RESUMO
OBJECTIVES: Musculoskeletal pain and fatigue are common features in systemic lupus erythematosus (SLE). The cholinergic anti-inflammatory pathway is a physiological mechanism diminishing inflammation, engaged by stimulating the vagus nerve. We evaluated the effects of non-invasive vagus nerve stimulation in patients with SLE and with musculoskeletal pain. METHODS: 18 patients with SLE and with musculoskeletal pain ≥4 on a 10 cm Visual Analogue Scale were randomised (2:1) in this double-blind study to receive transcutaneous auricular vagus nerve stimulation (taVNS) or sham stimulation (SS) for 4 consecutive days. Evaluations at baseline, day 5 and day 12 included patient assessments of pain, disease activity (PtGA) and fatigue. Tender and swollen joint counts and the Physician Global Assessment (PGA) were completed by a physician blinded to the patient's therapy. Potential biomarkers were evaluated. RESULTS: taVNS and SS were well tolerated. Subjects receiving taVNS had a significant decrease in pain and fatigue compared with SS and were more likely (OR=25, p=0.02) to experience a clinically significant reduction in pain. PtGA, joint counts and PGA also improved. Pain reduction and improvement of fatigue correlated with the cumulative current received. In general, responses were maintained through day 12. Plasma levels of substance P were significantly reduced at day 5 compared with baseline following taVNS but other neuropeptides, serum and whole blood-stimulated inflammatory mediators, and kynurenine metabolites showed no significant change at days 5 or 12 compared with baseline. CONCLUSION: taVNS resulted in significantly reduced pain, fatigue and joint scores in SLE. Additional studies evaluating this intervention and its mechanisms are warranted.
Assuntos
Fadiga/terapia , Lúpus Eritematoso Sistêmico/complicações , Dor Musculoesquelética/terapia , Estimulação Elétrica Nervosa Transcutânea/métodos , Estimulação do Nervo Vago/métodos , Adulto , Idoso , Método Duplo-Cego , Fadiga/imunologia , Feminino , Humanos , Pessoa de Meia-Idade , Dor Musculoesquelética/imunologia , Medição da Dor , Projetos Piloto , Resultado do TratamentoRESUMO
OBJECTIVE: Bone health in SLE is adversely affected by vitamin D deficiency, inflammatory cytokines and glucocorticoid use. We hypothesised that vitamin D supplementation would increase markers of bone formation and decrease markers of bone resorption in SLE subjects. METHODS: We studied 43 vitamin D-deficient SLE subjects who participated in a 12-week randomised controlled trial of 2000-4000 IU/day vitamin D supplementation versus placebo. Subjects had inactive SLE (SLE Disease Activity Index ≤4) and were taking <20 mg prednisone daily at baseline. We assayed baseline and week 12 serum 25-hydroxyvitamin D, N-terminal propeptide of type 1 collagen (P1NP) and C-telopeptide (CTX). We tested the effect of vitamin D versus placebo on change (Δ) in P1NP and ΔCTX in an intention-to-treat analysis. Secondary analyses evaluated whether vitamin D affected bone turnover among subjects achieving vitamin D repletion (≥30 ng/mL) or currently taking glucocorticoids. RESULTS: 28 subjects were randomised to vitamin D and 15 to placebo. Mean age was 39 years and 40% were using glucocorticoids at enrolment. Repletion was achieved by 46% in the vitamin D group versus none in the placebo group. Changes in bone turnover markers were not significantly different in the vitamin D group versus placebo group (median ΔP1NP -0.2 vitamin D group vs -1.1 placebo group (p=0.83); median ΔCTX +3.5 vitamin D group vs -37.0 placebo group (p=0.50)). The effect of vitamin D did not differ based on achieving vitamin D repletion or baseline glucocorticoid use. CONCLUSION: Vitamin D supplementation did not affect the 12-week change in bone turnover markers among SLE subjects in this trial.
RESUMO
OBJECTIVE: Vitamin D modulates the immune response and blocks induction of an interferon (IFN) signature by systemic lupus erythematosus (SLE) sera. This study was undertaken to investigate the effects of vitamin D supplementation on the IFN signature in patients with SLE. METHODS: SLE patients (n = 57) with stable, inactive disease, a serum 25-hydroxyvitamin D (25[OH]D) level ≤20 ng/ml, an elevated anti-double-stranded DNA antibody level, and an IFN signature (as determined by measuring the expression levels of 3 IFN response genes) were randomized into a 12-week double-blind, placebo-controlled trial of vitamin D3 at doses of 2,000 IU or 4,000 IU. An IFN signature response was defined as a 50% reduction in the expression of 1 of the 3 genes or a 25% reduction in the expression of 2 of the 3 genes. Disease activity, adverse events, and endocrine effects were assessed. RESULTS: Baseline characteristics of the patients in the 3 treatment groups (placebo, low-dose vitamin D3 , or high-dose vitamin D3 ) were similar. Repletion of 25(OH)D (i.e., levels ≥30 ng/ml) was not observed in any of the patients who were receiving placebo, while repletion was observed in 16 of 33 patients receiving vitamin D3 . The percentage of patients with an IFN signature response did not differ among the treatment groups. Moreover, there was no difference in the percentage of patients with an IFN signature response between those who remained vitamin D deficient and those who demonstrated repletion of vitamin D. Modular microarray analysis of a subset of patients (n = 40) did not reveal changes from baseline in any modules (including the IFN-inducible module) in any of the treatment groups, and no differences in expression were found between patients who demonstrated vitamin D repletion and patients who were persistently vitamin D deficient. Vitamin D3 was well tolerated, and there were no safety concerns. CONCLUSION: Vitamin D3 supplementation up to 4,000 IU daily was safe and well-tolerated but failed to diminish the IFN signature in vitamin D-deficient SLE patients. Higher 25(OH)D levels sustained for a longer duration may be required to affect immunologic outcomes.
