Analysis of 65 Renal Biopsies From Patients With Rheumatoid Arthritis (1976-2015): Change in Treatment Strategies Decreased Frequency and Modified Histopathological Findings.

INTRODUCTION: No inherent renal lesions are known in rheumatoid arthritis (RA), but urinary abnormalities and renal dysfunction have been described. OBJECTIVE: First, we describe the histopathological findings of renal biopsies (RBs) in patients with RA and associated clinical manifestations. Second, we evaluated time evolution of RA and the relationship between drugs and renal disease. Last, we investigate whether changes in the management of RA from 1976 to 2015 influenced RBs indication, frequency, and type of histopathological findings. PATIENTS AND METHODS: This is a retrospective and observational study conducted at a university hospital from Argentina. Patients with a diagnosis of RA (ACR, 1987) and RBs between 1976 and 2015 were included. Sixty-five patients met the inclusion criteria. The histopathological findings and associated clinical manifestations were evaluated. Time evolution of RA and the relationship between drugs and renal disease were also determined. To clarify these issues, we characterized 3 groups according to changes in the management of RA: 1976-1989, 1990-2002, and 2003-2015. RESULTS: The most common histopathological finding was renal amyloidosis in 31% (n = 20), followed by mesangial glomerulonephritis in 18% (n = 12), membranous nephropathy in 17% (n = 11), extracapillary proliferative glomerulonephritis in 15% (n = 10), focal segmental glomerular sclerosis in 9% (n = 6), minimal change nephropathy in 5% (n = 3), and tubulointerstitial nephritis in 5% (n = 3). Time evolution of renal amyloidosis was significantly higher than other RBs (15 ± 12 vs 7 ± 6.5 years). Nephrotic syndrome was the most common clinical manifestation (60%) followed by hematuria (46%) with or without proteinuria. Membranous nephropathy was related to the use of gold salts in 45% of cases, and its frequency decreased since 1990. Before 2003, renal amyloidosis was the leading cause of kidney disease, but mesangial glomerulonephritis reached the same frequency between 2003 and 2015. We found that RBs decreased 20% in the second period (1990-2002) and 40% in the last period (2003-2015). Nephrotic syndrome remained the main RB indication during the entire study period. CONCLUSION: This is the first report on RBs findings in patients with RA from Latin America. We found a significant reduction in RBs frequency and modified histological patterns throughout the study period, although RB indication was not modified. Changes in the management of RA might have influenced these findings.

Rheumatoid arthritis in Latin Americans enriched for Amerindian ancestry is associated with loci in chromosomes 1, 12, and 13, and the HLA class II region.

OBJECTIVE: To identify susceptibility loci for rheumatoid arthritis (RA) in Latin American individuals with admixed European and Amerindian genetic ancestry. METHODS: Genotyping was performed in 1,475 patients with RA and 1,213 control subjects, using a customized BeadArray containing 196,524 markers covering loci previously associated with various autoimmune diseases. Principal components analysis (EigenSoft package) and Structure software were used to identify outliers and define the population substructure. REAP software was used to define cryptic relatedness and duplicates, and genetic association analyses were conducted using Plink statistical software. RESULTS: A strong genetic association between RA and the major histocompatibility complex region was observed, localized within BTNL2/DRA-DQB1- DQA2 (P = 7.6 × 10(-10) ), with 3 independent effects. We identified an association in the PLCH2-HES5-TNFRSF14-MMEL1 region of chromosome 1 (P = 9.77 × 10(-6) ), which was previously reported in Europeans, Asians, and Native Canadians. We identified one novel putative association in ENOX1 on chromosome 13 (P = 3.24 × 10(-7) ). Previously reported associations were observed in the current study, including PTPN22, SPRED2, STAT4, IRF5, CCL21, and IL2RA, although the significance was relatively moderate. Adjustment for Amerindian ancestry improved the association of a novel locus in chromosome 12 at C12orf30 (NAA25) (P = 3.9 × 10(-6) ). Associations with the HLA region, SPRED2, and PTPN22 improved in individuals positive for anti-cyclic citrullinated peptide antibodies. CONCLUSION: Our data define, for the first time, the contribution of Amerindian ancestry to the genetic architecture of RA in an admixed Latin American population by confirming the role of the HLA region and supporting the association with a locus in chromosome 1. In addition, we provide data for novel putative loci in chromosomes 12 and 13.

