Targeting the underlying pathophysiology in X-linked hypophosphatemic rickets in adults.

X-linked hypophosphatemic rickets (XLHR) is a life-long phosphate waste disorder that presents in early childhood with lower limb deformities, stunted growth, and bone and joint pain. In adults, osteomalacia and fractures may develop, aggravating bone and joint pain, stiffness, and disability. A 50-year-old woman with XLHR was referred to Rheumatology for incapacitating pain in her left lower limb with gait impairment. A pseudofracture was identified in the radiography of long bones, and secondary hyperparathyroidism was also observed. Treatment was optimized, and marked clinical improvement occurred. The authors review and discuss the underlying pathophysiology of this disease and its adequate management.

Predictors of hospitalization in patients with systemic lupus erythematosus: a 10-year cohort study.

INTRODUCTION/OBJECTIVES: Recognising systemic lupus erythematosus (SLE) patients at higher risk for hospitalization, aiming at developing tailored management strategies, may help minimize admissions and improve long-term health outcomes. Our study aimed to identify predictors for hospitalization in patients with SLE. METHOD: Cohort study of SLE patients followed in a referral centre. All hospitalizations from study baseline up to 120 months were identified, and the primary indication for admission was categorized as follows: (1) SLE disease activity; (2); infection; and (3) other conditions. Demographic, clinical, and laboratory parameters at baseline were sought as predictors of hospitalization for (i) any cause, (ii) disease activity, and (iii) infection using survival analysis with Kaplan-Meier curves and log-rank tests. Potential predictors were further tested using multivariate Cox proportional hazards regression models. RESULTS: We included 398 patients (median follow-up: 120 months). The incidence rate of hospitalization was 17.7 per 100 patient-years. The most frequent indications for hospitalization were SLE disease activity (29.4%) and infection (23.4%). In multivariate analysis, male gender, age > 50 years, antiphospholipid antibodies positivity (aPL), SLEDAI-2 K > 5, organ damage, and prednisone daily dose (PDN) predicted hospitalization for any cause. SLEDAI-2 K > 5, aPL, PDN, and IS medication predicted hospitalization for active SLE. Male gender, prior biopsy-proven lupus nephritis, aPL, organ damage, and ongoing treatment with high-risk IS predicted hospitalization for infection. Treatment with antimalarials was associated with a lower risk of hospitalization for any cause and for infection. CONCLUSIONS: Positive aPL identifies SLE patients presenting a higher risk of hospitalization, while medication with antimalarials was associated with a lower risk. Key Points • Positive aPL is predictive of hospitalization for any medical condition, disease activity, and infection • Organ damage is predictive of hospitalization for any condition and infection • Antimalarials are predictive of a lower risk of hospitalization for any condition and infection.

Antimalarial treatment and minimizing prednisolone are associated with lower risk of infection in SLE: a 24-month prospective cohort study.

INTRODUCTION/OBJECTIVES: Infections are a major cause of morbidity and death in systemic lupus erythematosus (SLE). Perfecting the understanding of contributors to infection burden in SLE is pivotal to improve management and outcomes. This study aims to identify clinical predictors of infection in SLE. METHOD: We conducted a prospective cohort study at a referral SLE clinic. Infections were identified at each visit and categorized as (a) any type, (b) serious, (c) non-serious, and (d) bacterial. Survival analysis followed by multivariate Cox regression with an estimation of hazard ratios (HR) with 95% confidence intervals (95%CI) was performed. RESULTS: We included 259 patients during a mean follow-up of 23.3 ± 5.7 months. The incidence rate of infection of any type was 59.3 cases per 100 patient-years. Multivariate Cox models showed that (a) prednisolone ≥ 7.5 mg/day (HR = 1.95, 95%CI 1.26-3.03) and female gender (HR = 2.08, 95%CI 1.12-3.86) were associated with higher risk of infection of any type; (b) prednisolone ≥ 10 mg/day was associated with higher (HR = 4.32, 95%CI 1.39-13.40), and antimalarials with lower risk (HR = 0.18, 95%CI 0.06-0.51) of serious infection; (c) female gender (HR = 1.92, 95%CI 1.04-3.57) and prednisolone ≥ 7.5 mg/day (HR = 1.89, 95%CI 1.21-2.96) were associated with higher risk of non-serious infection; (d) antimalarials were associated with lower (HR = 0.49, 95%CI 0.26-0.93) and female gender (HR = 5.12; 95%CI 1.62-16.18) with higher risk of bacterial infection. CONCLUSIONS: The risk of infection was higher in females in this young, well-controlled, low-comorbidity SLE cohort. Antimalarials were associated with lower and prednisolone ≥ 7.5 mg with higher risk of infection. Key Points • Lupus patients treated with prednisolone ≥ 7.5 mg/day were 89% more likely to present infections. • Lupus patients receiving prednisolone ≥ 10 mg/day were four times more likely to present serious infections. • Lupus patients receiving antimalarials were 82% less likely to present serious infections.