Assuntos
Antígenos/sangue , Proteínas de Transporte/sangue , Colecalciferol/farmacologia , Proteínas do Citoesqueleto/sangue , Regulação da Expressão Gênica/efeitos dos fármacos , Lúpus Eritematoso Sistêmico/sangue , Proteínas de Resistência a Myxovirus/sangue , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Anticorpos Anti-Idiotípicos/sangue , Antígenos/genética , Proteínas de Transporte/genética , Colecalciferol/administração & dosagem , Proteínas do Citoesqueleto/genética , DNA/imunologia , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Proteínas de Resistência a Myxovirus/genética , Estudos Prospectivos , Proteínas de Ligação a RNA , Vitamina D/análogos & derivados , Vitamina D/sangueRESUMO
BACKGROUND: Excessive activity of dendritic cells (DCs) is postulated as a central disease mechanism in Systemic Lupus Erythematosus (SLE). Vitamin D is known to reduce responsiveness of healthy donor DCs to the stimulatory effects of Type I IFN. As vitamin D deficiency is reportedly common in SLE, we hypothesized that vitamin D might play a regulatory role in the IFNalpha amplification loop in SLE. Our goals were to investigate the relationship between vitamin D levels and disease activity in SLE patients and to investigate the effects of vitamin D on DC activation and expression of IFNalpha-regulated genes in vitro. METHODOLOGY/PRINCIPAL FINDINGS: In this study, 25-OH vitamin D (25-D) levels were measured in 198 consecutively recruited SLE patients. Respectively, 29.3% and 11.8% of African American and Hispanic SLE patient had 25-D levels <10 ng/ml. The degree of vitamin D deficiency correlated inversely with disease activity; R = -.234, p = .002. In 19 SLE patients stratified by 25-D levels, there were no differences between circulating DC number and phenotype. Monocyte-derived DCs (MDDCs) of SLE patients were normally responsive to the regulatory effects of vitamin D in vitro as evidenced by decreased activation in response to LPS stimulation in the presence of 1,25-D. Additionally, vitamin D conditioning reduced expression of IFNalpha-regulated genes by healthy donor and SLE MDDCs in response to factors in activating SLE plasma. CONCLUSIONS/SIGNIFICANCE: We report on severe 25-D deficiency in a substantial percentage of SLE patients tested and demonstrate an inverse correlation with disease activity. Our results suggest that vitamin D supplementation will contribute to restoring immune homeostasis in SLE patients through its inhibitory effects on DC maturation and activation. We are encouraged to support the importance of adequate vitamin D supplementation and the need for a clinical trial to assess whether vitamin D supplementation affects IFNalpha activity in vivo and, most importantly, improves clinical outcome.
Assuntos
Células Dendríticas/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Deficiência de Vitamina D/sangue , Vitamina D/sangue , Proteínas Adaptadoras de Transdução de Sinal , Adolescente , Adulto , Negro ou Afro-Americano/estatística & dados numéricos , Idoso , Antígenos/genética , Povo Asiático/estatística & dados numéricos , Proteínas de Transporte/genética , Células Cultivadas , Criança , Proteínas do Citoesqueleto/genética , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Feminino , Citometria de Fluxo , Proteínas de Ligação ao GTP/genética , Expressão Gênica/efeitos dos fármacos , Hispânico ou Latino/estatística & dados numéricos , Humanos , Imunofenotipagem , Lúpus Eritematoso Sistêmico/etnologia , Lúpus Eritematoso Sistêmico/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Resistência a Myxovirus , Proteínas de Ligação a RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Vitamina D/farmacologia , Deficiência de Vitamina D/etnologia , População Branca/estatística & dados numéricos , Adulto JovemRESUMO
Protection against microbial invasion depends not only on the host's ability to mount an immune response, but on its ability to mount the correct immune response. Whether an antibody response is protective or not depends on both the fine antigenic specificity, that may be associated with particular idiotypes and epitope binding characteristics, and the isotype, determining antibody effector function. Thus, both the variable and the constant region of the antibodies induced by a peptide mimotope must be considered when assessing the success of any immunization. Phosphorylcholine (PC), an epitope present on the cell-wall C-polysaccharide of all pneumococcal serotypes, is capable of eliciting a protective antibody response to pneumococcal infection in mice and provides an attractive model system for understanding the immune response generated by peptide mimics. In this system, both the idiotype and isotype of protective antibodies have been determined and the characteristics of the in vivo response are well described and highly reproducible. We describe here the immune response generated by two peptide mimics of PC. Mice immunized with the peptides developed antibodies binding PC and C-polysaccharide. The idiotypic profile of the response differed depending on the peptide, but never included canonical T15(+) antibodies. The isotype of the response to peptide mimics differed depending on a combination of peptide and adjuvant, and included both IgG2a and IgG2b antibodies which are not typically seen in the response to PC. Thus, peptide mimotopes may elicit anti-polysaccharide responses, but fail to elicit the idiotypes and isotypes observed in the protective response to the microbial antigen.