Maternal and fetal outcomes of 72 pregnancies in Argentine patients with systemic lupus erythematosus (SLE).

The purpose of the following study was to analyze maternal and fetal outcomes in pregnant patients with systemic lupus erythematosus (SLE) and the influence of SLE exacerbations on those pregnancies. Seventy-two pregnancies in 61 SLE patients treated between January 1986 and February 2004 in Hospital de Clínicas "José de San Martin" were reviewed retrospectively. Patient age was 28.1 +/- 6.2 years (mean+/-standard deviation [SD]). Mean SLE duration was 4.5 +/- 3.2 years (range 6 months-10 years). No patient acquired the disorder during gestation. Four (5.5%) patients had signs of active disease at the beginning of her pregnancy. Sixteen patients, accounting for 20 pregnancies, had a history of lupus nephritis. Nine patients met secondary antiphospholipid syndrome criteria and had 13 pregnancies. There were 14 exacerbations of the disease during pregnancy (19.4%), with most flares being mild. The most common obstetric complications were gestational hypertension in 15 pregnancies (20.8%) and preeclampsia in 8 pregnancies (11%). Forty-six percent of pregnancies ended in preterm deliveries. There were 62 live births (1 twin birth; 85%), 6 stillbirths (8%), and 5 spontaneous abortions (7%). Thirty-nine percent of newborns had low birth weight. Adequate pregnancy follow-up and delivery care by an interdisciplinary team in Argentine SLE patients with no pre-gestational preparation resulted in maternal and fetal outcomes similar to those seen in world reference centers.

Clinical Relevance of Galectin-1 and Galectin-3 in Rheumatoid Arthritis Patients: Differential Regulation and Correlation With Disease Activity.

Galectins, a family of animal lectins, play central roles in immune system regulation, shaping both innate and adaptive responses in physiological and pathological processes. These include rheumatoid arthritis (RA), a chronic multifactorial autoimmune disease characterized by inflammatory responses that affects both articular and extra-articular tissues. Galectins have been reported to play central roles in RA and its experimental animal models. In this perspective article we present new data highlighting the regulated expression of galectin-1 (Gal-1) and galectin-3 (Gal-3) in sera from RA patients under disease-modifying anti-rheumatic drugs (DMARDs) and/or corticoid treatment in the context of a more comprehensive discussion that summarizes the roles of galectins in joint inflammation. We found that Gal-1 levels markedly increase in sera from RA patients and positively correlate with erythrocyte sedimentation rate (ERS) and disease activity score 28 (DAS-28) parameters. On the other hand, Gal-3 is downregulated in RA patients, but positively correlates with health assessment questionnaire parameter (HAQ). Finally, by generating receiver-operator characteristic (ROC) curves, we found that Gal-1 and Gal-3 serum levels constitute good parameters to discriminate patients with RA from healthy individuals. Our findings uncover a differential regulation of Gal-1 and Gal-3 which might contribute to the anti-inflammatory effects elicited by DMARDs and corticoid treatment in RA patients.

Effects of Amerindian Genetic Ancestry on Clinical Variables and Therapy in Patients with Rheumatoid Arthritis.

