Anna Wozniacka

Chloroquine treatment influences proinflammatory cytokine levels in systemic lupus erythematosus patients

Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex pathogenesis. Published data have revealed that serum levels of proinflammatory cytokines are increased in SLE patients. The aim of our study was to evaluate whether monotherapy with chloroquine phosphate affects IL- 1β, IL-6, IL-18 and TNF-α serum levels in SLE patients. The study group consisted of 25 SLE patients with mild or moderate disease activity and 25 age- and sex-matched healthy control subjects. In SLE patients the cytokine levels were measured just before and three months after starting chloroquine treatment at a dose of 125 mg twice daily. Although the majority of SLE patients had a low systemic lupus activity measure (SLAM) index, the levels of IL-6, IL-18 and TNF-α were significantly higher than in the control group. After three-months of chloroquine therapy the mean level of IL-6, IL-18 and TNF-α decreased significantly. Minimal erythema doses (MEDs) were significantly increased in SLE patients after three months of chloroquine therapy. The results indicate that chloroquine treatment lowers some proinflammatory cytokines and may provide a photoprotective effect.

Phase I, Randomized, Double-Blind, Placebo-Controlled, Multiple Intravenous, Dose-Ascending Study of Sirukumab in Cutaneous or Systemic Lupus Erythematosus

OBJECTIVE We undertook a 2-part, phase I, double-blind, placebo-controlled study to evaluate the safety and pharmacokinetics of multiple intravenous infusions of sirukumab, a human anti-interleukin-6 monoclonal antibody, in patients with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE). METHODS In part A, patients with histologically confirmed CLE were randomized to 4 infusions of placebo or 1, 4, or 10 mg/kg sirukumab every 2 weeks. In part B, SLE patients diagnosed according to American College of Rheumatology criteria with a score of 5-12 on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index were randomized to 4 infusions of placebo or 10 mg/kg sirukumab every 2 weeks. RESULTS We treated 31 CLE patients (23 with sirukumab, 8 with placebo) and 15 SLE patients (10 with sirukumab, 5 with placebo). Adverse events (AEs) occurred more often with sirukumab than placebo in CLE patients (91% versus 63%) and in SLE patients (90% versus 80%). Sirukumab led to sustained, dose-independent decreases in white blood cell counts, absolute neutrophil counts (neutropenia), and platelet counts (thrombocytopenia) and to minor elevations in total cholesterol levels. The majority of infections were mild respiratory infections. which were reported similarly across CLE cohorts but more often in sirukumab-treated than in placebo-treated SLE patients. Two serious AEs of infection occurred (pneumonia in the 10 mg/kg-treated group and iatrogenic wound infection in the 4 mg/kg-treated group). Sirukumab showed linear pharmacokinetics in CLE patients. Systemic exposure and half-life were comparable between CLE and SLE patients. No patient developed antibodies to sirukumab through 22 weeks. C-reactive protein and serum amyloid A mean concentrations were suppressed with sirukumab from week 1 to week 14. CONCLUSION Treatment with intravenous sirukumab infusions was generally well tolerated in both CLE and SLE patients with mild, stable, active disease. Sirukumab demonstrated linear pharmacokinetics over the dose range studied and comparable systemic exposure and half-life in CLE and SLE patients.

Vitamin D status in systemic lupus erythematosus patients and its association with selected clinical and laboratory parameters

Objectives: To identify relationships between vitamin D serum levels and the presence of autoantibodies directed against vitamin D and levels of interleukin(IL)-17 and IL-23 in patients with systemic lupus erythematosus (SLE). Methods: The study included 49 patients with SLE. Serum concentrations of 25(OH)D3 were measured with electrochemiluminescence immunoassay (ECLIA). Enzyme-linked immunosorbent assays (ELISA) were used to determine antibodies directed against 1,25(OH)2D3 and levels of IL-17 and IL-23 in serum of SLE patients. In evaluation of vitamin D status, the control group consisted of 49 age and gender matched healthy individuals, whereas in assessment of anti-vitamin D antibodies the control group comprised 30 sera from blood donors. Results: Serum concentration of 25(OH)D3 in SLE patients during the warm season was 18.47 ± 9.14 ng/ml, which was significantly decreased as compared with that of the control group – 31.27 ± 12.65 ng/ml (p = 0.0005). During the cold season a trend toward lower concentration of 25(OH)D3 in SLE patients was revealed; however, it did not reach statistical significance (11.71 ± 7.21 ng/ml vs. 16.01 ± 8.46 ng/ml; p = 0.054). Results within the recommended range for vitamin D (30–80 ng/ml; 70–200 nmol/l) were observed only in three patients. The 25(OH)D3 concentration was decreased in SLE patients with renal disease or leucopenia as compared with the levels in patients who did not have either problem (p = 0.006 and p = 0.047, respectively). The cold season was found to be a risk factor for vitamin D deficiency (<20 ng/ml) (odds ratio = 9.25; p = 0.005). Autoantibodies directed against 1,25(OH)2D3 were detected in three SLE patients. No significant difference in 25(OH)D3 serum concentrations was found between SLE patients with and without these autoantibodies. No link was shown between the existence of autoantibodies against 1,25(OH)2D3 and clinical or laboratory findings, including IL-17 and IL-23 levels. However, serum concentrations of IL-23 were lower in patients with vitamin D deficiency (p = 0.037). Conclusions: SLE patients, especially those with leucopenia or renal involvement, are at high risk of vitamin D deficiency and require vitamin D supplementation. Some SLE patient sera contained 1,25(OH)2D3 antibodies, but these antibodies do not appear to affect vitamin D levels.

