Pathophysiology of bone disease in chronic kidney disease: from basics to renal osteodystrophy and osteoporosis.

Chronic kidney disease (CKD) is a highly prevalent disease that has become a public health problem. Progression of CKD is associated with serious complications, including the systemic CKD-mineral and bone disorder (CKD-MBD). Laboratory, bone and vascular abnormalities define this condition, and all have been independently related to cardiovascular disease and high mortality rates. The "old" cross-talk between kidney and bone (classically known as "renal osteodystrophies") has been recently expanded to the cardiovascular system, emphasizing the importance of the bone component of CKD-MBD. Moreover, a recently recognized higher susceptibility of patients with CKD to falls and bone fractures led to important paradigm changes in the new CKD-MBD guidelines. Evaluation of bone mineral density and the diagnosis of "osteoporosis" emerges in nephrology as a new possibility "if results will impact clinical decisions". Obviously, it is still reasonable to perform a bone biopsy if knowledge of the type of renal osteodystrophy will be clinically useful (low versus high turnover-bone disease). However, it is now considered that the inability to perform a bone biopsy may not justify withholding antiresorptive therapies to patients with high risk of fracture. This view adds to the effects of parathyroid hormone in CKD patients and the classical treatment of secondary hyperparathyroidism. The availability of new antiosteoporotic treatments bring the opportunity to come back to the basics, and the knowledge of new pathophysiological pathways [OPG/RANKL (LGR4); Wnt-ß-catenin pathway], also affected in CKD, offers great opportunities to further unravel the complex physiopathology of CKD-MBD and to improve outcomes.

Serum metabolomic profiling identifies potential biomarkers in arthritis in older adults: an exploratory study.

BACKGROUND: Seronegative elderly-onset rheumatoid arthritis (EORA)neg and polymyalgia rheumatica (PMR) have similar clinical characteristics making them difficult to distinguish based on clinical features. We hypothesized that the study of serum metabolome could identify potential biomarkers of PMR vs. EORAneg. METHODS: Arthritis in older adults (ARTIEL) is an observational prospective cohort with patients older than 60 years of age with newly diagnosed arthritis. Patients' blood samples were compared at baseline with 18 controls. A thorough clinical examination was conducted. A Bruker Avance 600 MHz spectrometer was used to acquire Nuclear Magnetic Resonance (NMR) spectra of serum samples. Chenomx NMR suite 8.5 was used for metabolite identification and quantification.Student t-test, one-way ANOVA, binary linear regression and ROC curve, Pearson's correlation along with pathway analyses were conducted. RESULTS: Twenty-eight patients were diagnosed with EORAneg and 20 with PMR. EORAneg patients had a mean disease activity score (DAS)-Erythrocyte Sedimentation Rate (ESR) of 6.21 ± 1.00. All PMR patients reported shoulder pain, and 90% reported pelvic pain. Fifty-eight polar metabolites were identified. Of these, 3-hydroxybutyrate, acetate, glucose, glycine, lactate, and o-acetylcholine (o-ACh), were significantly different between groups. Of interest, IL-6 correlated with different metabolites in PMR and EORAneg suggesting different inflammatory activated pathways. Finally, lactate, o-ACh, taurine, and sex (female) were identified as distinguishable factors of PMR from EORAneg with a sensitivity of 90%, specificity of 92.3%, and an AUC of 0.925 (p < 0.001). CONCLUSION: These results suggest that EORAneg and PMR have different serum metabolomic profiles that might be related to their pathobiology and can be used as biomarker to discriminate between both diseases.

Imbalance Between Omega-6- and Omega-3-Derived Bioactive Lipids in Arthritis in Older Adults.

