Factors predictive of serious infections over time in systemic lupus erythematosus patients: data from a multi-ethnic, multi-national, Latin American lupus cohort.

AIM: The aim of this study was to identify factors predictive of serious infections over time in patients with systemic lupus erythematosus (SLE). METHODS: A multi-ethnic, multi-national Latin American SLE cohort was studied. Serious infection was defined as one that required hospitalization, occurred during a hospitalization or led to death. Potential predictors included were sociodemographic factors, clinical manifestations (per organ involved, lymphopenia and leukopenia, independently) and previous infections at baseline. Disease activity (SLEDAI), damage (SLICC/ACR Damage Index), non-serious infections, glucocorticoids, antimalarials (users and non-users), and immunosuppressive drugs use; the last six variables were examined as time-dependent covariates. Cox regression models were used to evaluate the predictors of serious infections using a backward elimination procedure. Univariable and multivariable analyses were performed. RESULTS: Of the 1243 patients included, 1116 (89.8%) were female. The median (interquartile range) age at diagnosis and follow-up time were 27 (20-37) years and 47.8 (17.9-68.6) months, respectively. The incidence rate of serious infections was 3.8 cases per 100 person-years. Antimalarial use (hazard ratio: 0.69; 95% confidence interval (CI): 0.48-0.99; p = 0.0440) was protective, while doses of prednisone >15 and ≤60 mg/day (hazard ratio: 4.18; 95 %CI: 1.69-10.31; p = 0.0019) and >60 mg/day (hazard ratio: 4.71; 95% CI: 1.35-16.49; p = 0.0153), use of methylprednisolone pulses (hazard ratio: 1.53; 95% CI: 1.10-2.13; p = 0.0124), increase in disease activity (hazard ratio: 1.03; 95% CI: 1.01-1.04; p = 0.0016) and damage accrual (hazard ratio: 1.22; 95% CI: 1.11-1.34; p < 0.0001) were predictive factors of serious infections. CONCLUSIONS: Over time, prednisone doses higher than 15 mg/day, use of methylprednisolone pulses, increase in disease activity and damage accrual were predictive of infections, whereas antimalarial use was protective against them in SLE patients.

Causes of fetal third-degree atrioventricular block and use of hydroxychloroquine in pregnant women with Ro/La antibodies.

INTRODUCTION/OBJECTIVES: Complete congenital atrioventricular block (AVB) may be due to cardiac malformations or the presence of maternal antibodies (autoimmune AVB). Our objective was to estimate the prevalence of autoimmune AVB among all AVB in newborns treated at our hospital. Secondly, we estimated the prevalence of AVB among mothers with anti-Ro/La antibodies and examined the relationship of those fetal AVB with mother's use of hydroxychloroquine during pregnancy. METHODS: Retrospective cohort in which we reviewed electronic medical records from years 2000 to 2014 of (a) all mothers with children born with third degree AVB and (b) all pregnant women with anti-Ro/La-positive antibodies. RESULTS: Twenty-three AVBs were diagnosed. Ten (43.5%, 95% CI 23.2-65.5) were associated with maternal rheumatologic disease. The remaining 13 were associated with cardiac malformations. Sixty-two pregnancies in 47 mothers with Ro/La antibodies were identified; eight (12.9%, 95% CI 5.7-23.8) suffered AVB. Fourteen mothers consumed hydroxychloroquine during full pregnancy (one newborn (7.1%) suffered AVB) and 48 did not (7 newborns with AVB (14.6%); p = 0.5). CONCLUSIONS: All congenital AVB diagnosed at our hospital without cardiac malformations were associated with a maternal rheumatologic disease/antibodies. Therefore, if a AVB is diagnosed in a newborn without structural heart disease, the mother should be studied for an autoimmune disease. We found a high prevalence of AVB among mothers with anti-Ro/La antibodies. Although not statistically significant, AVBs in mothers with Ro/La antibodies were numerically more frequent in those not using hydroxychloroquine.Key Points• Although structural heart malformations were the predominant cause of third-degree AVB, autoimmune AVB was still a significant cause.• The distinction between structural or non-structural cause of AVB constitutes an essential issue since it determines the prognostic of these fetuses in terms of complications.• Although not statistically significant, AVBs in mothers with Ro/La antibodies were more frequent in those not using hydroxychloroquine.• If an AVB is diagnosed in a newborn without structural heart disease, the mother should be studied for an autoimmune disease.

