Growth velocity and interleukin 6 concentrations in juvenile idiopathic arthritis

OBJECTIVE: .To evaluate associations of growth velocity with inflammatory markers and cumulative dose of glucocorticoid in a cohort of patients with juvenile idiopathic arthritis (JIA) followed during 1 year. METHODS: Seventy-nine patients were evaluated. Disease activity was evaluated by a pediatric rheumatologist. Anthropometric data were classified according to the World Health Organization standards. Tanner growth velocity curves were used; values below the Z-score < or = -2 were considered low growth velocity. Serum concentrations of interleukin 6 (IL-6) were measured by ELISA, and values > 1 pg/ml were considered elevated. RESULTS: The prevalence of low growth velocity was 25.3%, and it was associated with active disease on followup visit, elevated IL-6, erythrocyte sedimentation rate and C-reactive protein, and higher cumulative glucocorticoid doses. In the multiple linear regression with growth velocity as the dependent variable, only elevated IL-6 level was independently and negatively associated with growth velocity. CONCLUSION: Low growth velocity is highly prevalent in children with JIA. Elevated IL-6 levels seem to have an important negative influence on growth in these children, while total glucocorticoid exposure appears to be a secondary factor.     

Antimalarial treatment may have a time‐dependent effect on lupus survival: Data from a multinational Latin American inception cohort

Objective

To evaluate the beneficial effect of antimalarial treatment on lupus survival in a large, multiethnic, international longitudinal inception cohort.

Methods

Socioeconomic and demographic characteristics, clinical manifestations, classification criteria, laboratory findings, and treatment variables were examined in patients with systemic lupus erythematosus (SLE) from the Grupo Latino Americano de Estudio del Lupus Eritematoso (GLADEL) cohort. The diagnosis of SLE, according to the American College of Rheumatology criteria, was assessed within 2 years of cohort entry. Cause of death was classified as active disease, infection, cardiovascular complications, thrombosis, malignancy, or other cause. Patients were subdivided by antimalarial use, grouped according to those who had received antimalarial drugs for at least 6 consecutive months (user) and those who had received antimalarial drugs for <6 consecutive months or who had never received antimalarial drugs (nonuser).

Results

Of the 1,480 patients included in the GLADEL cohort, 1,141 (77%) were considered antimalarial users, with a mean duration of drug exposure of 48.5 months (range 6–98 months). Death occurred in 89 patients (6.0%). A lower mortality rate was observed in antimalarial users compared with nonusers (4.4% versus 11.5%; P< 0.001). Seventy patients (6.1%) had received antimalarial drugs for 6–11 months, 146 (12.8%) for 1–2 years, and 925 (81.1%) for >2 years. Mortality rates among users by duration of antimalarial treatment (per 1,000 person‐months of followup) were 3.85 (95% confidence interval [95% CI] 1.41–8.37), 2.7 (95% CI 1.41–4.76), and 0.54 (95% CI 0.37–0.77), respectively, while for nonusers, the mortality rate was 3.07 (95% CI 2.18–4.20) (P for trend < 0.001). After adjustment for potential confounders in a Cox regression model, antimalarial use was associated with a 38% reduction in the mortality rate (hazard ratio 0.62, 95% CI 0.39–0.99).

Conclusion

Antimalarial drugs were shown to have a protective effect, possibly in a time‐dependent manner, on SLE survival. These results suggest that the use of antimalarial treatment should be recommended for patients with lupus.

     

Differential CCR5Delta32 allelic frequencies in juvenile idiopathic arthritis subtypes: evidence for different regulatory roles of CCR5 in rheumatological diseases

BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease of childhood and is characterized by persistent arthritis for at least 6 weeks. Its aetiopathogenesis is unknown but there is strong evidence that there is a substantial genetic component. Chemokine receptors genes are among the candidate genes for association with arthritis and other inflammatory diseases. The CC chemokine receptor 5 (CCR5)Delta32 polymorphism has been associated with rheumatoid arthritis (RA), conferring a protective effect. OBJECTIVE: To determine whether the CCR5Delta32 polymorphism is associated with JIA and RA in Brazilian patients. METHODS: We investigated 203 RA patients, 101 JIA patients, and 104 healthy individuals by amplification of the CCR5Delta32 deletion. We compared the allelic frequencies among these groups, as well as among different JIA subtypes. RESULTS: The frequency of the Delta32 allele was higher in JIA patients (9.4%) as compared to control subjects (3.8%) and RA patients (3.2%). Grouping the patients according to JIA subtypes, we observed a higher CCR5Delta32 allelic frequency in the subtypes with a greater inflammatory component: 4.1% in oligoarticular (n = 49), 11.2% in polyarticular (n = 40) [9.5% in rheumatoid factor negative (RF-) and 33.3% in RF positive (+)], and 25% in systemic JIA (n = 12). CONCLUSIONS: This study suggests that in JIA, unlike in RA, CCR5Delta32 does not have a protective effect, but instead it could be a factor associated with more inflammatory forms of the disease. These observations give rise to new questions about the mechanism and the cellular types involved in JIA as well as about the aetiology of JIA.     

