Antibodies to M-type phospholipase A2 receptor (PLA2R) in membranous lupus nephritis.

BACKGROUND: Antibodies to M-type phospholipase A2 receptor (a-PLA2R) have been identified in most patients with idiopathic membranous nephropathy, but the prevalence in membranous lupus nephritis (MLN) is still unclear. The objective of this study was to assess the prevalence of a-PLA2R antibodies in a large cohort of patients with lupus nephritis. METHODS: a-PLA2R antibodies were measured by ELISA in serum from patients with systemic lupus erythematosus ( n = 190), of whom 37 had a biopsy-proven MLN. Positive samples were confirmed by commercial ELISA kit, Western blot and immunohistochemistry in renal tissue. RESULTS: A total of 10 from 190 patients (5.3%) with systemic lupus erythematosus had circulating a-PLA2R measured by in-house ELISA assay. The antibodies were detected in 7 patients with MLN (18.9%) and 3 patients with non-renal lupus disease (3.2%). PLA2R staining was detected in the kidney biopsy of 5 of the 7 (71.4%) patients with MLN. a-PLA2R levels were associated with active disease but not proteinuria levels. Presence of a-PLA2R antibodies at baseline was associated with worse remission rates and longer time to remission compared to those patients serologically negative. CONCLUSIONS: a-PLA2R antibodies can be detected with low prevalence in MLN patients, but their detection is associated with a worse renal prognosis.

Microarray study reveals a transforming growth factor-ß-dependent mechanism of fibrosis in discoid lupus erythematosus.

BACKGROUND: Discoid lupus erythematosus (DLE) is characterized by scarring lesions that develop and perpetuate fibrotic lesions. These are not observed in subacute cutaneous lupus erythematosus (SCLE). The pathophysiological basis of this is currently unknown. OBJECTIVES: To identify contradistinctive signalling pathways and cellular signatures between the two type of lupus, with a focus on the molecular mechanisms leading to fibrosis. METHODS: We conducted a gene expression microarray analysis in lesional and nonlesional skin biopsy specimens of patients with DLE (n = 10) and SCLE (n = 10). Confirmatory reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry were performed on selected transcripts in a new cohort of paraffin-embedded skin biopsies (n = 20). Changes over time of a group of selected inflammatory and fibrotic genes were also evaluated in a second biopsy taken 12 weeks later. In vitro functional studies were performed in primary isolated fibroblasts. RESULTS: Compared with nonlesional skin, DLE samples expressed a distinctive T-cell gene signature. DLE samples displayed a significant CD4 T-cell enrichment with an imbalance towards T helper 1 cytokine predominance and a relative increased forkhead box (FOX)P3 response. RT-qPCR and immunochemical analysis over time showed a progressive increment of fibrotic markers and persistent FOXP3 recruitment. Ex vivo upregulation of SERPINE1, MMP9, TGFBR1, phosphorylated SMAD3 and TGFB1 suggested a transforming growth factor (TGF)-ß-dependent mechanism of fibrosis in DLE, also confirmed by the results observed following in vitro stimulation with TGF-ß. CONCLUSIONS: These results highlight major pathogenic pathways in DLE and provide novel molecular targets for the development of new therapies. The data suggest the existence of a TGF-ß-dependent pathway inducing fibrosis in DLE.

Available evidence and outcome of off-label use of rituximab in clinical practice.