Predictive factors of flares in systemic lupus erythematosus patients: data from a multiethnic Latin American cohort.

Purpose The purpose of this paper is to determine the factors predictive of flares in systemic lupus erythematosus (SLE) patients. Methods A case-control study nested within the Grupo Latino Americano De Estudio de Lupus (GLADEL) cohort was conducted. Flare was defined as an increase ≥4 points in the SLEDAI. Cases were defined as patients with at least one flare. Controls were selected by matching cases by length of follow-up. Demographic and clinical manifestations were systematically recorded by a common protocol. Glucocorticoid use was recorded as average daily dose of prednisone and antimalarial use as percentage of time on antimalarial and categorized as never (0%), rarely (>0-25%), occasionally (>25%-50%), commonly (˃50%-75%) and frequently (˃75%). Immunosuppressive drugs were recorded as used or not used. The association between demographic, clinical manifestations, therapy and flares was examined using univariable and multivariable conditional logistic regression models. Results A total of 465 cases and controls were included. Mean age at diagnosis among cases and controls was 27.5 vs 29.9 years, p = 0.003; gender and ethnic distributions were comparable among both groups and so was the baseline SLEDAI. Independent factors protective of flares identified by multivariable analysis were older age at diagnosis (OR = 0.929 per every five years, 95% CI 0.869-0.975; p = 0.004) and antimalarial use (frequently vs never, OR = 0.722, 95% CI 0.522-0.998; p = 0.049) whereas azathioprine use (OR = 1.820, 95% CI 1.309-2.531; p < 0.001) and SLEDAI post-baseline were predictive of them (OR = 1.034, 95% CI 1.005-1.064; p = 0.022). Conclusions In this large, longitudinal Latin American cohort, older age at diagnosis and more frequent antimalarial use were protective whereas azathioprine use and higher disease activity were predictive of flares.

Evaluation of learned helplessness, self-efficacy and disease activity, functional capacity and pain in Argentinian patients with rheumatoid arthritis.

OBJECTIVES: To evaluate the association between learned helplessness (LH) and self-efficacy (SE) with disease activity, functional capacity, and level of pain in patients with rheumatoid arthritis (RA) and to compare LH and SE between patients in remission and patients with active disease. METHOD: This multicentre, cross-sectional study included consecutive patients (aged ≥ 18 years) with RA according to 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria. LH was measured by the Rheumatology Attitude Index (RAI), Spanish version; SE with the Arthritis Self-efficacy Scale (ASES), Spanish version; functional capacity with the Health Assessment Questionnaire, Argentinian version (HAQ-A); and perceived pain by the visual analogue scale (VAS). Disease activity was measured by the Clinical Disease Activity Index (CDAI). RESULTS: A total of 115 patients (82% females) with a mean (± sd) age of 58 ± 13 years were included. We found a significantly positive correlation between LH and perceived pain (p < 0.001), HAQ-A score (p < 0.001), and CDAI (p < 0.001) and a significantly negative correlation between SE and perceived pain (p < 0.001), HAQ-A score (p < 0.001), and CDAI (p < 0.001). We found greater levels of SE and lower grades of LH in patients in remission compared to those with active disease (median 76 vs. 58; p < 0.001 and 6 vs. 11; p < 0.001, respectively). CONCLUSIONS: LH and SE correlated significantly with disease activity, functional capacity, and perceived pain. Levels of SE were higher in patients in remission compared to those with active disease as opposed to levels of LH, which were lower in patients in remission compared to those with active disease. These results show that cognitive factors are related to disease activity and their modifications may have importance in the management of RA.

Lupus in Latin-American patients: lessons from the GLADEL cohort.