Shear-Wave Elastography Evaluation of Major Salivary Glands in Primary Sjögren's Syndrome.

OBJECTIVES: Salivary glands ultrasonography has recently been shown to be useful in the diagnosis of Primary Sjögren's Syndrome (pSS). Shear-wave elastography (SWE) is a promising tool for the quantitative assessment of tissues stiffness, but studies evaluating its role in pSS diagnosis are limited. This study aimed at investigating the diagnostic performance of SWE in pSS. MATERIALS AND METHODS: Cross-sectional study including patients fulfilling the 2016 ACR/EULAR classification criteria for pSS and healthy subjects. The four major salivary glands were assessed using SGUS. B-mode scans were rated using the Hocevar score, and shear-wave velocity (SWV) values were obtained using SWE. Intraclass-correlation coefficient (ICC) estimates were used to assess reliability. Cut-off values for differentiating pSS patients from healthy subjects were calculated using Receiver-Operating Characteristics (ROC) curves. RESULTS: We included 50 pSS and 25 healthy subjects. Inter-rater reliability of SWE was moderate (ICC=0.64) and intra-rater reliability was moderate to good (ICC= 0.73 to 0.83). Total SWV (2.09 m/s (0.32); p < 0.001), parotid SWV (2.25 m/s (0.40)) and submandibular SWV (1.92 m/s (0.38)) were significantly higher in pSS patients. Total and parotid SWV presented good diagnostic performance for pSS diagnosis (AUROC= 0.80 and 0.81, respectively). The Hocevar score demonstrated excellent diagnostic performance (AUROC= 0.98) and combining it with total SWV did not result in statistically significant improvement (p=0.301). CONCLUSIONS: SWE may contribute to the diagnosis of pSS. Large prospective studies including sicca and secondary SS patients, as well as the standardisation of SWE protocols, are warranted to assess the role of SWE in pSS management.

Juvenile Paget's Disease: Report of a successful treatment throughout the complete growth of a patient with a missense TNFRSF11B mutation.

INTRODUCTION: Juvenile Paget's Disease (JPD) is an ultra-rare inherited osteopathy featuring markedly accelerated bone turnover. Several clinical characteristics have been reported, including bone deformities developing in childhood and hearing loss. CASE REPORT: We report the case of a 2 ¾-year-old girl that presented with progressive bowing of both legs since the age of 2, lower limb pain and frequent falls with one consequent femur fracture. Plain radiographs revealed osteoectasia of the long bone's diaphysis, and laboratory tests showed extremely high serum total alkaline phosphatase levels. A missense mutation on the gene TNFRSF11B was identified in homozygosity, and the diagnosis of JPD was made. Treatment with bisphosphonates was initiated early and markedly improved lower limb bowing and pain. The patient reached adulthood with normal height, minor bone deformities, and no functional impairment. Despite the good skeletal symptom's response, bisphosphonates failed to prevent or improve sensorineural hearing loss. CONCLUSIONS: In this clinical case, early treatment with bisphosphonates was effective for the treatment of JPD skeletal deformities. New therapeutic strategies need to be developed to better control the extraskeletal manifestations of JPD.

Patient-Physician discordance in assessment of disease activity in Rheumatoid Arthritis patients.

BACKGROUND: In rheumatoid arthritis (RA), global disease activity is commonly evaluated, from the patient's and the physician's perspective, through a 100mm visual analogue scale (VAS) and plays an important role in the assessment of diseases activity and treatment decisions. Our aim was to determine patient-physician discordance in the assessment of disease activity and to explore its determinants. METHODS: Cross sectional study including RA patients (ACR/EULAR 2010 classification criteria). The discrepancy between patients-physicians (∆PPhGA) was defined as PGA minus PhGA, and a difference > |20mm| was considered as "discordant". Correlation between ∆PPhGA and other variables was assessed through Pearson's correlation and comparison between groups through t-test. Variables with p < 0.05 or considered clinically relevant were included in multivariable linear regression analysis to identify determinants for ∆PPhGA. A p < 0.05 was considered statistically significant. RESULTS: In total, 467 patients with RA were included (81.2% female; mean age 63.9% ± 12.2 years). PGA and PhGA were discordant in 61.7% of the cases. The proportion of concordance increased (p < 0.01) when considering only patients in remission (DAS 28 3V < 2.6). In multivariable analysis (R2adjusted=0.27), VAS-pain-patient (ß 0.74, 95% CI 0.62-0.88, p=0.00) and TJC (ß 0.16, 95% CI 0.45-0.48, p=0.02) remained associated with a higher ∆PPhGA. CONCLUSION: Our study confirmed that a significant discrepancy between patients and physicians in the assessment of global disease activity is frequent in clinical practice, and is probably due to valorization of different parameters by the two groups.

