Brief Report: How Do Patients With Newly Diagnosed Systemic Lupus Erythematosus Present? A Multicenter Cohort of Early Systemic Lupus Erythematosus to Inform the Development of New Classification Criteria.

OBJECTIVE: Systemic lupus erythematosus (SLE) presents with nonspecific signs and symptoms that are also found in other conditions. This study aimed to evaluate manifestations at disease onset and to compare early SLE manifestations to those of diseases mimicking SLE. METHODS: Academic lupus centers in Asia, Europe, North America, and South America collected baseline data on patients who were referred to them during the previous 3 years for possible SLE and who had a symptom duration of <1 year. Clinical and serologic manifestations were compared between patients diagnosed as having SLE and those diagnosed as having SLE-mimicking conditions. Diagnostic performance of the 1997 American College of Rheumatology (ACR) SLE classification criteria and the 2012 Systemic Lupus International Collaborating Clinics (SLICC) SLE classification criteria was tested. RESULTS: Data were collected on 389 patients with early SLE and 227 patients with SLE-mimicking conditions. Unexplained fever was more common in early SLE than in SLE-mimicking conditions (34.5% versus 13.7%, respectively; P < 0.001). Features less common in early SLE included Raynaud's phenomenon (22.1% versus 48.5%; P < 0.001), sicca symptoms (4.4% versus 34.4%; P < 0.001), dysphagia (0.3% versus 6.2%; P < 0.001), and fatigue (28.3% versus 37.0%; P = 0.024). Anti-double-stranded DNA, anti-ß2 -glycoprotein I antibodies, positive Coombs' test results, autoimmune hemolytic anemia, hypocomplementemia, and leukopenia were more common in early SLE than in SLE-mimicking conditions. Symptoms detailed in the ACR and SLICC classification criteria were significantly more frequent among those with early SLE. Fewer patients with early SLE were not identified as having early SLE with use of the SLICC criteria compared to the ACR criteria (16.5% versus 33.9%), but the ACR criteria demonstrated higher specificity than the SLICC criteria (91.6% versus 82.4%). CONCLUSION: In this multicenter cohort, clinical manifestations that could help to distinguish early SLE from SLE-mimicking conditions were identified. These findings may aid in earlier SLE diagnosis and provide information for ongoing initiatives to revise SLE classification criteria.

Canadian Rheumatology Association Recommendations for the Assessment and Monitoring of Systemic Lupus Erythematosus.

OBJECTIVE: To develop recommendations for the assessment of people with systemic lupus erythematosus (SLE) in Canada. METHODS: Recommendations were developed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. The Canadian SLE Working Group (panel of Canadian rheumatologists and a patient representative from Canadian Arthritis Patient Alliance) was created. Questions for recommendation development were identified based on the results of a previous survey of SLE practice patterns of members of the Canadian Rheumatology Association. Systematic literature reviews of randomized trials and observational studies were conducted. Evidence to Decision tables were prepared and presented to the panel at 2 face-to-face meetings and online. RESULTS: There are 15 recommendations for assessing and monitoring SLE, with varying applicability to adult and pediatric patients. Three recommendations focus on diagnosis, disease activity, and damage assessment, suggesting the use of a validated disease activity score per visit and annual damage score. Strong recommendations were made for cardiovascular risk assessment and measuring anti-Ro and anti-La antibodies in the peripartum period and conditional recommendations for osteoporosis and osteonecrosis. Two conditional recommendations were made for peripartum assessments, 1 for cervical cancer screening and 2 for hepatitis B and C screening. A strong recommendation was made for annual influenza vaccination. CONCLUSION: These are considered the first guidelines using the GRADE method for the monitoring of SLE. Existing evidence is largely of low to moderate quality, resulting in more conditional than strong recommendations. Additional rigorous studies and special attention to pediatric SLE populations and patient preferences are needed.

What is the prevalence of cognitive impairment in lupus and which instruments are used to measure it? A systematic review and meta-analysis.

