PAH-SSc), and the impact of interstitial lung disease (ILD) on PAH-SSc. Non-PAH-SSc patients from the Spanish SSc registry and PAH-SSc patients from the Spanish PAH registry were included. A total of 364 PAH-SSc and 1589 non-PAH-SSc patients were included. PAH-SSc patients had worse NYHA-functional class (NYHA-FC), worse forced vital capacity (FVC) (81.2 +/- 20.6% vs 93.6 +/- 20.6%, P < 0.001), worse tricuspid annular plane systolic excursion (TAPSE) (17.4 +/- 5.2 mm vs 19.9 +/- 6.7 mm, P < 0.001), higher incidence of pericardial effusion (30% vs 5.2%, P < 0.001) and similar prevalence of ILD (41.8% vs. 44.9%). In individuals with PAH-SSc, ILD was associated with worse hemodynamics and pulmonary function tests (PFT). Up-front combination therapy was used in 59.8% and 61.7% of patients with and without ILD, respectively. Five-year transplant-free survival rate was 41.1% in PAH-SSc patients and 93.9% in non-PAH-SSc patients (P < 0.001). Global survival of PAH-SSc patients was not affected by ILD regardless its severity. The multivariate survival analysis in PAH-SSc patients confirmed age at diagnosis, worse NYHA-FC, increased PVR, reduced DLCO, and lower management with up-front combination therapy as major risk factors. In conclusion, in PAH-SSc cohort risk of death was greatly increased by clinical, PFT, and hemodynamic factors, whereas it was decreased by up-front combination therapy. Concomitant ILD worsened hemodynamics and PFT in PAH-SSc but not survival regardless of FVC impairment

Impact of interstitial lung disease on the survival of systemic sclerosis with pulmonary arterial hypertension

To assess severity markers and outcomes of patients with systemic sclerosis (SSc) with or without pulmonary arterial hypertension (PAH-SSc/non-PAH-SSc), and the impact of interstitial lung disease (ILD) on PAH-SSc. Non-PAH-SSc patients from the Spanish SSc registry and PAH-SSc patients from the Spanish PAH registry were included. A total of 364 PAH-SSc and 1589 non-PAH-SSc patients were included. PAH-SSc patients had worse NYHA-functional class (NYHA-FC), worse forced vital capacity (FVC) (81.2 ± 20.6% vs 93.6 ± 20.6%, P &lt; 0.001), worse tricuspid annular plane systolic excursion (TAPSE) (17.4 ± 5.2 mm vs 19.9 ± 6.7 mm, P &lt; 0.001), higher incidence of pericardial effusion (30% vs 5.2%, P &lt; 0.001) and similar prevalence of ILD (41.8% vs. 44.9%). In individuals with PAH-SSc, ILD was associated with worse hemodynamics and pulmonary function tests (PFT). Up-front combination therapy was used in 59.8% and 61.7% of patients with and without ILD, respectively. Five-year transplant-free survival rate was 41.1% in PAH-SSc patients and 93.9% in non-PAH-SSc patients (P &lt; 0.001). Global survival of PAH-SSc patients was not affected by ILD regardless its severity. The multivariate survival analysis in PAH-SSc patients confirmed age at diagnosis, worse NYHA-FC, increased PVR, reduced DLCO, and lower management with up-front combination therapy as major risk factors. In conclusion, in PAH-SSc cohort risk of death was greatly increased by clinical, PFT, and hemodynamic factors, whereas it was decreased by up-front combination therapy. Concomitant ILD worsened hemodynamics and PFT in PAH-SSc but not survival regardless of FVC impairment

Características clínicas, epidemiológicas y valor pronóstico de anticuerpos específicos poco prevalentes en la esclerodermia