PURPOSE: To analyze the therapeutic indications for off-label use of rituximab, the available evidence for its use, the outcomes, and the cost. METHODS: This was a retrospective analysis of patients treated with rituximab for off-label indications from January 2007 to December 2009 in two tertiary hospitals. Information on patient characteristics, medical conditions, and therapeutic responses was collected from medical records. Available evidence for the efficacy of rituximab in each condition was reviewed, and the cost of treatment was calculated. RESULTS: A total of 101 cases of off-label rituximab use were analyzed. The median age of the patients involved was 53 [interquartile range (IQR) 37.5-68.0] years; 55.4 % were women. The indications for prescribing rituximab were primarily hematological diseases (46 %), systemic connective tissue disorders (27 %), and kidney diseases (20 %). Available evidence supporting rituximab treatment for these indications mainly came from individual cohort studies (53.5 % of cases) and case series (25.7 %). The short-term outcome (median 3 months, IQR 2-4 months) was a complete response in 38 % of cases and partial response in 32.6 %. The highest short-term responses were observed for systemic lupus erythematosus and membranous glomerulonephritis, and the lowest was for neuromyelitis optica, idiopathic thrombocytopenic purpura, and miscellaneous indications. Some response was maintained in long-term follow-up (median 23 months IQR 12-30 months) in 69.2 % of patients showing a short-term response. Median cost per patient was €5,187.5 (IQR €5,187.5-7,781.3). CONCLUSIONS: In our study, off-label rituximab was mainly used for the treatment of hematological, kidney, and systemic connective tissue disorders, and the response among our patient cohort was variable depending on the specific disease. The level of evidence supporting the use of rituximab for these indications was low and the cost was very high. We conclude that more clinical trials on the off-label use of rituximab are needed, although these may be difficult to conduct in some rare diseases. Data from observational studies may provide useful information to assist prescribing in clinical practice.

Beta2-glycoprotein I gene polymorphisms Val247Leu and Trp316Ser in Spanish patients with primary antiphospholipid syndrome.

The significance of beta2-glycoprotein I (ß2GPI) polymorphisms in the production of anti-ß2GPI and other antiphospholipid autoantibodies (aPL) and in the pathogenesis of primary antiphospholipid syndrome (PAPS) is not well understood. We performed a study comparing the distribution of polymorphisms at codons 247 (Val247Leu) and 316 (Trp316Ser) of the ß2GPI gene in a Caucasian Spanish population of PAPS patients and healthy controls, and then making correlations with the development of anti-ß2GPI antibodies and other aPL and associated clinical manifestations. A total of 57 PAPS patients and 100 control subjects were included. In the analysis of Val247Leu polymorphism, alleles (V and L) and genotypes (V/V, V/L, L/L) were similarly distributed in PAPS patients and controls (P = 0.66 and P = 0.22, respectively). Regarding Trp316Ser polymorphism, we found a higher percentage of patients with respect to controls expressing S allele (11.4 vs. 5%, P = 0.02) and T/S genotype (22.8 vs. 10%, P = 0.02). However, when we compared T/T and T/S genotypes in PAPS patients, we found no differences regarding generation of anti-ß2GPI, other aPL and clinical manifestations favoring any genotype. Our findings suggest that among Spanish Caucasians, polymorphisms at codon 247 (Val247Leu) do not seem to influence PAPS pathogenesis. On the contrary, polymorphisms at codon 316 (Trp316Ser), by means of an increased S allele and T/S genotype presence in Spanish Caucasian patients, might play a role in the pathogenic development of PAPS, although mechanism would not involve an increased production of anti-ß2GPI and other aPL.

Thalidomide in the treatment of refractory cutaneous lupus erythematosus: prognostic factors of clinical outcome.

BACKGROUND: Although thalidomide has been shown to be effective in patients with refractory cutaneous lupus erythematosus (CLE), its use is still hampered by its potential severe side-effects and the current restricted availability. OBJECTIVES: To evaluate prospectively the clinical efficacy and safety of low-dose thalidomide in an observational study and to establish prognostic factors of clinical outcome. METHODS: Sixty consecutive patients with refractory CLE were treated with thalidomide (100 mg daily). Clinical response was assessed by the CLE Disease Area and Severity Index (CLASI). Clinical and immunological parameters were evaluated during treatment. RESULTS: Patients were followed for up to 8 years (range 2-18). One patient discontinued treatment because of side-effects. Of the 59 remaining patients, 58 (98%) achieved clinical response, already noticeable at 2 weeks following treatment. Complete response occurred in 50 patients (85%). Clinical relapse was frequent (70%) and usually occurred 5 months after withdrawal or reduction of thalidomide. Subacute CLE (SCLE) was the predicting factor of long-term remission after therapy discontinuation [odds ratio (OR) 30, 95% confidence interval (CI) 5·82-154·63], whereas discoid lupus erythematosus (DLE) was predictive of relapse (OR 5·71, 95% CI 1·36-24·06). Eleven patients (18%) reported paraesthesia; in five of the 11, nerve conduction studies confirmed a sensory polyneuropathy. Neurological symptoms resolved in 12 months (range 6-18) after thalidomide withdrawal. Two patients, heavy smokers and without antiphospholipid antibodies, had a cerebral ischaemic event. CONCLUSIONS: Low-dose thalidomide is an effective treatment for refractory CLE, but its benefits need to be balanced against the potential adverse effects. Whereas DLE forms tended to relapse and required a long-term maintenance dose of thalidomide, SCLE forms showed a sustained remission after withdrawal.