The need for comprehensive published epidemiologic and clinical data from Latin American systemic lupus erythematosus (SLE) patients motivated the late Dr Alarcón-Segovia and other Latin American professionals taking care of these patients to spearhead the creation of the G: rupo L: atino A: mericano D: e E: studio del L: upus (GLADEL) cohort in 1997. This inception cohort recruited a total of 1480 multiethnic (Mestizo, African-Latin American (ALA), Caucasian and other) SLE patients diagnosed within two years from the time of enrollment from 34 Latin American centers with expertise in the diagnosis and management of this disease. In addition to the initial 2004 description of the cohort, GLADEL has contributed to improving our knowledge about the course and outcome of lupus in patients from this part of the Americas. The major findings from this cohort are highlighted in this review. They have had important clinical implications for the adequate care of SLE patients both in Latin America and worldwide where these patients may have emigrated.

Late-onset systemic lupus erythematosus in Latin Americans: a distinct subgroup?

OBJECTIVE: To examine the characteristics of patients who developed late onset systemic lupus erythematosus (SLE) in the GLADEL (Grupo Latino Americano de Estudio del Lupus) cohort of patients with SLE. METHODS: Patients with SLE of less than two years of disease duration, seen at 34 centers of nine Latin American countries, were included. Late-onset was defined as >50 years of age at time of first SLE-related symptom. Clinical and laboratory manifestations, activity index (SLEDAI), and damage index (SLICC/ACR- DI) were ascertained at time of entry and during the course (cumulative incidence). Features were compared between the two patient groups (<50 and ≥50) using descriptive statistics and hypothesis tests. Logistic regression was performed to examine the association of late-onset lupus, adjusting for other variables. RESULTS: Of the 1480 patients included, 102 patients (6.9 %) had late-onset SLE, 87% of which were female. Patients with late-onset SLE had a shorter follow-up (3.6 vs. 4.4 years, p < 0.002) and a longer time to diagnosis (10.1 vs. 5.8 months, p < 0.001) compared to the younger onset group. Malar rash, photosensitivity, and renal involvement were less prevalent while interstitial lung disease, pleural effusions, and sicca symptoms were more frequent in the older age group (p > 0.05). In multivariable analysis, late onset was independently associated with higher odds of ocular (OR = 3.66, 95% CI = 2.15-6.23), pulmonary (OR = 2.04, 95% CI = 1.01-4.11), and cardiovascular (OR = 1.76, 95% CI = 1.04-2.98) involvement and lower odds of cutaneous involvement (OR = 0.41, 95% CI = 0.21-0.80), number of cumulative SLE criteria (OR = 0.79, 95% CI = 0.64-0.97), use of cyclophosphamide (OR = 0.47, 95% CI = 0.24-0.95), and anti-RNP antibodies (OR = 0.43, 95% CI = 0.20-0.91). A Cox regression model revealed a higher risk of dying in older onset than the younger-onset SLE (OR = 2.61, 95% CI = 1.2-5.6). CONCLUSION: Late-onset SLE in Latin Americans had a distinct disease expression compared to the younger-onset group. The disease seems to be mild with lower cumulative SLE criteria, reduced renal/mucocutaneous involvements, and less use of cyclophosphamide. Nevertheless, these patients have a higher risk of death and of ocular, pulmonary, and cardiovascular involvements.

Value of repeat biopsy in lupus nephritis flares.

OBJECTIVES: Renal flares are common in lupus nephritis (LN), and class switch is thought to be characteristic. There is no agreement on indications for performing a repeat renal biopsy. Our objective was to retrospectively review patients who had more than one renal biopsy performed on clinical indications, and analyse clinical, pathological and treatment changes after successive biopsies. METHODS: Forty-five patients with LN and one or more repeat renal biopsies were included, with a total of 116 biopsies. RESULTS: Of the 71 repeat biopsies, pathological transition occurred in 39 (54.9%). When having a previous biopsy with a proliferative lesion, class switch occurred in 55.6%, with 24.4% evolving into non-proliferative classes. When previous biopsy was class V, transition to other classes occurred in 58.3% and changes were all into proliferative classes. Conversion from one pure proliferative form to another (class III to class IV or vice versa) happened in 11.3% of the rebiopsies, with 62 rebiopsies (87.3%) leading to a change in the treatment regimen. CONCLUSIONS: Histological transformations were common, and they occurred when the previous biopsy had non-proliferative lesions as well as when lesions were proliferative. Treatments were modified after repeat renal biopsy in the majority of patients. In this experience, kidney repeat biopsies were useful in guiding treatment of LN flares.

Systemic sclerosis in Argentina: evaluation of a large cohort from a single centre and comparison with other international series.