La esclerodèrmia (ES) és una malaltia autoimmune multisistèmica en la qual l'expressió d'anticossos específics té implicacions clínic pronòstiques importants. Els anticossos són útils per predir les manifestacions clíniques de la malaltia, i l'expressió de cada un d'ells confereix un pronòstic diferent. Els anticossos més prevalents de l'ES estan ben estudiats per la disponibilitat de les tècniques de detecció dels mateixos. No obstant això, hi ha anticossos específics menys prevalents i menys estudiats però que clínicament s'associen a afecció orgànica greu. L'objectiu d'aquest treball va ser estudiar la prevalença, les associacions clíniques i la supervivència de dos anticossos poc prevalents a l'ES: l'anti-RNA polimerasa III (anti-RNAP III) i l'anti-RNPC3 o anti-U11 / U12. En el primer estudi es van seleccionar 221 pacients amb ES i es van comparar els pacients positius per anti-RNAP III (mesurat mitjançant ELISA i immunoblot) enfront dels negatius per anti-RNAP III. Descrivim una prevalença de l'anti-RNAP III de 11.8%. Clínicament els pacients que van expressar anti-RNAP III tenien més freqüència d'ES subtipus cutani difusa, artritis, crisi renal esclerodèrmica (CRE) i hipertensió arterial (HTA). No obstant això, no hem trobat associació amb càncer ni amb èctasi vascular antral gàstrica. En relació a la supervivència, no hi va haver diferències en les corbes de Kaplan Meier entre els dos grups. Els factors independents associats a pitjor pronòstic en la cohort anti-RNAP III van ser la crisi renal esclerodèrmica, la malaltia pulmonar intersticial (MPI) amb FVC <50% i la hipertensió arterial pulmonar En el segon estudi, es van seleccionar 447 pacients amb ES de 2 diferents centres (Barcelona n = 286 i Milà n = 161), i es van comparar els pacients positius per anti-RNPC3 (mesurat mitjançant PMAT) enfront dels pacients negatius. La prevalença trobada va ser de l'4.3%. Els pacients amb anti-RNPC3 van presentar una major freqüència de MPI, de MPI greu, de malaltia pulmonar terminal i una pitjor supervivència. No es va evidenciar associació amb càncer ni amb afecció gastrointestinal. Els factors de risc independents associats a pitjor supervivència van ser l'edat i la presència d'HAP. Els factors de risc independents associats a pitjor pronòstic (mort i / o manifestacions greus) van ser la presència d'anti-RNPC3, el subtipus cutani difusa, l'edat a l'inici, la presència de MPI, l'HAP i l'expressió de ATA I. En el subgrup amb EPI, la supervivència lliure de mort o manifestacions greus va ser menor en els pacients que van expressar anti-RNPC3 comparat amb els pacients que van expressar ATA I. El fenotip clínic descrit en els pacients que expressen anti-RNPC3 determinat per PMAT és similar a què es va definir en l'estudi l'anti-RNPC3 on es va detectar per IP. Per tant, la tècnica de PMAT pot ser útil per determinar anti-RNPC3 en la pràctica clínica diària. Podem concloure que l'anti-RNAP III i l'anti-RNPC3 són anticossos poc prevalents però amb gran transcendència clínica ja que prediuen un perfil clínic determinat, i la seva expressió pot ajudar-nos en el seguiment i tractament dels pacients.La esclerodermia (ES) es una enfermedad autoinmune multisistémica en la que la expresión de anticuerpos específicos tiene implicaciones clínico pronósticas importantes. Los anticuerpos son útiles para predecir las manifestaciones clínicas de la enfermedad, y la expresión de cada uno de ellos confiere un pronóstico diferente. Los anticuerpos más prevalentes de la ES están bien estudiados debido a la disponibilidad de las técnicas de detección de los mismos. Sin embargo, existen anticuerpos específicos que menos prevalentes y menos estudiados pero que clínicamente se asocian a afección orgánica grave. El objetivo de este trabajo fue estudiar la prevalencia, las asociaciones clínicas y la supervivencia de dos anticuerpos poco prevalentes en la ES: el anti-RNA polimerasa III (anti-RNAP III) y el anti-RNPC3 o anti-U11/U12. En el primer estudio se seleccionaron 221 pacientes con ES y se compararon los pacientes positivos para anti-RNAP III (medido mediante ELISA e inmunoblot) frente a los negativos para anti-RNAP III. Describimos una prevalencia del anti-RNAP III de 11.8%. Clínicamente los pacientes que expresaron anti-RNAP III tenían más frecuencia de ES subtipo cutáneo difusa, artritis, crisis renal esclerodérmica (CRE) e hipertensión arterial (HTA). Sin embargo, no hemos encontrado asociación con cáncer ni con ectasia vascular antral gástrica. En relación a la supervivencia, no hubo diferencias en las curvas de Kaplan