Echocardiography at diagnosis of antiphospholipid syndrome provides prognostic information on valvular disease evolution and identifies two subtypes of patients.

The evolution of valvular disease in antiphospholipid syndrome (APS) is barely known. In order to evaluate whether the presence or absence of valvular disease at the time of diagnosis of APS, assessed by an initial echocardiogram, predicts its subsequent evolution, we performed a prospective cohort study. We included 53 patients with APS. An initial transthoracic echocardiogram was performed on patients at the time of diagnosis of APS. Serial echocardiograms were conducted along a 12-year follow-up. Final echocardiograms were used for comparative purposes. We started with 29 patients (54%) with and 24 (45%) without valvulopathy at initial echo. At the final echocardiogram, 27 of 29 patients with initial valvulopathy continued to have valvular disease (a 93% observed likelihood), and 22 of 24 patients without initial valvulopathy demonstrated an absence of valvular disease (a 91% observed likelihood). Patients with valvulopathy in comparison with those without presented more arterial thrombotic events (69% vs. 20%, P < 0.001), atherosclerotic risk factors (62% vs. 29%, P = 0.01), livedo (48% vs. 16%, P = 0.01) and migraine (41% vs. 12%, P = 0.02). We have identified two subtypes of APS patients with and without valvulopathy by defining differential clinical features and with little crossover in valvular involvement over a long follow-up period, giving a high prognostic value to the initial echocardiographic assessment.

Metástasis pleural de un osteosarcoma: imagen gammagráfica / Pleural metastasis of an osteosarcoma: scintigraphic image

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[Ochronotic arthropathy: the value of bone scintigraphy in alkaptonuria]. / Artropatía ocronótica: utilidad diagnóstica de la gammagrafía ósea en la alcaptonuria.

We report the case of a 62 year old man diagnosed of alkaptonuria who was referred to our department to undergo bone scintigraphy for polyarthralgia. The patient had a history of pain in lumbar and thoracic spine, right shoulder and left knee. Bone scintigraphy showed multiple joint disease with increased uptake in both shoulders, knees and spine. Higher uptake stood out in painful right shoulder and left knee joints. Ochronotic arthropathy that is developed in alkaptonuric patients is a degenerative joint disease. X-ray studies in this patient showed marked degenerative arthrosis in knees and shoulders, without more intense involvement in the symptomatic joints. Lumbar spine X-rays showed intervertebral disk calcification with disk collapse and fusion of the vertebral bodies with relative sparing of sacroiliac joint, which is a classic feature of ochronotic arthropathy. This case highlights the utility of bone scintigraphy in the evaluation of joint involvement as well as its correlation with clinical course and potential usefulness in the follow-up of this disease.

Artropatía ocronótica: utilidad diagnóstica de la gammagrafía ósea en la alcaptonuria / Ochronotic arthropathy: the value of bone scintigraphy in alkaptonuria. A case report

Presentamos el caso de un varón de 62 años diagnosticado de alcaptonuria remitido a nuestro servicio solicitando un estudio gammagráfico óseo para valoración de su poliartralgia. El paciente refería dolor dorso-lumbar, en hombro derecho y rodilla izquierda. La gammagrafía ósea mostró una afectación poliarticular con hipercaptaciones en ambos hombros, rodillas y columna vertebral. Destacaba la elevada intensidad de captación en las articulaciones dolorosas del hombro derecho y rodilla izquierda. La artropatía ocronótica que desarrollan los pacientes alcaptonúricos es de tipo degenerativo, presentando las radiografías del paciente signos evidentes de degeneración artrósica en rodillas y hombros; sin que existiera una afectación más intensa en las articulaciones sintomáticas. En el estudio radiológico lumbar que se le practicó resalta la calcificación de los espacios intervertebrales con colapso y fusión de los cuerpos vertebrales, junto a la relativa indemnidad de las articulaciones sacroilíacas, hallazgo considerado clásico en la artropatía ocronótica. Este caso destaca la utilidad de la gammagrafía ósea en el diagnóstico de extensión de la afectación articular, así como su correlación con la sintomatología clínica, apuntando su potencial utilidad en la monitorización del seguimiento evolutivo (AU)