Remission and low disease activity matrix tools: results in real-world rheumatoid arthritis patients under anti-TNF therapy.

BACKGROUND: Remission/ low disease activity (LDA) are the main treatment goals in rheumatoid arthritis (RA) patients. Two tools showing the ability to predict golimumab treatment outcomes in patients with RA were published. OBJECTIVES: To estimate the real-world accuracy of two quantitative tools created to predict RA remission and low disease activity. METHODS: Multicenter, observational study, using data from the Rheumatic Diseases Portuguese Register (Reuma.pt), including biologic naïve RA patients who started an anti-TNF as first-line biologic and with at least 6 months of follow-up. The accuracy of two matrices tools was assessed by likelihood-ratios (LR), sensitivity (SN), specificity (SP), positive predictive value (PPV), negative predictive value (NPV) and area under the ROC curve (AUC). RESULTS: 674 RA patients under first-line anti-TNF (266 etanercept, 186 infliximab, 131 adalimumab, 85 golimumab, 6 certolizumab pegol) were included. The median (IQR) age was 53.4 (44.7-61.1) years and the median disease duration was 7.7 (3.7-14.6) years. The majority were female (72%). Most patients were RF and/or ACPA positive (75.5%) and had erosive disease (54.9%); 58.6% had comorbidities. At 6-months, 157 (23.3%) patients achieved remission (DAS28 ESR < 2.6) and 269 (39.9%) LDA (DAS28 ESR ≤ 3.2). Area under the curve for remission in this real-world sample was 0.756 [IC 95% (0.713-0.799)] and for LDA was 0.724 [IC 95% (0.686 -0.763)]. The highest LR (8.23) for remission state was obtained at a cut-off ≥ 67%, with high specificity (SP) (99.6%) but low sensitivity (SN) (3.2%). A better balance of SN and SP (65.6% and 73.9%, respectively) was observed for a cut-off >30%, with a LR of 2.51, PPV of 43.3% and NPV of 87.6%. CONCLUSION: In this population, the accuracy of the prediction tool was good for remission and LDA. Our results corroborate the idea that these matrix tools could be helpful to select patients for anti-TNF therapy.

Carvedilol-Induced Liver Injury, a Rare Cause of Mixed Hepatitis: A Clinical Case.

INTRODUCTION: Drug-induced liver injury is an increasingly prevalent consequence of the diversification of available therapeutic weapons, mostly idiosyncratic and with several possible mechanisms and patterns of specific damage for each drug. Carvedilol, a widely used non-selective alpha and beta blocker leads, in very rare cases, to injury of the bile ducts by toxic metabolites, resulting in a mixed-pattern hepatitis with possible progression to chronic cholestatic syndrome and cirrhosis. The authors report the second known case of this important toxicity. CLINICAL CASE: An 83-year-old woman was admitted to the Internal Medicine ward for etiological clarification of a mixed-pattern hepatitis. Clinical history was unremarkable and structural, infectious, and autoimmune causes were excluded by blood tests and imaging exams, ultimately leading to the diagnosis of toxic hepatitis that was further confirmed by liver biopsy with morphologic findings of mixed-pattern liver injury. Carvedilol, started 6 months before, was deemed the causal agent since it was the only drug with a clinically, temporally, analytically, and histologically compatible pattern. The withdrawal of the drug resulted in slow reversal of the referred abnormalities. CONCLUSION: In very rare cases, carvedilol can cause important liver toxicity as a chronic cholestatic syndrome which can evolve to cirrhosis. It should be taken in consideration as causal agent in similar cases and stopped immediately upon suspicion, as the timely withdrawal results in reversion of the pathological findings.

