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.

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.

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.

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.

Hypophosphatemic osteomalacia induced by tenofovir in HIV-infected patients.

Tenofovir disoproxil fumarate (TDF) is an adenine analogue reverse transcription inhibitor widely used in first-line treatment of human immunodeficiency virus (HIV) infection and also in hepatitis B virus infection. Its use has been linked to sporadic Fanconi syndrome, renal failure and bone disease. We present the clinical characteristics of tenofovir-induced osteomalacia, discuss bone biopsy findings, describe predisposing factors and compare our results with other reported cases. We describe five cases of hypophosphatemic osteomalacia induced by TDF and recorded at the rheumatology service of a university hospital between 2010 and 2014. We also report the characteristics of bone biopsies of this pathology, which have not been previously described. We include a review of published cases of proximal renal tubulopathy (PRT) and osteomalacia induced by TDF (PubMed 1995-2014; keywords: osteomalacia, tenofovir, Fanconi syndrome, hypophosphatemic osteomalacia, proximal renal tubulopathy, bone biopsy). Five HIV patients who developed hypophosphatemic osteomalacia under TDF treatment (>5 years) presented increasing bone pain and a progressive inability to walk without assistance as a result of multiple insufficiency fractures. Bone biopsy performed in three patients after tetracycline labelling showed increased osteoid thickness, confirming osteomalacia. A literature review retrieved 17 publications on this condition, including 53 cases: 26 patients developed isolated PRT, 25 presented PRT and with multiple insufficiency fractures and two presented isolated bone disease, including osteomalacia and osteoporosis. Rheumatologists should be alert to this complication in patients receiving tenofovir. The main complaint reported by these patients is diffuse pain, predominantly in the lower limbs, indicating multiple stress fractures. Serum phosphate and appropriate screening for abnormal proximal tubule function should be monitored. Bone scintigraphy should be carried out in cases of limb pain before the occurrence of more severe complications.

Septic arthritis due to methylcyllin-resistant Staphylococcus aureus in adults.

INTRODUCTION: Septic arthritis due to methylcyllin resistant Staphylococcus aureus (MRSA) is a serious infection that has increased in incidence in the past 10years. METHODS: We conducted a retrospective study (1984-2011) in which a description of the clinical and epidemiological characteristics of MRSA arthritis in adults was performed and then compared to native joint infections caused by MRSA vs. methylcyllin sensitive Staphylococcus aureus (MSSA). RESULTS: Fourteen MRSA infections were included (7 native joint, 5 prosthetic and 2 bursae). No case was polyarticular. There was significant comorbidity, although none was associated to rheumatoid arthritis. Seven patients had bacteremia. Four required surgical treatment. Six died. When comparing the 7 patients with native joint MRSA infection with the 17 cases caused by MSSA, no significant differences in risk factors were seen, except more malignancies in the MRSA group. The infection was polyarticular in 7 cases (41%) of the MSSA group. Bacteremia was more frequent in the MRSA group (71.4 vs 58.8%). Empirical antibiotic was useful in 28.6% of MRSA cases versus 100% of MSSA cases. There was a greater tendency to associated mortality in MRSA arthritis (57.1% vs 17.6%, P=.07). CONCLUSIONS: MRSA septic arthritis is a serious condition that occurs in the elderly and patients with high comorbidity. It is usually monoarticular, with positive blood cultures and higher mortality than MSSA arthritis. In patients at risk, vancomycin empiric antibiotic therapy is indicated.

[Amyloidosis complicating spondyloarthropathies: Study of 15 cases]. / Amiloidosis secundaria a espondiloartritis: estudio de 15 casos.