Endothelial nitric oxide synthase T-786C polymorphism in rheumatoid arthritis: association with extraarticular manifestations

Several genetic factors were implicated in the pathogenesis of rheumatoid arthritis (RA). A case–control study was carried out to verify the associations of T-786C polymorphism in the promoter region of the endothelial nitric oxide synthase (eNOS) gene with RA. One hundred and five consecutive RA patients and 100 healthy controls were genotyped. The distribution of the T-786C genotype and alleles did not differ significantly between RA patients and controls. Nevertheless, the frequency of extraarticular manifestations was significantly greater among the carriers of the C/C genotype than among carriers of the T/C and T/T genotypes (P = 0.022). The C/C genotype was significantly associated with extraarticular manifestations compared with the T/T and T/C genotypes taken together (OR = 4.9, 95% CI = 1.3–18.9). The C allele was significantly associated with extraarticular manifestations of RA (P _corr = 0.032). The results suggested the existence of an association between the T-786C polymorphism of the eNOS gene and extraarticular manifestations of RA.     

Raised serum S100B protein levels in neuropsychiatric lupus

OBJECTIVE: To test serum S100B protein levels in patients with and without neuropsychiatric systemic lupus erythematosus (NPSLE) and controls. METHODS: 87 patients with SLE, 23 with and 64 without neuropsychiatric involvement, and 25 control subjects were prospectively evaluated. NPSLE diagnosis was made according to the American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Serum S100B protein levels were determined with a luminescence immunoassay. Statistical analysis was performed using Mann-Whitney and Kruskal-Wallis tests. RESULTS: Among the patients with NPSLE, 9 presented psychosis; 4, cranial neuropathy; 3, cerebrovascular disease; 1, seizures; 1, chorea; 1, peripheral polyneuropathy; 1, multiplex mononeuropathy; 3, dementia. Serum concentrations of S100B protein were significantly higher in patients with NPSLE (median 0.164 ng/ml, interquartile range 0.113-0.332) than in non-NPSLE patients (0.062 ng/ml, 0.026-0.109) and controls (0.088 ng/ml, 0.013-0.124) (p<0.001). Patients with anti-dsDNA antibodies had higher S100B protein levels (p = 0.001). No significant associations were found of lupus activity (among non-NPSLE cases), antiphospholipid antibodies, and reduced complement levels with S100B concentration. CONCLUSIONS: Serum S100B protein level is raised in NPSLE, reflecting continuing neurological damage. The association of anti-dsDNA antibodies with higher S100B protein concentration deserves further study.     

Real-life data of survival and reasons for discontinuation of biological disease-modifying drugs ‘in’ rheumatoid arthritis

Background Rheumatoid arthritis is a chronic, autoimmune disease in which treatment has evolved with a variety of therapeutic classes. Biological disease-modifying antirheumatic drugs have improved therapy; however, the continued long-term use of these drugs with sustained safety and efficacy remains a challenge. ObjectiveThe objective of this study was to analyze time of use and reasons for discontinuation of biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis.SettingIt is as part of REAL (Rheumatoid Arthritis in Real Life), a multicenter project that evaluated Brazilian patients with rheumatoid arthritis in a real-life setting. Eleven referral centers for the treatment in the public network participated in the study.MethodsWe conducted a cross-sectional analysis of data collected in the REAL study from August to October 2015 study. The patients were submitted to clinical evaluation and analysis of medical records.Results1125 patients were included (89.5% women; median age: 56.6 years; and disease time: 12.8 years). A total of 406 (36.09%) participants were on a biological disease-modifying antirheumatic drugs. Infliximab was the drug with the longest time of use (12 years). Most (64.4%) drug suspension episodes were due to inefficacy. Adalimumab and certolizumab had a greater number of suspensions due to primary inefficacy, while discontinuations for abatacept were due more to secondary inefficacy. Infliximab had fewer suspensions due to primary inefficacy and golimumab had fewer episodes of secondary inefficacy. Regarding side effects, infliximab was suspended a greater number of times because of clinical and laboratory side effects. Abatacept and adalimumab had fewer suspensions due to clinical side effects, and certolizumab, rituximab and tocilizumab had fewer laboratory adverse effects. Conclusion Among the biological disease-modifying antirheumatic drugs being used for long periods, infliximab had greater time of use. Most drug suspensions (64%) were due to primary or secondary inefficacy. Number of discontinuations due to clinical and laboratory adverse effects for each drug was analyzed, and these data should be confirmed by other real-life studies. Knowledge of what is happening in real life is essential to health professionals, who need to be aware of the most common adverse effects and to health managers, who aim for greater cost-effectiveness in the choice of medications.