Elderly-onset rheumatoid arthritis (EORA) and polymyalgia rheumatica (PMR) are common rheumatic diseases in older adults. Oxylipins are bioactive lipids derived from omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFAs) that serve as activators or suppressors of systemic inflammation. We hypothesized that arthritis symptoms in older adults were related to oxylipin-related perturbations. Arthritis in older adults (ARTIEL) is an observational prospective cohort with 64 patients older than 60 years of age with newly diagnosed arthritis. Patients' blood samples at baseline and 3 months posttreatment were compared with 18 controls. A thorough clinical examination was conducted. Serum oxylipins were determined by mass spectrometry. Data processing and statistical analysis were performed in R. Forty-four patients were diagnosed with EORA and 20 with PMR. At diagnosis, EORA patients had a mean DAS28CRP (Disease Activity Score 28 using C-reactive protein) of 5.77 (SD 1.02). One hundred percent of PMR patients reported shoulder pain and 90% reported pelvic pain. Several n-6- and n-3-derived oxylipin species were significantly different between controls and arthritis patients. The ratio of n-3/n-6 PUFA was significantly downregulated in EORA but not in PMR patients as compared to controls. The top two candidates as biomarkers for differentiating PMR from EORA were 4-HDoHE, a hydroxydocosahexaenoic acid, and 8,15-dihydroxy-eicosatrienoic acid (8,15-diHETE). The levels of n-3-derived anti-inflammatory species increased in EORA after treatment. These results suggest that certain oxylipins may be key effectors in arthrtis in older adults and that the imbalance between n-6- and n-3-derived oxylipins might be related to pathobiology in this population.

Influence of age on the occurrence of adverse events in rheumatic patients at the onset of biological treatment: data from the BIOBADASER III register.

OBJECTIVES: To assess whether age, at the beginning of biologic treatment, is associated with the time a first adverse event (AE) appears in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), or psoriatic arthritis (PsA). METHODS: All patients in the BIOBADASER registry diagnosed with RA, AS, and PsA, and classified as young (< 25 years old), adult (25-64 years old), elderly (65-75 years old) or very elderly (> 75 years old) at start of biological treatment were included. Factors associated with the appearance of a first AE using adjusted incidence rate ratios (IRR) (Poisson regression) were analyzed. Survival to first AE was studied by Kaplan-Meier analysis and hazard ratios (HR) by Cox regression. RESULTS: 2483 patients were included: 1126 RA, 680 PsA, and 677 AS. Age group stratification was as follows: 63 young, 2127 adults, 237 elderly, and 56 very elderly. Regression model revealed an increased probability of suffering a first AE at age 65 years or older [IRR elderly: 1.42 (CI95% 1.13-1.77)]. Other characteristics associated with AE were female gender, the use of DMARDs, including methotrexate, the presence of comorbidities, and the time of disease duration. Factors that had the greatest impact on survival over a first AE were age > 75 years [HR 1.50 (1.01-2.24)] and female gender [HR 1.42 (1.22-1.64)]. CONCLUSION: Age at the start of treatment and female gender are key factors associated with the appearance of a first AE with biologics. Other factors related to patient status and treatment were also associated with a first AE in rheumatic patients treated with biologics.

Measuring inflammation in rheumatoid arthritis with a new clinical and ultrasound index: development and initial validation.

With the aim to develop and validate a clinical + ultrasound (US) inflammation score in rheumatoid arthritis (RA) for use in clinical practice, a mixed-method study was conducted. The theoretical development of the index was achieved with qualitative methodology (discussion group and Delphi survey). Subsequently, a cross-sectional study was carried out to analyse issues related to scoring and validation of the new index. RA patients underwent clinical [28 swollen and tender joints count, patient and physician global assessment (PhGA), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)], and US assessments [synovitis or tenosynovitis by grey-scale (GS) and power Doppler (PD) of 42 structures]. An index was created based on statistical models and expert interaction. Construct validity was tested by correlation with DAS28, SDAI, CDAI, and PhGA. Reliability was evaluated in a subgroup of patients with the intraclass correlation coefficient (ICC). US assessment, CRP, and swollen joints were the items that passed the prioritization phase (Delphi study). For the cross-sectional study, 281 patients were randomly divided into design (n = 141) and validation samples (n = 140). The combination of US sites chosen (7 bilaterally) detected the maximum proportion of synovitis and PD present. Three scoring methods were tested: semiquantitative (0-3 GS + 0-3 PD), dichotomous (0/1 GS + 0/1 PD), and qualitative (0/1 based on algorithm). All showed strong correlation with activity measures (ρ ≥ 0.60), and reliability (ICC 0.89-0.93). The index with best parameters of validity, feasibility, and reliability was the qualitative. The final index chosen was the sum of swollen joint count, US qualitative score, and CRP. The UltraSound Activity score is a valid and reliable measure of inflammation in RA equal to the sum of 28 SJC, a simplified (0/1) US assessment of 11 structures and CRP. It is necessary further investigation to demonstrate additional value over existing indices.