OBJECTIVES: Prevalence of systemic sclerosis (SSc) and different clinical subsets varies across the world. Few data have been published on SSc patients in Latin America. Our objective was to describe a SSc cohort in Argentina and to compare clinical findings, disease subsets and antibodies with other international SSc populations. METHODS: Patients with SSc (n=234) seen at the Rheumatology section of the Hospital Italiano de Buenos Aires between 2000-2011 were retrospectively analysed. Data on clinical manifestations, disease subsets and antibodies were obtained. Patients were classified into diffuse cutaneous (dc) and limited cutaneous (lc) subsets. Comparison with other cohorts (France, United States, Germany, Italy, Mexico, EUSTAR and Brazil) was made based on published information. RESULTS: A higher female:male ratio (12:1) and a higher limited subset prevalence (76.1%) was found in this Argentine cohort comparing with others. We also found a lower prevalence of diffuse disease, anti Scl-70 (antitopoisomerase) and nucleolar pattern antinuclear antibodies. Within each subset, clinical findings were similar with other SSc populations except for a very low prevalence in renal crisis (0.02% of dc SS). CONCLUSIONS: With slight variations perhaps due to genetic, environmental or referral factors, SSc in this cohort appears to be similar to that described in other parts of the world.

Mestizos with systemic lupus erythematosus develop renal disease early while antimalarials retard its appearance: data from a Latin American cohort.

OBJECTIVES: The objective of this paper is to assess the predictors of time-to-lupus renal disease in Latin American patients. METHODS: Systemic lupus erythematosus (SLE) patients (n = 1480) from Grupo Latino Americano De Estudio de Lupus (GLADEL's) longitudinal inception cohort were studied. Endpoint was ACR renal criterion development after SLE diagnosis (prevalent cases excluded). Renal disease predictors were examined by univariable and multivariable Cox proportional hazards regression analyses. Antimalarials were considered time dependent in alternative analyses. RESULTS: Of the entire cohort, 265 patients (17.9%) developed renal disease after entering the cohort. Of them, 88 (33.2%) developed persistent proteinuria, 44 (16.6%) cellular casts and 133 (50.2%) both; 233 patients (87.9%) were women; mean (± SD) age at diagnosis was 28.0 (11.9) years; 12.2% were African-Latin Americans, 42.5% Mestizos, and 45.3% Caucasians (p = 0.0016). Mestizo ethnicity (HR 1.61, 95% CI 1.19-2.17), hypertension (HR 3.99, 95% CI 3.02-5.26) and SLEDAI at diagnosis (HR 1.04, 95% CI 1.01-1.06) were associated with a shorter time-to-renal disease occurrence; antimalarial use (HR 0.57, 95% CI 0.43-0.77), older age at onset (HR 0.90, 95% CI 0.85-0.95, for every five years) and photosensitivity (HR 0.74, 95% CI 0.56-0.98) were associated with a longer time. Alternative model results were consistent with the antimalarial protective effect (HR 0.70, 95% CI 0.50-0.99). CONCLUSIONS: Our data strongly support the fact that Mestizo patients are at increased risk of developing renal disease early while antimalarials seem to delay the appearance of this SLE manifestation. These data have important implications for the treatment of these patients regardless of their geographic location.

Validation of the Spanish, Portuguese and French versions of the Lupus Damage Index questionnaire: data from North and South America, Spain and Portugal.

We have previously developed and validated a self-administered questionnaire, modelled after the Systemic Lupus International Collaborating Clinics Damage Index (SDI), the Lupus Damage Index Questionnaire (LDIQ), which may allow the ascertainment of this construct in systemic lupus erythematosus (SLE) patients followed in the community and thus expand observations made about damage. We have now translated, back-translated and adapted the LDIQ to Spanish, Portuguese and French and applied it to patients followed at academic and non-academic centres in North and South America, Portugal and Spain while their physicians scored the SDI. A total of 887 patients (659 Spanish-speaking, 140 Portuguese-speaking and 80 French-speaking patients) and 40 physicians participated. Overall, patients scored all LDIQ versions higher than their physicians (total score and all domains). Infrequent manifestations had less optimal clinimetric properties but overall agreement was more than 95% for the majority of items. Higher correlations were observed among the Spanish-speaking patients than the Portuguese-speaking and French-speaking patients; further adjustments may be needed before the Portuguese and French versions of the LDIQ are applied in community-based studies. The relationship between the LDIQ and other outcome parameters is currently being investigated in a different patient sample.