OBJECTIVES: To systematically review the literature on the prevalence of Cognitive Dysfunction (CD) in SLE patients in studies that used a specified neuropsychological instrument. METHODS: This review was prepared with a protocol following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis-Protocols statement. Literature search in Ovid Medline, Embase, and Psyc INFO for articles on CD in adult SLE patients was conducted. Included studies were critically appraised (Newcastle-Ottawa Evaluation Scale) and the Pooled Prevalence (PP) of CD was studied for all instruments. The association between demographics and CD, the risk of CD in SLE compared to healthy subjects and patients with RA, and the course of CD over time were studied narratively whenever sufficient information was available. RESULT: Of 8054 references, 670 were selected for detailed review and 78 were included in the final analysis. Comprehensive Battery (CB) was utilized in 35 studies in 2463 SLE patients and PP was 38% (95%; CI: 33-43%). The CD prevalence was higher in NPSLE [PP 39% (95% CI: 24-55%]. Automated Neuropsychological Assessment Metric (ANAM) was utilized in 7 studies in 438 patients (PP of CD 26% (95% CI: 12-42%). Other less frequently utilized tools were the Modified Mini-Mental State Exam (MMSE), Montreal Cognitive Assessment (MoCA), Controlled Oral Word Association Test (COWAT) and The Hopkins Verbal Learning Test-Revised (HVLT-R) and subjective tools and others. The relative risk for CD in SLE was greater when compared to RA and to healthy individuals; RR being 1.80 and 2.80, respectively. Information on demographics and its association with CD was very heterogeneous among studies. CONCLUSION: Patients with lupus have a high prevalence of CD. The delay in diagnosis of CD is complex; although caregivers and patients express concerns about cognitive function, testing for CD often imposes administrative and cost burdens. There is an unmet need to identify the best screening, diagnostic metrics of CD. The assessment of cognitive function over time, and the association of demographics with CD, will require further research.

Effect of complete or partial proteinuria recovery on long-term outcomes of lupus nephritis.

BACKGROUND/PURPOSE: We aimed to evaluate the effect of complete recovery (CR), partial recovery (PR), and no recovery (NR) of proteinuria at 2 years from the diagnosis of LN on long-term renal and extra-renal outcomes. METHODS: Patients with LN and proteinuria attending the Lupus Center from 1970 to 2015 were analyzed. At 2 years from diagnosis of LN, patients were divided into three groups (CR, PR, and NR), and long-term outcomes were studied up to 15 years or last visit available. CR was defined as resolution of proteinuria, PR as a reduction ≥50% in baseline proteinuria, and NR as a reduction <50% compared to baseline. Long-term outcomes examined included renal outcomes [low eGFR, ESRD, and composite renal (low eGFR, ESRD, and dialysis/transplant)], cardiovascular outcomes, damage, and death. Kaplan-Meier plots, time-independent and time-dependent Cox proportional hazards models were applied to examine the effect of CR, PR, or NR on long-term outcomes. RESULTS: Of 277 patients, 71.8% achieved CR, 18.4% PR, and 9.8% NR at 2 years. CR compared to NR and CR compared to PR were protective against low eGFR and composite renal outcome in time-independent and time-dependent analyses. CR compared to PR protected against damage in the time-independent analysis. Overall, the comparison of CR and PR favored CR for long-term renal outcomes. CONCLUSION: CR at 2 years from diagnosis of LN protected against renal outcomes (low eGFR, ESRD/dialysis, and transplant). CR is more favorable compared to PR and clinicians should aim for CR to improve long-term outcomes in LN.

Comparison of Spot Urine Protein to Creatinine Ratio to 24-Hour Proteinuria to Identify Important Change Over Time in Proteinuria in Lupus.