OBJECTIVE: To define whether Amerindian genetic ancestry correlates with clinical and therapeutic variables in admixed individuals with rheumatoid arthritis (RA) from Latin America. METHODS: Patients with RA (n = 1347) and healthy controls (n = 1012) from Argentina, Mexico, Chile, and Peru were included. Samples were genotyped for the Immunochip v1 using the Illumina platform. Clinical data were obtained through interviews or the clinical history. RESULTS: Percentage of Amerindian ancestry was comparable between cases and controls. Morning stiffness (p < 0.0001, OR 0.05), rheumatoid factor (RF; p < 0.0001, OR 0.22), radiographic changes (p < 0.0001, OR 0.05), and higher number of criteria were associated with lower Amerindian ancestry after Bonferroni correction. Higher Amerindian ancestry correlated only with weight loss (pBonferroni < 0.0001, OR 2.85). Increased Amerindian ancestry correlated with higher doses of azathioprine (p < 0.0001, OR 163.6) and sulfasalazine (p < 0.0001, OR 48.6), and inversely with methotrexate (p = 0.001, OR 0.35), leflunomide (p = 0.001, OR 0.16), and nonsteroidal antiinflammatory drugs (pBonferroni = 0.001, OR 0.37). Only the presence of RF and weight loss were modified after confounders adjustment. CONCLUSION: Amerindian ancestry protects against most major clinical criteria of RA, but regarding the association of RF with increased European ancestry, age, sex, and smoking are modifiers. Ancestry also correlates with the therapeutic profiles.

[Pachydermoperiostosis (primary hypertrophic osteoarthropathy)]. / Paquidermoperiostosis (osteoartropatia hipertrofica primaria).

Pachydermoperiostosis or primary hypertrophic osteoarthropathy is a rare disease characterized by cutaneous and osteoarthicular involvement. We describe two patients with finger clubbing, watch crystal nails, bones thickenings, arthritis and different grades of skin affection, without other clinical manifestations. Both did not know of having relatives with the same alterations. Radiological studies of the affected areas showed periostosis. Because of normal laboratory results and chest radiography plus the absence of other underlying causes, diagnosis of primary hypertrophic osteoarthropathy was made.

Multiple avascular necrosis in a patient with systemic lupus erythematosus/systemic sclerosis overlap syndrome.

A white female patient developed overlapping features of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) with severe pulmonary compromise. She was treated with steroids and azathioprine, which improved her clinical condition and spirometric status. In May 2002 she presented with continuous pain in her left ankle that continued even during rest and under treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). Magnetic resonance imaging (MRI) showed multiple avascular necrosis (AVN). Rest and kinesitherapy were indicated for 1 year, and gradually an orthosis was introduced allowing the patient to walk normally.

Anti-ribonucleoproteins autoantibodies in patients with systemic autoimmune diseases. Relation with cutaneous photosensitivity.

A common feature between patients with a certain group of systemic autoimmune pathologies (SAPs) with rheumatic component, such as lupus erythematosus (LE) in all its forms, is the presence of cutaneous photosensitivity (CP) as well as the existence of autoantibodies (Aabs). These Aabs have also high incidence in other SAPs that do not present CP, like primary Sjögren's syndrome and rheumatoid arthritis. Cutaneous photosensitivity is a condition that consists of an exacerbated skin reaction to solar radiations; its incidence can reach 90% in systemic LE. The mechanisms involved in the development of CP have been extensively studied focusing on different approaches; however, the exact mechanism has not been fully elucidated yet. There are many theories that relate specifically the presence of circulating anti-Ro/SS-A Aabs with the CP phenomenon, though there are several studies which are in disagreement. In this study, we evaluated the Aabs profile (anti-Ro/SS-A 52 kDa, anti-Ro/SS-A 60 kDa, anti-La/SS-B, anti-Sm and ANAs) as well as their titer or reactivity, in a local cohort of 169 patients with SAPs. We related those Aabs profiles and titers with the presence or absence of CP, and we found that there was no significant association between the presence of anti-Ro/SS-A Aabs and the occurrence of CP. On the other hand, a statistically significant positive association was found between CP and high reactivity anti-Sm Aabs, though this fact could be biased by the incidence of both events in SLE patients. To sum up, in the particular population studied, there is no direct relationship between anti-Ro/SS-A Aabs and CP, which is in agreement with some authors and in disagreement with many others, contributing to the endless discussion of this issue.