We report the case of a 62 year old man diagnosed of alkaptonuria who was referred to our department to undergo bone scintigraphy for polyarthralgia. The patient had a history of pain in lumbar and thoracic spine, right shoulder and left knee. Bone scintigraphy showed multiple joint disease with increased uptake in both shoulders, knees and spine. Higher uptake stood out in painful right shoulder and left knee joints. Ochronotic arthropathy that is developed in alkaptonuric patients is a degenerative joint disease. X-ray studies in this patient showed marked degenerative arthrosis in knees and shoulders, without more intense involvement in the symptomatic joints. Lumbar spine X-rays showed intervertebral disk calcification with disk collapse and fusion of the vertebral bodies with relative sparing of sacroiliac joint, which is a classic feature of ochronotic arthropathy. This case highlights the utility of bone scintigraphy in the evaluation of joint involvement as well as its correlation with clinical course and potential usefulness in the follow-up of this disease (AU)

Predictors of poor renal outcome in patients with lupus nephritis treated with combined pulses of cyclophosphamide and methylprednisolone.

Lupus nephritis remains a major cause of morbidity and mortality in patients with systemic lupus erythematosus. Although the renal prognosis has improved, the optimal therapeutic regime has not been definitively established, and significant challenges remain in the management of disease progression and recurrent renal relapse. We performed a prospective study to evaluate the outcome of 38 patients with severe lupus nephritis treated with standard cyclophosphamide and methylprednisolone pulse therapy, and to determine the variables associated with poor outcome. Five patients developed end-stage renal disease (ESRD) (13%), 10 (26%) developed persistent proteinuria (> 1 g/24h) and 15 (39%) suffered at least one relapse after 8 years of follow-up. A high chronicity index, interstitial fibrosis (P = 0.04), persistent hypertension (P < 0.0001) and hypocomplementaemia (P = 0.002) after treatment were the major variables associated with ESRD. Tubular atrophy (P = 0.01), persistent hypertension (P = 0.0001) and hypocomplementaemia after treatment (P = 0.0281) were associated with persistent proteinuria. Persistence of anti-dsDNA antibodies and hypocomplementaemia after treatment (P = 0.0118) were associated with renal relapse. Our data suggest that the group of patients with persistence of hypocomplementaemia and raised anti-dsDNA antibodies titres are at high risk of renal relapse and may be candidates for continuation of immunosuppressive treatment. Patients with persistent proteinuria alone or a high chronicity index are less likely to respond to immunosuppression, and strict control of the hypertension may be the best approach.

Murine glomerular mesangial cell uptake of apoptotic cells is inefficient and involves serum-mediated but complement-independent mechanisms.

An increased number of apoptotic bodies have been detected in glomeruli of non-nephritic kidneys of C1q-deficient mice. In these mice an in vivo impaired uptake of apoptotic cells by peritoneal macrophages was also demonstrated. Here we investigated whether C1q plays a role in the in vitro clearance of apoptotic cells by glomerular mesangial cells. Phagocytosis was assessed using a novel flow cytometric assay that was validated by immunofluorescence studies. The uptake of apoptotic cells by mesangial cells, measured as percentage of mesangial cells ingesting apoptotic cells, was approximately 25%, 10% and 10% for a T cell lymphoma line (RMA), thymocytes and neutrophils, respectively. The uptake reached a plateau phase after 3 h, was specific for apoptotic cells and was mediated by serum but not by complement components C1q or C3. The phagocytosis of apoptotic cells was significantly inhibited by Arg-Gly-Asp-Ser (RGDS), a peptide capable of blocking the interaction of thrombospondin with CD36 or the vitronectin receptor. Pretreatment of the mesangial cells with dexamethasone (200 nm) but not with LPS increased the uptake markedly. These findings indicate that murine mesangial cells are capable of taking up syngeneic apoptotic cells, although much less efficiently than professional phagocytic cells. They also show that serum proteins other than complement components mediate the removal of apoptotic cells by murine mesangial cells in vitro.