OBJECTIVES: The aim of this study was to determine whether spot urine protein-to-creatinine ratio (PCR) accurately measures the change in proteinuria compared with 24-hour proteinuria (24H-P). METHODS: This was a retrospective analysis on patients' paired visits and paired urine samples for PCR and 24H-P. Patients with both abnormal 24H-P (>0.5 g/d) and PCR (>0.05 g/mmol) or both normal 24H-P (≤0.5 g/d) and PCR (≤0.05 g/mmol) at baseline visit were identified.The first follow-up visit with partial recovery (50% decrease in proteinuria) or complete recovery (≤0.5 g/d) was identified for those with abnormal baseline 24H-P, and new proteinuria (>0.5 g/d) was identified for those with normal 24H-P. Twenty-four-hour urine collection and PCR end-point frequencies were compared. Twenty-four-hour urine collection results were converted to 24H-PCR. Twenty-four-hour PCR and PCR were utilized to measure the magnitude of change (by standardized response mean [SRM]) in patients who achieved the end points. RESULTS: Of 230 patients, at baseline, 95 patients had abnormal and 109 had normal 24H-P and PCR. On follow-up, 57 achieved partial recovery, and 53 achieved complete recovery by 24H-P. Standardized response mean was -1.03 and -1.10 for 24H-PCR and PCR, respectively. By PCR, 53 patients had partial recovery, and 27 had complete recovery. Standardized response mean was -1.25 and -0.86 by 24H-PCR and PCR, respectively.For new proteinuria, 28 patients were identified by 24H-P and 21 by PCR. Twenty-four-hour PCR SRM was 0.80, and PCR SRM was 0.68. CONCLUSIONS: Protein-to-creatinine ratio does not have sufficient accuracy compared with 24H-P for improvement and worsening to be used in lieu of 24H-P.

The utility of lupus serology in predicting outcomes of renal transplantation in lupus patients: Systematic literature review and analysis of the Toronto lupus cohort.

OBJECTIVES: To study the utility of lupus serology as a predictor for kidney graft outcome in (a) a systematic literature review (SLR) and (b) the Toronto lupus cohort (TLC). METHODS: For the SLR, a comprehensive literature search was performed to identify the articles reporting on the serology at renal transplantation (RT) and on the outcome of RT. Studies were critically appraised using the Newcastle Ottawa Scale (NOS). Patients who underwent RT in the TLC were identified and grouped into graft failure and graft survival. The serology in both groups was studied. RESULTS: Of the 749 references, 742 did not have serological status of the patient or were not relevant to the research question. Seven studies in addition to TLC (n = 76) were included in the SLR. The NOS revealed limitations because of small sample size and a short follow-up period. The majority of the grafts survived to at least 1 year regardless of the serology results pre-transplant which is consistent with results of the TLC. Overall, 32 of 1783 patients in the TLC had a RT. In all, 2 patients had a nonfunctional graft, 5 patients had graft failure, and 25 patients had graft survival. Overall, 40% of the graft failures had positive serology compared to 52% in the graft survival, 1 year prior to RT. CONCLUSION: The results of this SLR found that the persistence of serological abnormalities at the time of RT was not associated with graft failure. These results are consistent with the results of the TLC.

Recent advances in the biologic therapy of lupus: the 10 most important areas to look for common pitfalls in clinical trials.

INTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune disease affecting different organs. The improved knowledge of the disease's pathogenesis has contributed to the emergence of immune targets and new biologic drugs directed at them. Although rheumatologists continue to use off-label biologics in SLE resistant to other immunosuppressants, only belimumab has been approved as a biological therapy since 2011. AREAS COVERED: In this review, an overview is provided on: 1) the classification of the biologic drugs in clinical trials and of those under research; 2) the results of clinical trials of biologic therapy with an interpretation of pitfalls and syntheses of potential approaches to overcome these pitfalls and, 3) the commonly used disease activity metrics and composite indices for assessing response to drugs. EXPERT OPINION: Some drugs that have failed in previous drug trials have shown to be efficacious in the treatment of lupus in observational studies. Moreover, the post-hoc analyses of the data of negative drug trials have shown that results of the same trials could be altered with the modification of some pitfalls. For future clinical trials, the consideration of these pitfalls is crucial when designing clinical trials. This could potentially enhance the approval of novel drugs for SLE.

Associations of the Levels of C4d-bearing Reticulocytes and High-avidity Anti-dsDNA Antibodies with Disease Activity in Systemic Lupus Erythematosus.