BACKGROUND AND OBJECTIVE: Secondary amyloidosis (AA) is a rare complication of rheumatic diseases. OBJECTIVE: The aim of this study was to determine the frequency of symptomatic amyloidosis AA in patients with spondyloarthropathy. PATIENTS AND METHOD: Retrospective study (1984-2013). We reviewed the medical records of patients with spondyloarthropathy who had a histological diagnosis of amyloidosis AA (15 patients). RESULTS: We identified 1.125 patients with spondyloarthropathies. Fifteen (1.3%) patients with amyloidosis AA were recruited. It was suspected in 14 patients (93.3%) because of nephrotic syndrome in most of them: 14 were symptomatic (93.3%): 5 (33.3%) ankylosing spondylitis (AS), 5 (33.3%) spondylitis associated with inflammatory bowel diseases (IBD), 4 (26.7%) psoriatic arthritis, and one (6.7%) reactive arthritis. The mean disease duration was 23.9 years. Mortality after one and 5 years of follow-up was 30 and 50% respectively. CONCLUSIONS: The frequency of clinical amyloidosis AA in our patients was 1.3%. There was a marked male predominance, with AS or IBD. Clinical amyloidosis was diagnosed at a relatively late stage in spondyloarthropathy.

[Löfgren syndrome: a study of 80 cases]. / Síndrome de Löfgren: estudio de 80 casos.

BACKGROUND AND OBJECTIVE: Löfgren's syndrome is characterized by hiliar adenopathies, erythema nodosum and arthritis. It is a benign variant of sarcoidosis, common in the Mediterranean area. To describe the clinical characteristics, treatment and outcome of a series of patients diagnosed with Löfgren's syndrome. PATIENTS AND METHODS: Retrospective design (1984-2013). SETTING: Two university hospitals with a reference population of 1,015,000 inhabitants. RESULTS: Eighty patients were diagnosed: 29 men and 51 women (mean age 42.3 years). Forty eight patients (60%) presented with the classical triad: hiliar adenopathies, erythema nodosum and arthritis; 18 (22%) with hiliar adenopathy and arthritis; 13 (16%) hiliar adenopathies and erythema nodosum. All showed abnormalities in the chest study. According to the radiological pattern, patients were classified in stage i-ii. Biopsy was performed in 39 patients and was diagnostic in 28. Treatment was based on non-steroidal anti-inflammatory drugs (54 patients, 67%) and corticosteroids (33 patients, 41%). Fourteen patients (17%) suffered a recurrence of the disease. CONCLUSIONS: Löfgren's syndrome is a benign form of sarcoidosis with a well defined clinical pattern. Biopsy is usually not required. Recurrence is scarce. The disease has a good prognosis.

Interferon-gamma release assays in the detection of latent tuberculosis infection in patients with inflammatory arthritis scheduled for anti-tumour necrosis factor treatment.

Biological agents, particularly anti-Tumour Necrosis Factor (TNF)-α agents, have emerged as an effective treatment in patients with chronic inflammatory diseases. An association between anti-TNF-α antibodies and reactivation of latent tuberculosis infection (LTBI) has been established. Appropriate screening for TB infection has become mandatory before starting a treatment based on TNF-α inhibition. The objective was to determine the usefulness of IFN-γ release assays in diagnosing LTBI in patients with inflammatory rheumatic diseases scheduled for anti-TNF-α treatment. The study included 53 individuals with inflammatory rheumatism. All patients had a TST, a chest radiograph, QuantiFERON Gold In-Tube (QFN-G-IT) and T-SPOT.TB. To investigate the influence of non-tuberculous mycobacteria (NTM) infections on non-BCG-vaccinated patients, with a positive TST result and both negative IFN-γ assays, we performed an ex vivo ELISPOT, stimulating the cells separately with NTM sensitins. TST was positive in 7 cases, T-SPOT.TB in 11 and QFN-G-IT in 9 cases. Agreement between TST and T-SPOT.TB and QFN-G-IT was 77.35% (κ = 0.33 and κ = 0.40, respectively), and between both in vitro tests, it was 83.01% (κ = 0.57). Of the three patients with positive TST and negative T-SPOT.TB and QFN-G-IT, one positive ELISPOT result was obtained after stimulation with NTM sensitins. Positive TST, T-SPOT.TB and QFN-G-IT results were not affected by the immunosuppressive therapies. IFN-γ release assays are useful methods for avoiding TST false-positive results, but in those patients with a high risk of developing active TB and in the absence of predictive value studies in this specific kind of population for knowing how safe is the use of IGRAs alone, the combined use of TST and IFN-γ tests should be recommended in order to increase the overall number of LTBI diagnoses.