Clinical predictors of fetal and maternal outcome in systemic lupus erythematosus: a prospective study of 103 pregnancies.

OBJECTIVE: Our aim was to assess the outcome of pregnancy in a cohort of patients with SLE and to evaluate clinical and laboratory markers for fetal outcome and maternal flares. METHODS: Sixty patients with 103 pregnancies were evaluated prospectively between 1984 and 1999. RESULTS: There were 68 live births, 15 spontaneous abortions, 12 stillbirths and eight therapeutic abortions. Of liveborn infant births, 19 were premature, 24 had suffered intrauterine growth restriction and one had neonatal lupus. Maternal lupus flares occurred in 33% of pregnancies, mostly in the second trimester (26%) and in the post-partum period (51%). Flares during pregnancy showed a statistically significant association with discontinuation of chloroquine treatment, a history of more than three flares before gestation, and a SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) score of >or=5 in these flares. Antiphospholipid antibodies, C3 hypocomplementaemia and hypertension during pregnancy were significantly associated with fetal loss, prematurity and intrauterine growth restriction. CONCLUSIONS: Patients with more active SLE and those with aPL antibodies and hypertension should be monitored and managed carefully during pregnancy.

[Effectiveness of (67)Ga scintigraphy in the diagnosis of lymphoma relapse]. / Efectividad de la gammagrafía con 67Ga en el diagnóstico de recidiva de linfomas.

PURPOSE: To establish the clinical effectiveness of 67Ga in lymphoma recurrence. PATIENTS AND METHODS: Thirty-nine patients were assessed on 43 occasions (31 for Hodgkin's disease and 12 for non-Hodgkin's lymphoma) either for a suspected recurrence or to monitor the evolution of the disease. A computed tomography (CT) and a 67Ga whole body scan were performed. Independent observers who did not know the definitive diagnosis performed the CT and 67Ga readings. The gold standard was the biopsy results or the follow-up during a 12 months period. RESULTS: Recurrence was confirmed in 17 cases, while 26 continued to have complete remission. Using 67Ga resulted in true positive (TP), 24 true negative (TN), 2 false positive (FP) and 2 false negative (FN) results with a sensitivity of 0.88 (15/17), specificity of 0.92 (24/26), positive predictive value (PPV) of 0.88 (15/17) and negative predictive value (NPV) of 0.92 (24/26), while CT produced 12 TP, 20 TN, 6 FP and 5 FN, with a sensitivity of 0.7 (12/17), specificity of 0.77 (20/26), PPV of 0.88 (12/18) and NPV of 0.92 (20/25). CONCLUSIONS: 67Ga is a useful indicator and has better diagnostic effectiveness than CT for both the confirmation and exclusion of lymphoma recurrence.

Efectividad de la gammagrafía con 67Ga en el diagnóstico de recidiva de linfomas / Effectiveness of 67Ga scintigraphy in the diagnosis of lymphoma relapse

Objetivo: Establecer los parámetros de efectividad clínica del 67Ga en el diagnóstico de confirmación o exclusión de recidiva de linfomas. Pacientes y Métodos: Se han estudiado retrospectivamente, 39 pacientes en 43 ocasiones (31 linfomas Hodgkin y 12 no Hodgkin) evaluados, bien por sospecha de recaída o por seguimiento de su enfermedad. Se realizó tomografía computarizada (TC) tóraco-abdominal y estudio con 67Ga (8 mCi) (cuerpo completo y SPET torácico y abdominal). La lectura de TC y 67Ga se realizó de forma ciega e independiente. El gold standard fue la biopsia y/o el seguimiento por un período mínimo de 1 año. Resultados: En 17 casos se confirmó la recidiva, mientras que 26 continuaron en remisión completa. El 67Ga tuvo 15 VP, 24 VN, 2 FP y 2 FN, mientras que la TC tuvo 12 VP, 20 VN, 6 FP y 5 FN. Para el 67Ga la sensibilidad fue de 0,88 (IC95 per cent: 0,64-0,98), la especificidad de 0,92 (0,74-0,99), el valor predictivo positivo de 0,88 (0,64-0,98) y el valor predictivo negativo de 0,92 (0,75-0,99), mientras que la TC tuvo 0,7 (0,44-0,89), 0,77 (0,56-0,91), 0,66 (0,41-0,87) y 0,8 (0,59-0,93), respectivamente. Conclusiones: Los resultados señalan que los datos de efectividad clínica del 67Ga en la confirmación o exclusión de recidiva de linfoma son adecuados y superiores a los de TC, por lo que debería incluirse en el control rutinario de estos pacientes (AU)