OBJECTIVE: There are no laboratory tools that detect early flares in systemic lupus erythematosus (SLE). Our aim was to validate in our population the previous findings of the association of C4d-bearing reticulocytes (R-C4d) compared to anti-dsDNA antibodies, with disease activity assessed by the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) and the British Isles Lupus Assessment Group (BILAG) 2004 scales. METHODS: All patients who met the 1987 American College of Rheumatology classification criteria and were seen consecutively in 2013 at a specialized SLE care clinic were included. Disease activity was established by the SELENA-SLEDAI and BILAG 2004. Anti-dsDNA and R-C4d were quantified in peripheral blood. Comparisons were made between values of active and inactive patients, and the correlations between the SELENA-SLEDAI and serum levels of anti-dsDNA and R-C4d were measured. RESULTS: Sixty-two patients (83.9% women) were included. A total of 32.3% had active disease according to the SELENA-SLEDAI. There was a significant statistical difference (p = 0.0001) in the distribution of R-C4d between disease activity groups. The correlation coefficient between R-C4d and the SELENA-SLEDAI score was rs = 0.738 (p = 0.0001). R-C4d differed between patients with and without activity in the BILAG 2004 constitutional, mucocutaneous, gastrointestinal, renal, and hematological domains. CONCLUSION: R-C4d showed a higher correlation with SLE activity measured by the SELENA-SLEDAI and BILAG 2004 than anti-dsDNA did, suggesting a possible involvement in diagnosing disease activity. Prospective studies that confirm these findings and evaluate its involvement in followup are needed.

Pulmonary alveolar microlithiasis / Microlitiasis alveolar pulmonar

Pulmonary alveolar microlithiasis is an uncommon disease of unknown etiology, and is characterized by the presence of multiple sub-pleural and intra-alveolar microcalcifications. We present the case of a patient with rheumatoid arthritis and chronic renal disease, but with no respiratory symptoms.

La microlitiasis pulmonar alveolar es una enfermedad infrecuente, de etiología desconocida, caracterizada por la presencia de múltiples microcalcificaciones intraalveolares y subpleurales. Presentamos el caso de un paciente asintomático respiratorio, con historia clínica de artritis reumatoide y enfermedad renal crónica.

Utility of Urinary Protein-Creatinine Ratio and Protein Content in a 24-Hour Urine Collection in Systemic Lupus Erythematosus: A Systematic Review and Meta-Analysis.

OBJECTIVE: To systematically review literature on the utility of spot urinary protein-creatinine ratio (PCR) as a screening test for proteinuria and its ability to accurately measure proteinuria compared with 24-hour urine collection (24H-P) in patients with systemic lupus erythematosus (SLE). METHODS: We conducted a literature search (1900-2015) for articles comparing PCR and 24H-P in SLE patients in the databases Medline, Web of Science, and Embase. Included studies and their results were critically appraised and analyzed. RESULTS: Thirteen studies (1,001 patients; 84.01% women) were included. Ten studies reported on Pearson's correlation (range 0.67-0.94), and 3 studies reported on Spearman's correlation (range 0.78-1.00). The meta-analysis of studies with Pearson's correlation showed a high overall correlation of 0.80 between 24H-P and PCR, yet with high heterogeneity (I(2) = 97.2%). Correlation analysis is not sufficient to evaluate the utility of a new test against the gold standard test, and analysis on agreement is required. Seven studies reported on agreement: 3 studies analyzed concordance correlation coefficient (0.48-0.94), 3 analyzed intraclass correlation coefficient (0.66-0.95), and 1 analyzed kappa coefficient (0.58). These results confirmed that the agreement between 24H-P and PCR was inappropriate. Three studies included Bland-Altman plots, and the results also demonstrated poor agreement between both tests. CONCLUSION: The PCR has a utility as a screening test for proteinuria in SLE patients. The studies' results of 24H-P and PCR showed poor agreement between both tests, signifying that PCR should not be a substitute for the gold standard test (24H-P) to accurately measure proteinuria.

Utility of untimed single urine protein/creatinine ratio as a substitute for 24-h proteinuria for assessment of proteinuria in systemic lupus erythematosus.