Impact of Host Genetics and Biological Response Modifiers on Respiratory Tract Infections.

Host susceptibility to respiratory tract infections (RTI) is dependent on both genetic and acquired risk factors. Repeated bacterial and viral RTI, such as pneumonia from encapsulated microorganisms, respiratory tract infections related to respiratory syncytial virus or influenza, and even the development of bronchiectasis and asthma, are often reported as the first symptom of primary immunodeficiencies. In the same way, neutropenia is a well-known risk factor for invasive aspergillosis, as well as lymphopenia for Pneumocystis, and mycobacterial infections. However, in the last decades a better knowledge of immune signaling networks and the introduction of next generation sequencing have increased the number and diversity of known inborn errors of immunity. On the other hand, the use of monoclonal antibodies targeting cytokines, such as tumor necrosis factor alpha has revealed new risk groups for infections, such as tuberculosis. The use of biological response modifiers has spread to almost all medical specialties, including inflammatory diseases and neoplasia, and are being used to target different signaling networks that may mirror some of the known immune deficiencies. From a clinical perspective, the individual contribution of genetics, and/or targeted treatments, to immune dysregulation is difficult to assess. The aim of this article is to review the known and newly described mechanisms of impaired immune signaling that predispose to RTI, including new insights into host genetics and the impact of biological response modifiers, and to summarize clinical recommendations regarding vaccines and prophylactic treatments in order to prevent infections.

Chronic arthritis in chikungunya virus infection. / Artritis crónica en la infección por virus de Chikunguña.

INTRODUCTION: Chikungunya virus infection causes arthralgia and arthritis in the acute phase of the disease but, in more than half of the cases, musculoskeletal manifestations can be prolonged over time and, in some cases, become chronic. Although polyarthralgia is the most frequent chronic manifestation, forms with polyarthritis, tenosynovitis and enthesopathy are also common. OBJECTIVE: To analyze the clinical characteristics of patients with persistent articular manifestations after infection with the Chikungunya virus. PATIENTS: Report of 3 cases of chronic arthritis after infection with chikungunya virus diagnosed at outpatient care in a university hospital of Catalonia, all of them imported after exposure in areas of epidemic infection between 2013-2015. RESULTS: All three patients had inflammatory joint pain for more than one year after acute disease (3, 2 and 1 years, respectively). In all cases, it appeared as polyarthritis with involvement of small joints of hands and feet (pseudorheumatoid arthritis-like). Laboratory tests showed a slight elevation of acute phase reactants, and analyses for immune markers were negative. Two of the patients required treatment with glucocorticoids and hydroxychloroquine. The course led to slow clinical improvement, but only one of them came to be completely asymptomatic. CONCLUSION: In the differential diagnosis of chronic polyarthritis, Chikungunya virus disease should also be considered in areas in which it is not endemic.

Coexistence of septic and crystal-induced arthritis: A diagnostic challenge. A report of 25 cases. / Coexistencia de artritis séptica y microcristalina: un reto diagnóstico. A propósito de 25 casos.