[Granulomatosis with polyangiitis (Wegener). Description of 15 cases]. / Granulomatosis con poliangeítis (Wegener). Descripción de 15 casos.

BACKGROUND: Granulomatosis with polyangiitis (GP) is a necrotizing vasculitis of unknown etiology that involves small and medium caliber vessels. It is associated with anti neutrophil cytoplasm antibodies (ANCA). It most often affects the respiratory tract and the kidneys and its most important pathologic feature is the presence of necrotizing granulomas. OBJECTIVES: To detail the features of 15 patients with GP diagnosed in a university referral center. PATIENTS AND METHODS: Retrospective study: between 1984 and 2009, 15 patients with GP were diagnosed in our center. Epidemiological, clinical, laboratory test as well as pathologic studies and treatment were retrospectively analyzed. Biopsy diagnosis of GP was considered as an inclusion criterion. RESULTS: Fifteen patients were diagnosed: 12 men and 3 women. Mean age at diagnosis: 52.2 years (14-78). 12 patients had a history of smoking. A biopsy was diagnostic in all patients. ANCA were positive in 11 cases, 6 had a cytoplasmic c-ANCA pattern. All patients had pulmonary involvement and seven (40%) had renal involvement. All patients received intravenous glucocorticoids and cyclophosphamide as induction therapy. During the disease progression 5 patients died. CONCLUSIONS: The clinical features of this series do not differ from those described by other authors. However, a history of smoking is more common than expected. Frequently used drugs were glucocorticoids and cyclophosphamide (oral and pulse therapy). The course was usually unfavorable, with outbreaks or complications due to immunosuppression, except for those with limited forms. Immunosuppressive therapy should be maintained indefinitely in most cases.

Brown tumor of the cervical spine: a case report and review of the literature.

Brown tumors (BT) are benign focal bone lesions that may appear in the context of primary and secondary hyperparathyroidism (HPT). Involvement of the spine is exceedingly rare. We present a case of brown tumor involving the cervical spine, the third reported in the literature. In the literature review (until August 2010), we found nine cases of spinal BT in primary HPT and 14 cases in secondary HPT. Fifteen patients (65%) had evidence of spinal cord compression. A 34-year-old woman on long-term hemodialysis, with secondary HPT, presented with a 9-month history of persistent neck pain. Radiographs of the cervical spine revealed an expansive osteolytic lesion in the posterior arch of the second cervical vertebra. MR imaging revealed an expansive mass on C2 affecting the vertebral body, odontoid process, right pedicle, laminas, and spinous process; there were no signs of spinal edema. A CT-guided needle biopsy of the lesion showed destruction of trabecular bone, infiltration of the fibroblastic cells, and abundant osteoclast-like multinucleated giant cells with hemorrhage and hemosiderin pigment, and the diagnosis of brown tumor was made. Cervical pain disappeared within a few days of parathyroidectomy, and rapid remineralization of C2 was evident within a few months. BT must always be considered in the context of hyperparathyroidism and osteolytic lesions. Vertebral BT can be particularly devastating due to medullar compression symptoms. Regression or complete disappearance of these lesions after parathyroidectomy is common, but prompt surgical decompression is necessary in case of medullar compression symptoms.

Bone mineral density and bone fracture in male patients receiving long-term suppressive levothyroxine treatment for differentiated thyroid carcinoma.