Optimal Use of Antimalarials in Treating Cutaneous Lupus Erythematosus

Antimalarials have been used to treat cutaneous and systemic lupus erythematosus (LE) for decades. Although controlled studies comparing the efficacy of antimalarials versus placebo and other treatments are generally lacking, many case reports and series support the therapeutic efficacy of these agents in treating both LE-specific and -nonspecific skin lesions. Currently, the two most frequently used antimalarial agents are chloroquine and hydroxychloroquine. There may be a delay of weeks to months in the onset of therapeutic effects of antimalarials when treating LE. Smoking appears to inhibit the therapeutic efficacy of antimalarials when treating cutaneous LE. Antimalarials have been associated with a number of potentially serious adverse effects, including irreversible loss of vision. The aim of this review is to discuss the many facets of antimalarials that will help clinicians optimally utilize these agents when treating cutaneous LE.

Effect of chloroquine phosphate treatment on serum MMP-9 and TIMP-1 levels in patients with systemic lupus erythematosus

Antimalarials are widely used for the treatment of systemic lupus erythematosus. However, their mechanisms of action have not been fully elucidated. Literature data indicate that matrix metalloproteinases may play a role in the immune response and tissue damage that occur in autoimmune skin diseases. The aim of this study was to determine the effect of 3 months of chloroquine treatment on serum levels of MMP-9 and TIMP-1 in patients with systemic lupus erythematosus. The study group consisted of 25 patients with systemic lupus erythematosus and 25 sex- and age-matched healthy volunteers. Before drug administration, serum levels of MMP-9 and TIMP-1 were determined by enzyme-linked immunosorbent assay. The same procedure was performed after chloroquine treatment. We found significantly higher median serum levels of MMP-9 in patients with systemic lupus erythematosus before therapy (57.20 ng/ml) when compared with controls (44.50 ng/ml) (p < 0.001). After chloroquine therapy the median MMP-9 serum level of systemic lupus erythematosus patients decreased significantly (43 ng/ml; p < 0.001). Before treatment the median TIMP-1 serum level in the patients with systemic lupus erythematosus was significantly higher than in the control group (500 vs. 200 ng/ml; p < 0.001), and after therapy it increased significantly (750 ng/ml TIMP-1; p < 0.001). The results suggest that chloroquine treatment may affect the matrix metalloproteinase network, and this effect may contribute to the immunoregulatory and anti-inflammatory properties of antimalarials.

Lupus vulgaris: report of two cases

Although there has been a steady decline in the incidence of tuberculosis in recent years, it persists in some regions, and where AIDS is especially prevalent, the number of new cases has been increasing. 1–3 Thus, cutaneous tuberculosis has re‐emerged in areas with a high incidence of HIV infection and multidrug‐resistant pulmonary tuberculosis. Lupus vulgaris has been and remains the most common form of cutaneous tuberculosis. 1 Cutaneous manifestations of disseminated tuberculosis are unusual, being seen in less than 0.5% of cases. 4 Scrofuloderma, tuberculosis verrucosa cutis and lupus vulgaris comprise most cutaneous tuberculosis cases. 2

Estimation of SLE activity based on the serum level of chosen cytokines and superoxide radical generation

We estimated the serum levels of IL-6, TNF-alpha and IL-10, and generation of superoxide radicals, as well as their mutual dependence, in 63 SLE patients at various stages of disease activity. Our results indicate a statistically significant increase of the serum levels studied, and an increase of superoxide anion generation by granulocytes, in correlation with SLE activity. These results indicate that oxygen metabolism and the examined cytokines play an important role in pathogenesis of SLE. The assessment of these parameters can be useful in the estimation of disease activity.

The influence of antimalarial treatment on IL-1β, IL-6 and TNF-α mRNA expression on UVB-irradiated skin in systemic lupus erythematosus

Background  There are very few data addressing the mechanisms of antimalarial treatment benefit locally within the skin of patients with lupus erythematosus, at the level of cytokine messenger RNA (mRNA) expression.

Repeated low-dose ultraviolet (UV) B exposures of humans induce limited photoprotection against the immune effects of erythemal UVB radiation

Background  Exposure of human subjects to ultraviolet (UV) B radiation causes immunosuppression. Most experiments to date have not tested the effects of low daily doses of UVB radiation.

Photoprovocation in Cutaneous Lupus Erythematosus: A Multicenter Study Evaluating a Standardized Protocol

Photosensitivity is an important and distinguishing sign in various subtypes of cutaneous lupus erythematosus (CLE); however, it remains poorly defined. The purpose of this study was to evaluate whether standardized photoprovocation is a reproducible method to assess photosensitivity in subjects with CLE. A total of 47 subjects with CLE (subacute cutaneous lupus erythematosus (SCLE), n=14; discoid lupus erythematosus (DLE), n=20; lupus erythematosus tumidus (LET), n=13) and 13 healthy volunteers underwent photoprovocation at seven European sites. Of these, 22 (47%) subjects (57% SCLE, 35% DLE, and 54% LET) and none of the healthy volunteers developed photoprovoked lesions according to clinical analysis. Of these 22 subjects, 19 (86%) developed lesions that were histopathologically confirmed as specific for lupus erythematosus (LE). In CLE subjects who developed UV-induced lesions, 86% had Fitzpatricks phototypes I or II, and the mean minimal erythema dose (MED) was significantly lower compared with subjects without UV-induced lesions (P=0.004). No significant differences in photoprovocation results were observed between study sites. Safety parameters showed no clinically meaningful differences between CLE subjects and healthy volunteers after photoprovocation. In conclusion, a standardized, safe, and reproducible protocol for photoprovocation using UVA and UVB radiation induced skin lesions in approximately half of all CLE subjects and showed comparable results across multiple sites. This method may therefore be used for future diagnostic testing and clinical trials.