OBJECTIVE: Septic arthritis is a medical emergency and crystal-induced arthritis is a risk factor for its development. If both occur simultaneously, crystal-induced arthritis may mask the diagnosis of infection and delay antibiotic therapy. METHOD: Retrospective analysis of patients with coexistence of septic and crystal-induced arthritis. We included only patients with isolation of crystals in synovial fluid analysis and positive culture of synovial fluid and/or blood culture. RESULTS: A total of 25 patients (17 men and 8 women) with a mean age of 67 years. The most commonly affected joint was the knee. In synovial fluid cytological studies, the most frequently identified crystals were monosodium urate. Risk factors included diabetes and chronic renal failure. The most frequently isolated germs were methicillin-sensitive S. aureus (48%), methicillin-resistant S. aureus (12%) and Mycobacterium tuberculosis (12%). In all, 36% of subjects required surgical drainage (excluding those caused by M. tuberculosis). Clinical outcome was favorable in 56%, although intercurrent complications were usual (40%). Mortality was 8%. CONCLUSIONS: Coexistence of septic and crystal-induced arthritis represents a diagnostic challenge and requires a high index of suspicion. Gout was the most prevalent crystal-induced arthritis. S. aureus was the most commonly causative pathogen, with a high rate of methicillin-resistant S. aureus infection. If treated early, the outcome is usually favorable, making synovial fluid microbiological study imperative.

Immune-mediated inflammatory diseases differently affect IGRAs' accuracy for latent tuberculosis infection diagnosis in clinical practice.

BACKGROUND: Clinical accuracy of IGRAs remains unclear on patients with immune-mediated inflammatory diseases (IMIDs). Here, we assess the impact of immunosuppressants and IMIDs on QuantiFERON-TB Gold In-Tube (QFN-G-IT) and T-SPOT.TB accuracy. METHODS: Patients with IMIDs who required latent tuberculosis infection (LTBI) screening were enrolled and classified into: (i) 50 patients with inflammatory rheumatic diseases, (ii) 50 patients with psoriasis and (iii) 30 patients with Crohn's disease. A total of 44 healthy individuals without immunosuppression were also included as controls. Tuberculin skin test (TST), T-SPOT.TB and QFN-G-IT assays were performed. IGRAs were performed following manufacturer's instructions. RESULTS: Immunosuppressant's intake was more frequent on patients with Crohn's disease and psoriasis. Positive IGRAs and TST results were reduced in Crohn's disease patients, whereas rate of indeterminate T-SPOT.TB results was increased in this group with respect to the other IMIDs analysed and controls. When IFN-γ response was studied, the levels of this cytokine after mitogen stimulation were significantly lower in Crohn's and inflammatory rheumatic diseases than in psoriasis. Interestingly, psoriatic patients were the only ones not receiving corticosteroids. Furthermore, a negative correlation was observed between the IFN-γ secreted after mitogen stimulation and corticosteroids dose. CONCLUSIONS: IMIDs seem to negatively affect the clinical accuracy of IGRAs, being Crohn's disease patients the most affected individuals due to their concomitant drug-profile and impaired immune response.

Use of IFN-γ and IP-10 detection in the diagnosis of latent tuberculosis infection in patients with inflammatory rheumatic diseases.

OBJECTIVES: Biologic agents are used against rheumatic diseases, however, they increase the risk of developing severe infections and diseases such as tuberculosis. We aimed to determine the benefits of IP-10 detection to diagnose latent tuberculosis infection (LTBI) in patients with inflammatory rheumatic diseases on different immunosuppressive drug regimens, and compare these results with IFN-γ detection. MATERIALS AND METHODS: We included 64 patients with inflammatory rheumatic diseases. We used QuantiFERON Gold In-Tube (QFN-G-IT) and T-SPOT.TB to detect IFN-γ production, and an in-house ELISA for IP-10 detection from the previous QFN-G-IT stimulated samples. We assessed the combined use of IFN-γ release assays (IGRAs) and IP-10 test, and analyzed the influence of immunotherapy on the tests performance. RESULTS: We obtained 34.9% positive results by T-SPOT.TB, 25.0% by QFN-G-IT and 31.3% by IP-10 test. The combined use of IGRAs and IP-10 detection increased significantly the amount of positive results (p < 0.0001). Treatment intake had no significant effect on in vitro tests (p > 0.05). CONCLUSIONS: IP-10 and IFN-γ detection is comparable and their combined use could increase the number of positive results in the diagnosis of LTBI in rheumatic patients. The tested assays were not influenced by rheumatoid immunosuppressive therapy. Thus, IP-10 could be of use in the development of new and improved LTBI diagnostic tools.