Anticuerpos antipéptidos cíclicos citrulinados como marcadores de diagnóstico y actividad en artritis reumatoidea temprana / Anti-cyclic citrullinated peptide antibodies as diagnostic and activity markers in early rheumatoid artritis

Objetivos: Determinar el valor diagnóstico de los Ac aCCP de segunday tercera generación para AR de reciente comienzo y compararloscon el valor diagnóstico del FR. Evaluar la actividad de la enfermedadmediante el score DAS28 al establecer el diagnóstico de AR. Resultados: Se analizaron los datos de 149 pacientes (75,3% mujeres y 24,7% varones). La edad media de los pacientes fue 58 ± 14. Al final del estudio, 61 (40,9%) cumplieron criterios para AR. Los valores de cribaje de estos anticuerpos demuestran una sensibilidad superior para las dos generaciones de Ac aCCP con respecto al FR, con una specificidad similar para todos los anticuerpos. La actividad de la enfermedad al momentodel diagnóstico medida por DAS28 fue similar en todos los grupos. Conclusiones: Los resultados indican que no existen diferencias estadísticamente significativas en los valores de cribaje entre los Ac anti CCP de las dos generaciones para el diagnóstico de AR. Los valores de cribaje de estos anticuerpos demuestran una sensibilidadsuperior para las dos generaciones de Ac aCCP con respecto al FR, con una especificidad similar para todos los anticuerpos. No hubo diferencias en la actividad de la enfermedad al inicio.

Objetives: To determine the diagnostic value of Ac ACCP second and third generation in the early AR compared to the diagnostic value of FR. To assess disease activity by DAS28 score to establish the diagnosis of RA.Results: We analyzed data from 149 patients (75.3% women and 24.7% males). The average age of patients was 58 ± 14. At the end of the study, 61 (40.9%) met criteria for RA. The values of screening for these antibodies demonstrated a higher sensitivity for the two generations of Ac aCCP with respect to the FR, with a similar specificity for all antibodies. Disease activity at diagnosis by DAS28 score wassimilar in all groups. Conclusions: The results indicate that there were no statistically significant differences among two generations of Ac aCCP for the diagnosis of RA, with a large difference with respect to the RF. Thevalues of screening for these antibodies demonstrated a higher sensitivity for the two generations of Ac aCCP with respect to the FR, with a similar specificity for all antibodies. The activity at the onset of the disease was similar for all the groups.

Paquidermoperiostosis (osteoartropatia hipertrofica primaria) / Pachydermoperiostosis (primary hypertrophic osteoarthropathy)

La paquidermoperiostosis u osteoartropatía hipertrófica primaria es una rara enfermedadcaracterizada por compromiso cutáneo y osteoarticular. Comunicamos dos casos que presentabanhipocratismo digital, uñas en vidrio de reloj, agrandamiento óseo, tumefacción articular y diferentes grados deafectación cutánea, sin otros hallazgos clínicos relevantes. Ambos desconocían antecedentes familiares similares.El estudio radiográfico de las zonas comprometidas mostró periostosis. Con resultados de laboratorio yradiografía de tórax normales, y ausencia de evidencia clínica de otra enfermedad subyacente, se realizó diagnósticode osteoartropatía hipertrófica primaria.

Pachydermoperiostosis orprimary hypertrophic osteoarthropathy is a rare disease characterized by cutaneous and osteoarthicularinvolvement. We describe two patients with finger clubbing, watch crystal nails, bones thickenings,arthritis and different grades of skin affection, without other clinical manifestations. Both did not know of havingrelatives with the same alterations. Radiological studies of the affected areas showed periostosis. Because ofnormal laboratory results and chest radiography plus the absence of other underlying causes, diagnosis of primaryhypertrophic osteoarthropathy was made.