     

Physical activity prevents bone loss in premenopausal women with rheumatoid arthritis: a cohort study

The aim of the study was to compare the bone loss and the influence of physical activity between premenopausal women with rheumatoid arthritis (RA) and healthy women. A total of 71 patients with RA and 29 healthy premenopausal women with the criteria of the American College of Rheumatology for RA were followed for 2 years. Of these 85% were Caucasian, aged 38 +/- 6.6 years and with a duration of disease of 88 +/- 50 months and 48 (71.8%) used GC, mean daily dose, 7.3 +/- 3.5 mg. There was a reduction in the T-score of the femoral neck (P = 0.04) and in the Ward region (P = 0.05) in RA. Through logistic regression, it was found that sedentarism was a risk factor for osteopenia in RA, with relative risk of 1.6 (IC = 1.238-1.734). Moderate physical activity reduced the risk of osteopenia by 50%. Sedentarism and low weight are the main factors associated with bone loss. Physical activity reduces bone loss. Early preventive and therapeutic measures must be encouraged.     

The role of mannose-binding lectin in systemic lupus erythematosus

Susceptibility to systemic lupus erythematosus (SLE) is associated with genetic, hormonal, immunological, and environmental factors. Many genes have been related with the appearance of SLE, including several loci that code different complement components and their receptors. Some genetic deficiencies of complement molecules are strongly associated with SLE, probably because these deficiencies could cause decreased clearance of apoptotic cell material. As a consequence of the apoptotic material accumulation, high levels of autoantigens can be presented inappropriately to the immune system in an inflammatory context, resulting in an imbalance on the mechanisms of immunological tolerance, immune system activation, and autoantibody production. Recent studies proposed a role to the mannose-binding lectin (MBL) in the SLE physiopathogenesis. This protein activates the complement system, and the presence of several polymorphisms at the promoter and coding regions of the MBL-2 gene determines alterations at the plasma levels of MBL. Some of these polymorphisms have been associated with SLE susceptibility, as well as with clinical and laboratory typical features of this disease, cardiovascular events, and infections. Besides, it has been described that the presence of anti-MBL autoantibodies in sera of SLE patients can influence MBL plasma levels and its functional activity.     

Killer cell immunoglobulin-like receptor (KIR) genes in systemic sclerosis

A previous study has suggested that the combination KIR2DS2⁺/KIR2DL2^‐ was related to increased risk for systemic sclerosis (SSc), while others have failed to reproduce this finding. Our objective was to study this matter further and test the association of other KIR genes with SSc. One hundred and ten SSc patients and 115 healthy bone marrow donors were enrolled in a case–control study. Blood was collected for DNA extraction; typing of 15 KIR genes and human leucocyte antigen‐C (HLA‐C) was made by polymerase chain reaction with sequence specific primers (PCR–SSP), followed by electrophoresis on agarose gel. Patients underwent clinical evaluation, serology, Doppler echocardiography and chest high‐resolution computed tomography. The frequency of the inhibitory KIR2DL2 was significantly lower in patients [29·1% versus 65·2% in controls, P < 0·0001; odds ratio (OR) = 0·22, 95% confidence interval 0·12–0·40]. When combinations of activating and inhibitory KIR genes were analysed, the presence of KIR2DS2 in the absence of KIR2DL2 (KIR2DS2⁺/KIR2DL2^‐) was more frequent in patients than in controls (25·5% versus 1·7%, respectively; P < 0·0001; OR = 19·29, 4·24–122·26). However, the presence of both KIR2DS2 and KIR2DL2 (KIR2DS2⁺/KIR2DL2⁺) was more frequent in controls (57·4%) than in patients (28·2%, P < 0·0001), suggesting a preponderant protective effect of KIR2DL2 over KIR2DS2. Stratification for HLA‐C1 status did not change these results. No statistically significant associations were found between KIR phenotypes and clinical and laboratory features of SSc. Our results suggest a protective role of KIR2DL2⁺ phenotype and confirmed the association of the combination KIR2DS2⁺/KIR2DL2^‐ with increased risk for SSc.