Treatment with ustekinumab in a Spanish cohort of patients with psoriasis and psoriatic arthritis in daily clinical practice.

After approval of the use of ustekinumab for treatment of moderate to severe psoriasis, patients with psoriatic arthritis have treated with this drug in daily clinical practice. The aims of this study were to describe baseline characteristics and evolution of a cohort of patients with psoriasis and psoriatic arthritis treated with ustekinumab and to compare differences between patients who discontinued treatment and those who maintained. A retrospective multicenter observational study including patients who had received ustekinumab for a minimum of 3 months from 2009 to 2015 was performed. The baseline characteristics of the cohort of patients, the main indication for treatment, number and percentage of patients who maintained and discontinued treatment, reasons for discontinuation and differences between patients who discontinued and maintained ustekinumab were evaluated. Fifty-eight patients were included. The main indication was dermatological (72.4% of cases), and treatment with ustekinumab was maintained in most patients (62.1% of cases) with low discontinuation by side effects and rheumatological lack of efficacy. Discontinuation of ustekinumab was correlated with more number of obese patients, less presence of plaque psoriasis and more number of previous biological therapies. Ustekinumab demonstrated efficacy and safety in the management of patients with psoriasis and psoriatic arthritis in daily clinical practice in our cohort of patients.

SAPHO syndrome presenting as an osteolytic lesion of the neck. / Lesión osteolítica cervical como presentación del síndrome SAPHO.

We report a case of acute-onset multifocal vertebral osteitis with a marked impact on the patient's general health. The radiological, scintigraphic and magnetic resonance findings made it necessary to carry out a differential diagnosis to distinguish it from an infiltrative neoplastic process and determine whether it had an infectious or an inflammatory etiology. The presence of noninfectious multifocal osteitis and sternoclavicular arthritis and the subsequent development of plantar pustulosis pointed to SAPHO syndrome. Treatment with infliximab led to improvement in the clinical symptoms, laboratory values and radiological abnormalities.

Quality standards for rheumatology outpatient clinic. The EXTRELLA project. / Estándares de calidad asistencial para las consultas externas de reumatología. El proyecto EXTRELLA.

INTRODUCTION: In recent years, outpatient clinics have undergone extensive development. At present, patients with rheumatic diseases are mainly assisted in this area. However, the quality standards of care are poorly documented. OBJECTIVE: To develop specific quality criteria and standards for an outpatient rheumatology clinic. METHOD: The project was based on the two-round Delphi method. The following groups of participants took part: scientific committee (13 rheumatologists), five nominal groups (45 rheumatologists and 12 nurses) and a group of discussion formed by 9 patients. Different drafts were consecutively generated until a final document was obtained that included the standards that received a punctuation equal or over 7 in at least 70% of the participants. RESULTS: 148 standards were developed, grouped into the following 9 dimensions: a) structure (22), b) clinical activity and relationship with the patients (34), c) planning (7), d) levels of priority (5), e) relations with primary care physicians, with Emergency Department and with other clinical departments, f) process (26), g) nursing (13), h) teaching and research (13) and i) activity measures (8). CONCLUSION: This study established specific quality standards for rheumatology outpatient clinic. It can be a useful tool for organising this area in the Rheumatology Department and as a reference when proposing improvement measures to health administrators.