INTRODUÇÃO: A lesão hepática induzida por drogas é uma consequáncia cada vez mais prevalente da diversificação de armas terapáuticas disponíveis. São principalmente reacções idiossincráticas, com vários mecanismos possíveis e padrões de danos específicos de cada droga. O carvedilol, bloqueador alfa e beta não seletivo amplamente utilizado, leva, em casos muito raros, a lesão dos canalículos biliares por metabólitos tóxicos, resultando numa hepatite padrão misto com possível progressão a síndrome colestática crónica e potencialmente cirrose. Os autores relatam o segundo caso conhecido desta importante toxicidade. CASO CLÍNICO: Uma mulher idosa foi admitida na enfermaria de Medicina Interna para esclarecimento etiológico de uma hepatite de padrão misto. Esta investigação que incluiu uma extensa pesquisa de antecedentes, exclusão de causas estruturais, infecciosas e auto-imunes por análises sanguíneas e exames de imagem, levou ao diagnóstico de uma hepatite tóxica, confirmada por biópsia hepática com achados morfológicos de um padrão misto de lesão hepática. O carvedilol, introduzido 6 meses antes, foi considerado o agente causal dado ser a única substância com padrão clínico, temporal, analítico e histológico compatível. A retirada do medicamento resultou na reversão lenta das referidas anormalidades. DISCUSSÃO: Em casos muito raros, o carvedilol pode causar toxicidade hepática importante sob a forma de síndrome colestástica crónica que pode evoluir até uma cirrose hepática. Deve ser tomado em consideração como potencial agente causal em casos semelhantes e retirado imediatamente após suspeita, sendo que a suspensão atempada resulta na reversão completa dos achados patológicos.

Perspectivas jurídicas da interrupção da gravidez com infecção pelo vírus zika a partir das consequencias médicas, emocionais e sociais / Juridical perspectives of interruption of pregnancy with zika virus infection regarding medical, emotional and social consequences

INTRODUCTION: The Zika virus was identified in 1947 in Rhesus monkeys in the Republic of Uganda and isolated in humans in 1952 in the same country. Up to 2007 there were few cases of human infection in African and Asian countries. The first outbreak of the Zika virus occurred in Brazil in 2015, becoming a serious public health problem due to the increase in the number of cases of microcephaly in infected pregnant women. OBJECTIVE: To describe the legal abortion at Zika virus infection during pregnancy regarding medical, emotional and social consequences. perspectives of abortion for the pregnant woman with Zika virus regarding the medical, emotional and social consequences. METHODS: This is a documentary study based on documents about abortion and its outcomes in Brazil. Technical norms, textbooks, indexed articles of Scopus and PubMed, documents extracted from international human rights treaties and conventions, and legal documents on the subject were used. It was decided to direct the text based on the experiences of each theme on abortion and its outcomes in Brazil, with a synthesis of the current scenario. RESULTS: Recognizing the exceptional nature of this situation, it is sought to confer an interpretation according to the Constitution and Article 128 of the Criminal Code, based on an analogical application, which seeks to protect the physical and mental health of women infected by the Zika virus. It is possible to qualify the practice of abortion in these circumstances as atypical conduct by the state of necessity, excluding the unlawfulness by comparing with articles 23, I and 24 of the Penal Code. CONCLUSION: Authorizing the termination of pregnancy after diagnosis of the virus Zika guarantees women the free exercise of their reproductive rights, which is not confused with state imposition of abortion or eugenic practice.

INTRODUÇÃO: O vírus Zika foi identificado em 1947 em macacos Rhesus na República de Uganda e isolado em seres humanos, em 1952, no mesmo país. Até 2007 registram-se poucos casos da infecção em humanos em países africanos e asiáticos. O primeiro surto epidêmico do vírus Zika ocorreu no Brasil, em 2015, tornando-se grave problema de saúde pública devido a elevação do número de casos de microcefalia em gestantes infectadas. OBJETIVO: Descrever as perspectivas jurídicas do aborto para a gestante com vírus Zika a partir das consequências médicas, emocionais e sociais. MÉTODO: Trata-se de estudo documental realizado a partir de documentos sobre o aborto e seus desfechos no Brasil. Utilizaram-se normativas técnicas, livros-texto, artigos em bases indexadas do Scopus e PubMed, documentos extraídos de tratados e convenções internacionais de Direitos Humanos e documentos jurídicos acerca da temática. Optou-se por direcionar o texto a partir das experiências de cada temática sobre o aborto e seus desfechos no Brasil, com síntese do cenário atual. RESULTADOS: Reconhecendo o caráter excepcional dessa situação, busca-se conferir uma interpretação conforme a Constituição e o artigo 128 do Código Penal, a partir de uma aplicação analógica, que busque tutelar a saúde física e psíquica das mulheres contaminadas pelo vírus Zika. É possível qualificar a prática do aborto nessas circunstâncias como conduta atípica pelo estado de necessidade, excluindo a ilicitude por equiparação aos artigos 23, I e 24, do Código Penal. CONCLUSÃO: Autorizar a interrupção da gravidez após o diagnóstico do vírus Zika garante às mulheres o livre exercício dos seus direitos reprodutivos, o que não se confunde com imposição estatal do aborto ou prática eugênica.