Meier entre ambos grupos. Los factores independientes asociados a peor pronóstico en la cohorte anti-RNAP III fueron la crisis renal esclerodérmica, la enfermedad pulmonar intersticial (EPI) con FVC < 50% y la hipertensión arterial pulmonar En el segundo estudio, se seleccionaron 447 pacientes con ES de 2 diferentes centros (Barcelona n = 286 y Milán n = 161), y se compararon los pacientes positivos para anti-RNPC3 (medido mediante PMAT) frente a los pacientes negativos. La prevalencia encontrada fue del 4.3%. Los pacientes con anti-RNPC3 presentaron una mayor frecuencia de EPI, de EPI grave, de enfermedad pulmonar terminal y una peor supervivencia. No se evidenció asociación con cáncer ni con afección gastrointestinal. Los factores de riesgo independientes asociados a peor supervivencia fueron la edad y la presencia de HAP. Los factores de riesgo independientes asociados a peor pronóstico (muerte y/o manifestaciones graves) fueron la presencia de anti-RNPC3, el subtipo cutáneo difusa, la edad al inicio, la presencia de EPI, la HAP y la expresión de ATAI. En el subgrupo con EPI, la supervivencia libre de muerte o manifestaciones graves fue menor en los pacientes que expresaron anti-RNPC3 comparado con los pacientes que expresaron ATAI. El fenotipo clínico descrito en los pacientes que expresan anti-RNPC3 determinado por PMAT es similar al que se definió en el estudio el anti-RNPC3 se detectó por IP. Por lo tanto, la técnica de PMAT puede ser útil para determinar anti-RNPC3 en la práctica clínica diaria. Podemos concluir que el anti-RNAP III y el anti-RNPC3 son anticuerpos poco prevalentes pero con gran trascendencia clínica ya que predicen un perfil clínico determinado, y su expresión puede ayudarnos en el seguimiento y tratamiento de los pacientes.Systemic Sclerosis (SSc) is an autoimmune disease in which the expression of specific antibodies has important clinical and prognostic implications. Antibodies are useful for predicting the clinical features of the disease, and the expression of each of them confers a different prognosis. The most prevalent antibodies in SSc are well studied due to the availability of detection techniques. However, some specific antibodies are less prevalent and less studied, but are associated with serious organic disease. The objective of this study was to determine the prevalence, clinical associations and survival of two antibodies with low prevalence in SSc: anti-RNA polymerase III (anti-RNAP III) and anti-RNPC3 (or anti-U11/U12). In the first study, 221 SSc patients were selected. Patients with positivity for anti-RNAP III were compared with anti-RNAP III negative patients. A prevalence of 11.8% was found. Patients who expressed anti-RNAP III had higher frequency of diffuse cutaneous SSc, arthritis, scleroderma renal crisis (SRC) and arterial hypertension. However, we have not found any association with cancer or gastric antral vascular ectasia. Regarding survival, there were no differences in the Kaplan Meier curves between both groups. The independent risk factors associated with a worse prognosis in the anti-RNAP III cohort were SRC, interstitial lung disease (ILD) with FVC < 50% and pulmonary arterial hypertension (PAH). In the second study, 447 SSc patients were selected from two different sites (Barcelona n=286 and Milan n=161), and anti-RNPC3+ patients were compared with negative patients. The prevalence found was 4.3%. Anti-RNPC3+ patients had a higher frequency of ILD, severe ILD terminal lung disease and worse survival. No association with cancer or gastrointestinal disease was observed. The independent risk factors associated with worse survival were age and the presence of PAH. The independent risk factors associated with worse prognosis (death and/or severe events) were the presence of anti-RNPC3, diffuse cutaneous subtype, age at onset, ILD, PAH and the expression of anti-topoisomerase I (ATA). Compared to ATA patients, anti-RNPC3 patients exhibited a shorter time to event free survival. The clinical phenotype described in anti-RNPC3+ patients determined by PMAT is similar to that defined in the study in which anti-RNPC3 was detected by immunoprecipitation. Therefore, the PMAT technique can be useful to determine anti-RNPC3 in daily clinical practice. We can conclude that anti-RNAP III and anti-RNPC3 are low prevalent antibodies that have great clinical significance since they predict specific profile, and their expression can help us in the monitoring and treatment of patients.Universitat Autònoma de Barcelona. Programa de Doctorat en Medicin