Studies on the effect of exogenous subclinical thyrotoxicosis on bone mineral density (BMD) in male patients treated with suppressive doses of levothyroxine for differentiated thyroid carcinoma (DTC) are not conclusive. In order to evaluate BMD (in femoral neck, lumbar spine, and distal radius) and bone fractures in men under long-term suppressive treatment with levothyroxine for DTC, we conducted a cross-sectional, retrospective study in 33 Caucasian men (mean ± SD age: 56 ± 14 years) under treatment for DTC. The control group comprised 33 healthy age- and body mass index-matched male volunteers. BMD was assessed by dual-energy X-ray absorptiometry (DXA). Bone turnover biomarkers (calcium, phosphate, alkaline phosphatase, PTH, vitamin D, urinary calcium, and N-Telopeptide/creatinine index) and testosterone were determined. Previous bone fractures were evaluated with a questionnaire and X-ray images of thoracic and lumbar vertebrae. Patients were treated for a mean duration of 15 ± 5 years. No differences were found between patients and controls in bone turnover biomarkers or areal BMD, T-scores or Z-scores in all sites evaluated. No earlier fractures or pain episodes were registered in either group and the incidence of asymptomatic vertebral fractures did not differ significantly between patient (18.8%) and control groups (16.7%), (P = 0.9). In conclusion, long-term suppressive treatment with levothyroxine in men with DTC does not appear to exert deleterious effects on bone mineral density or increase the prevalence of fracture.

Power Doppler ultrasonography assessment of entheses in spondyloarthropathies: response to therapy of entheseal abnormalities.

OBJECTIVE: To investigate the response to therapy of entheseal abnormalities assessed with power Doppler (PD) ultrasound (US) in spondyloarthropathies (SpA). METHODS: A total of 327 patients with active SpA who were starting anti-tumor necrosis factor (TNF) therapy were prospectively recruited at 35 Spanish centers. A PDUS examination of 14 peripheral entheses was performed by the same investigator in each center at baseline and at 6 months. The following elementary lesions were assessed at each enthesis (presence/absence): morphologic abnormalities (hypoechogenicity and/or thickening), entheseal calcific deposits, cortical abnormalities (bone erosion and/or proliferation), adjacent bursitis and intraenthesis and perienthesis (tendon body and/or bursa) PD signal. Response to therapy of each elementary lesion was assessed by calculating change in the cumulative presence from baseline to 6 months. Intraobserver reliability of PDUS was evaluated by blindly assessing the stored baseline images 3 months after the real-time examination. RESULTS: Complete data were obtained on 197 patients who received anti-TNF therapy for 6 months. In 91.4% of the patients there were gray-scale or PD elementary lesions at baseline and at 6 months. Cumulative entheseal morphologic abnormalities, intraenthesis PD, perienthesis PD, and bursitis showed a significant decrease from baseline to 6 months (p < 0.05). There was high intraobserver reliability for all elementary lesions (interclass correlation coefficient > 0.90, p < 0.0005). CONCLUSION: Entheseal morphologic abnormalities, PD signal, and bursitis were US abnormalities that were responsive to anti-TNF therapy in SpA. PDUS can be a reproducible method for multicenter monitoring of therapeutic response in enthesitis of SpA.

Visceral leishmaniasis and macrophagic activation syndrome in a patient with rheumatoid arthritis under treatment with adalimumab.

BACKGROUND: Visceral leishmaniasis is a protozoan infection usually asymptomatic, but can progress to fatal disease in immunocompromised hosts, especially in HIV patients. Visceral leishmaniasis is rare among patients under immunosuppressive therapies, and even more among patients under anti-TNF-alpha treatment, where only four cases have been described. OBJECTIVE: 1) To describe a patient with rheumatoid arthritis receiving adalimumab who developed fever, pancytopenia, splenomegaly, and extreme hyperferritinemia. 2) To perform a review of the published cases of visceral leishmaniasis and anti-TNF-alpha therapy, and cases of coexisting leishmaniasis and macrophagic activation syndrome by search in PubMed (period 1991-2008). RESULTS: Visceral leishmaniasis was established by bone marrow aspiration, and although there was no histological confirmation, according to HLH-2004 criteria, a secondary macrophagic activation syndrome was established. The patient had a favourable outcome. CONCLUSION: We report herein the fifth case of visceral leishmaniasis in a patient under TNF-alpha therapy, and the first one, to our knowledge, presenting a consequent secondary macrophagic activation syndrome.