Amerindian ancestry in Argentina is associated with increased risk for systemic lupus erythematosus.

Previous studies have demonstrated that in admixed populations, West African ancestry is associated with an increased prevalence of systemic lupus erythematosus (SLE). In the current study, the effect of Amerindian ancestry in SLE was examined in an admixed population in Argentina. The Argentine population is predominantly European with approximately 20% Amerindian admixture, and a very small (<2%) contribution from West Africa. The results indicate that Amerindian admixture in this population is associated with a substantial increase in SLE susceptibility risk (Odds Ratio=7.94, P=0.00006). This difference was not due to known demographic factors, including site of collection, age and gender. In addition, there were trends towards significance for Amerindian ancestry influencing renal disease, age of onset and anti-SSA antibodies. These studies suggest that populations with Amerindian admixture, like those with West African admixture, should be considered in future studies to identify additional allelic variants that predispose to SLE.

No evidence of association between genetic variants of the PDCD1 ligands and SLE.

PDCD1, an immunoreceptor involved in peripheral tolerance has previously been shown to be genetically associated with systemic lupus erythematosus (SLE). PDCD1 has two ligands whose genes are located in close proximity on chromosome 9p24. Our attention was drawn to these ligands after finding suggestive linkage to a marker (gata62f03, Z=2.27) located close to their genes in a genome scan of Icelandic families multiplex for SLE. Here, we analyse Swedish trios (N=149) for 23 single nucleotide polymorphisms (SNPs) within the genes of the PDCD1 ligands. Initially, indication of association to eight SNPs was observed, and these SNPs were therefore also analysed in Mexican trios (N=90), as well as independent sets of patients and controls from Sweden (152 patients, 448 controls) and Argentina (288 patients, 288 controls). We do not find support for genetic association to SLE. This is the first genetic study of SLE and the PDCD1 ligands and the lack of association in several cohorts implies that these genes are not major risk factors for SLE.

Male systemic lupus erythematosus in a Latin-American inception cohort of 1214 patients.

The objective of the study was to evaluate the influence of the male gender in the clinical presentation and outcome of systemic lupus erythematosus in a prospective inception cohort of Latin-American patients. Of the 1214 SLE patients included in the GLADEL cohort, 123 were male. Demographic characteristics as well as clinical manifestations, laboratory profile, activity and damage scores were evaluated at onset and during the course of the disease and compared with female patients. The median age at onset of the male patients was 27 and that at diagnosis 29.2 years. Delay to diagnosis was shorter in males (134 versus 185 days, P = 0.01). At onset, men more frequently showed fever (42.3 versus 27.0%, P = 0.001) and weight loss (23.6 versus 11.8%, P = 0.001). During disease course the incident of symptoms was: fever, 67.8 versus 55.6%, P = 0.012; weight loss, 47.2 versus 24.3%, P = 0.001; arterial hypertension, 37.4 versus 25.8%, P = 0.007; renal disease (persistent proteinuria and/or cellular casts), 58.5 versus 44.6%, P = 0.004); and hemolytic anemia, 19.5 versus 10.9%, P = 0.008. The laboratory results showed that: men more frequently had IgG anticardiolipin antibodies (68.2 versus 49%, P = 0.02) and low C3 (61.3 versus 48.1%, P = 0.03); 5/123 men died (4%) compared with 29/1091 women (2.7%). In conclusion, 10% of GLADEL's cohort patients were male. They showed a distinctive profile with shorter delay to diagnosis, higher incidence of fever, weight loss, arterial hypertension, renal disease, hemolytic anemia, IgG anticardiolipin antibodies and low C3. Although not statistically significant, mortality was higher in men.

Inflammatory muscle disease: therapeutic aspects.