Quantitative videocapillaroscopy correlates with functional respiratory parameters: a clue for vasculopathy as a pathogenic mechanism for lung injury in systemic sclerosis

Abstract Background To determine whether lung involvement is related to microvascular perturbations, nailfold videocapillaroscopy (NVC) was performed in patients with systemic sclerosis (SSc). Methods A cross-sectional study was consecutively accomplished in 152 SSc patients. NVC, a pulmonary function test and echocardiography were undergone within a 3-month period. Finally, 134 patients with at least eight NVC (200× magnification) images were selected for quantitative and qualitative examinations. Results Patients with interstitial lung disease presented lower median capillary density (4.86/mm vs 5.88/mm, p = 0.005) and higher median of neoangiogenesis (0.56/mm vs 0.31/mm, p = 0.005). A higher quantity of neoangiogenesis capillaries was found in patients with pulmonary arterial hypertension (0.70/mm vs 0.33/mm, p = 0.008). Multivariate linear regression analysis established a correlation between neoangiogenesis and decreased forced vital capacity (FVC) (p < 0.001): for each capillary with neoangiogenesis visualized on average per 1 mm, FVC was 7.3% reduced. In qualitative NVC, a late pattern as defined by Cutolo was also associated with lower FVC (p = 0.018). The number of giant capillaries was associated with reduced diffusion capacity of the lung for carbon monoxide (DLCO) (p = 0.016); for each giant capillary per 1 mm, DLCO was 11.8% diminished. Conclusions A good correlation was observed between distinctive quantitative and qualitative NVC features with lung functional parameters such as FVC and DLCO. It is suggested that vasculopathy could play a role in SSc lung involvement

High sensitivity and negative predictive value of the DETECT algorithm for an early diagnosis of pulmonary arterial hypertension in systemic sclerosis : application in a single center

Pulmonary arterial hypertension (PAH) is one of the most relevant causes of death in systemic sclerosis. The aims of this study were to analyse the recently published DETECT algorithm comparing it with European Society of Cardiology/European Respiratory Society (ESC/ERS) 2009 guidelines: as screening of PAH; (2) identifying median pulmonary arterial pressure (mPAP) ≥21 mmHg; and (3) determining any group of pulmonary hypertension (PH). Eighty-three patients fulfilling LeRoy's systemic sclerosis diagnostic criteria with at least right heart catheterization were studied retrospectively. Clinical data, serological biomarkers, echocardiographic and hemodynamic features were collected. SPSS 20.0 was used for statistical analysis. According to right heart catheterization findings, 35 patients with PAH and 28 with no PH met the standards for DETECT algorithm analysis: 27.0% of patients presented with functional class III/IV. Applying DETECT, the sensitivity was 100%, specificity 42.9%, the positive predictive value 68.6% and the negative predictive value 100%, whereas employing the ESC/ERS guidelines these were 91.4%, 85.7%, 88.9% and 89.3%, respectively. There were no missed diagnoses of PAH using DETECT compared with three patients missed (8.5%) using ESC/ERS guidelines. The DETECT algorithm also showed greater sensitivity and negative predictive value to identify patients with mPAP ≥21 mmHg or with any type of PH. The DETECT algorithm is confirmed as an excellent screening method due to its high sensitivity and negative predictive value, minimizing missed diagnosis of PAH. DETECT would be accurate either for early diagnosis of borderline mPAP or any group of PH

Anti-U11/U12 Antibodies as a Rare but Important Biomarker in Patients with Systemic Sclerosis: A Narrative Review

Anti-nuclear (ANA) are present in approximately 90% of systemic sclerosis (SSc) patients and are key biomarkers in supporting the diagnosis and determining the prognosis of this disease. In addition to the classification criteria autoantibodies for SSc [i.e., anti-centromere, anti-topoisomerase I (Scl-70), anti-RNA polymerase III], other autoantibodies have been associated with important SSc phenotypes. Among them, anti-U11/U12 ribonucleoprotein (RNP) antibodies, also known as anti-RNPC-3, were first reported in a patient with SSc, but very little is known about their association and clinical utility. The U11/U12 RNP macromolecular complex consists of several proteins involved in alternative mRNA splicing. More recent studies demonstrated associations of anti-anti-U11/U12 antibodies with SSc and severe pulmonary fibrosis as well as with moderate to severe gastrointestinal dysmotility. Lastly, anti-U11/U12 autoantibodies have been strongly associated with malignancy in SSc patients. Here, we aimed to summarize the knowledge of anti-U11/U12/RNPC-3 antibodies in SSc, including their seroclinical associations in a narrative literature review