INTRODUCTION: In this study, we determined: (1) the utility of an untimed sample of urine protein/creatinine ratio (PCR) as a screening test for proteinuria, (2) its ability to accurately measure proteinuria, and (3) cutoff values for PCR predicting protein content in a 24-h urine collection sample (24hP) of 0.5, 1.0, and 2.0 g/day. METHODS: Analysis was performed on data from a single lupus cohort (2008-2014). Proteinuria was measured in a 24hP and with PCR. On the basis of 24hP, samples were divided into 4 groups: group 1, <0.5 g/day; group 2, 0.5-0.99 g/day; group 3, 1-1.99 g/day; and group 4, ≥2 g/day. To determine the validity of PCR in screening for proteinuria, the Pearson correlation coefficient was determined for the urine samples with normal PCR (<0.05 g/mmol) and normal 24hP (<0.5 g/day). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PCR were calculated. To determine the ability of PCR to accurately measure the level of proteinuria, in addition to the correlation between 24hP and PCR, agreement was determined by intraclass correlation coefficient, concordance correlation coefficient, and Bland-Altman plot between 24hP/24hC and PCR. The best cutoffs for PCR predicting a 24hP of 0.5, 1.0, and 2.0 g/day were determined with the receiver operating characteristic curve. RESULTS: The correlation of the samples with normal PCR as well as 24hP (n = 552) was 0.29 (p < 0.0001). PCR sensitivity and specificity against 24hP were 91 % and 83 %, respectively. The PPV was 82.5 %, and the NPV was 91.4 %. The correlation for all samples (n = 1233) was high, but low to moderate for groups 1, 2, 3, and 4. The agreement for all samples was appropriate but poor for groups 1, 2, 3, and 4. PCR cutoffs for 24hP of 0.5, 1.0, and 2.0 g/day were 0.08, 0.16, and 0.35 g/mmol, respectively. CONCLUSIONS: PCR can be used as a screening test for proteinuria, and the best cutoff value to predict a 24hP of 0.5 g/day is 0.08 g/mmol (800 mg/g). The accurate level of proteinuria should be measured by the gold standard test, 24hP.

Uso de IECA o ARA II más espironolactona y su relación con hiperkalemia en pacientes ambulatorios / Use of ace inhibitors or ARA II plus spironolactone and their relationship with hyperkalemia in day care patients

Objetivo: establecer la relación existente entre la combinación farmacológica de un inhibidor de la enzima convertidora de angiotensina (IECA) o un bloqueante del receptor de angiotensina tipo II (ARA II) más espironolactona y los niveles de potasio sérico en los pacientes adultos con insuficiencia cardiaca y tasa de filtración glomerular (TFG) mayor o igual a 60 mL/min, que acuden a la consulta de cardiología de dos centros hospitalarios de la ciudad de Manizales.Diseño: estudio de tipo prospectivo, observacional, de casos incidentes.Material y métodos: se incluyeron 30 pacientes con diagnóstico de insuficiencia cardiaca, que recibían la combinación farmacológica IECA o ARA II más espironolactona, cuya depuración de creatinina fuera mayor o igual a 60 mL/min. Se hizo seguimiento durante seis meses, evaluando cada mes electrolitos y pruebas de función renal. El análisis estadístico, para las variables cualitativas, se realizó con la prueba de Chi cuadrado; para las variables cuantitativas se utilizó la prueba de t de Student. Se utilizó el programa EpiInfo Versión 6.04 d y Epidata 3.1...

Objective: to establish the relationship between the pharmacologic combination of an angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor blocking agent Type II(ARA II) plus spironolactone and the serum potassium levels in adult patients with heart failure, and glomerular filtration rate (GFR) higher or equal to 60 mL/min, who go for consultation in the cardiology unit of hospital centers in the city of Manizales. Design: prospective, observational study of incident cases. Material and methods: 30 patients with diagnosis of heart failure were included. They weregiven the pharmacologic combination of ACE inhibitors or ARA II plus spironolactone, with a creatinine clearance of more or equal to 60 mL/min. They were followed for 6 months, monthly assessments of the electrolytes as well as renal function. The statistical analysis for the quantitative variables was carried out with the Chi square test; for the quantitative variables the Student t wasused. The EpiInfo program Version 6.04 and Epidate 3.1 were used.Results: 368 patients with diagnosis of heart failure were found, 126 of them lived in Manizalez, of which 54 had creatinine clearance...