The present treatment of the inflammatory myopathies remains unsatisfactory in several areas, perhaps due in part to our incomplete knowledge of their aetiology. These conditions have been grouped together for practical purposes and because of a similar approach to treatment. However, recent data regarding pathological findings, serological patterns and different outcomes, suggest that some of these myopathies may be distinct, and perhaps approaches to treatment should be tailored according to these findings. This chapter will attempt to update our current management, offer an analysis of recent data regarding newer treatment modalities and highlight areas lacking solid data that need to be further addressed. Although corticosteroids are still considered to be the mainstay of treatment, the earlier use of immunosuppressive therapy will be discussed, as will the use of autoantibody profiles for tailoring treatment. Newer modalities for the monitoring of therapeutic response and their current place in clinical practice will be analysed. The management of refractory cases will be addressed as will the current management of calcinosis, a problem more frequently encountered in children.

Sjögren's in adult Still's disease?

The objective of the study was to search for clinical, ophthalmological and serological manifestations of Sjögren's syndrome in patients with adult onset Still's Disease (AOSD). Eight consecutive patients with AOSD were evaluated. In all cases a standardized questionnaire to disclose sicca symptoms as well as extraglandular manifestations commonly associated with Sjögren's syndrome(SS) was conducted. Ophthalmological and serological evaluation was undertaken in all patients. Oral involvement was investigated by minor salivary gland biopsy in 7 patients. One case presented symptomatic keratoconjunctivitis sicca and grade III Chisholm labial biopsy. A further 2 patients had grade IV (4 foci per 4 mm2) salivary gland biopsy, in the absence of xerostomia or xerophthalmia. The search for autoantibodies proved negative throughout. It was concluded that focal sialoadenitis was not uncommon in our patients with AOSD. Whether this finding corresponds to a true SS is not yet clearly determined.

Streptococcus pyomyositis occurring in a patient with dermatomyositis in a country with temperate climate.

We describe a man in whom pyomyositis developed in a temperate climate. Three facts make this case unique. First the pyomyositis developed in someone with underlying dermatomyositis, this being the second reported case to our knowledge. Second, the organism involved was a Streptococcus and not a Staphylococcus as in most cases described, and the course of the disease was acute and not subacute as is usually reported. Finally, contrary to most described cases, surgical drainage was not necessary, probably because of the early diagnosis. Pyomyositis should be considered a possible cause of localized pain in patients with underlying inflammatory muscle disease.

Baker's cysts, pseudothrombophlebitis, pseudo-pseudothrombophlebitis: where do we stand?

The diagnostic approach and therapeutic attitudes to be assumed when facing the dilemma of deep vein thrombosis versus a complicated Baker's cyst remain unclear. We examined our own approach with 16 Baker's cysts [11 presenting with a "thrombophlebitis picture" (TP)] recently diagnosed in our services, and reviewed the literature. All of our patients had an underlying joint disorder and previous knee effusions. The diagnostic approach (i.e., the request or not for venography) was related to the specialty of the physician who saw the patient first. The results of the venography led to anticoagulation treatment in 5 of the 6 patients on whom it was performed, although these patients did not otherwise differ from those with a similar clinical picture in whom no venogram was obtained. Arthrograms performed early after onset of the TP were more likely to reveal cyst rupture. The recent literature does not mention serious venous complications (in particular, pulmonary embolism) in patients in whom only the cyst was treated, without knowledge of possible coexisting venous occlusions. The need to perform venography, the importance of the localisation of the occlusions and the therapeutic consequences are discussed and a proposal is made to study these patients in a systematic way in order to better understand the inter-relationship between complicated popliteal cysts and venous alterations, and to decide the best approach to assume in the future.

Clinical and serologic characteristics of patients with overlap syndrome: is mixed connective tissue disease a distinct clinical entity?

We discuss the clinical and serologic features of 27 patients with overlap syndrome followed prospectively by our group. The findings are similar to those of other reports, but we have drawn attention to the presence of peritendinous nodules in these patients and mentioned some peculiar neurologic manifestations. Rheumatoid arthritis was the most common diagnosis in our patients. The presence of high-titer antibodies against the nuclear ribonucleoprotein fraction of extractable nuclear antigen (nRNP) did not allow the identification of a particular subgroup. However, patients with this antibody tended to fulfill more criteria of more diseases than those without it. The findings lead us to conclude that antibodies to nRNP do not identify a particular subgroup within the overlap syndromes and that mixed connective tissue disease does not appear to be a distinct entity.