El renograma diurético en la estrategia diagnóstica de la hidronefrosis prenatal / The diuretic renography in the diagnostic strategy of prenatal hidronephrosis

Objetivo: Comprobar la utilidad del renograma diurético con 99mTc-MAG3 en pacientes con diagnóstico prenatal de hidronefrosis ante la sospecha de obstrucción del tracto urinario. En un neonato con dilatación del tracto urinario superior, la dificultad se plantea en diferenciar una verdadera obstrucción de una dilatación sin obstrucción. Material y métodos: Estudio retrospectivo que incluye 40 pacientes consecutivos, de los 181 recién nacidos con diagnóstico prenatal de hidronefrosis durante el período comprendido entre enero de 1993 y diciembre de 1998. La edad media de realización del primer renograma fue 2,6 meses. Resultados: El diagnóstico final correspondió (excluidos previamente los reflujos vésico-ureterales) a: estenosis pieloureteral (EPU) 16, megaureter 15, ureterocele 3 y ectasia simple 6. En la mayoría de los pacientes se adoptó un tratamiento conservador, sin embargo, diecisiete precisaron tratamiento quirúrgico por el elevado riesgo de daño renal permanente. Conclusiones: 1) La EPU es la causa más frecuente de hidronefrosis neonatal (HN) y por tanto de solicitud de renogramas diuréticos. Debido a que es la entidad con mayor tasa de intervenciones quirúrgicas (por el alto riesgo de daño renal permanente) es donde el renograma con 99mTcMAG3 tiene mayor influencia en la decisión terapéutica, identificando quienes y cuando deben ser operados. 2) La indicación quirúrgica de la HN esta basada en los parámetros del renograma diurético y/o en la aparición de sintomatología. En nuestra serie de pacientes intervenidos ninguno de los que mostraban una función renal diferencial <20 por ciento respecto al contralateral, mostró una recuperación tras la cirugía (control a los 6 meses post-intervención) (AU)

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[Diuretic renography in the diagnostic approach of prenatal hydronephrosis]. / El renograma diurético en la estrategia diagnóstica de la hidronefrosis prenatal.

OBJECTIVE: To verify the utility of diuretic renography using 99mTc-MAG3 in the evaluation of the urinary tract obstruction in patients with prenatal diagnosis of hydronephrosis. In a neonate with upper urinary tract dilatation, it is difficult to differentiate a true obstruction from a dilated non-obstructed system. MATERIAL AND METHODS: The retrospective study (january 1993-december 1998) included 40 consecutive patients selected from 181 newborns with a prenatal diagnosis of hydronephrosis. The mean age of the performance of the first renography was 2.6 months. RESULTS: The final diagnosis (once the vesicoureteral reflux was ruled out) was: ureteropelvic junction obstruction (UPJ) 16, megaureter 15, ureterocele 3 and stasis 6. Conservative treatment was applied in most of the patients. Nevertheless, 17 of them needed surgical treatment due to the high risk of the permanent renal damage. CONCLUSIONS: 1) UPJ is the most frequent cause of neonatal hydronephrosis (NH) and consequently, of the request for diuretic renographies. The renography with 99mTc-MAG3 has the greatest influence in the therapeutic decision (identifying who should be operated on and when this should be done), due to the fact that it is the disease with the highest rate of surgical interventions. 2). The surgical indication in NH is based on the diuretic renography parameters and/or on the presence of symptomatology. In our series of surgical patients, none of those who had a differential renal function <20% with regard to the contralateral one showed recuperation after surgery (control 6 months later).