G. Chehab

Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID)

IntroductionEvidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkins lymphoma in a real-life clinical setting.MethodsPatients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators.ResultsA total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physicians visual analogue scale; mean improvement from baseline of 12.1 mm).ConclusionsData from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.

Elevated levels of human beta-defensin 2 and human neutrophil peptides in systemic lupus erythematosus:

Objective: Defensins are immunomodulatory peptides and components of the innate immune response. They have been shown to be modulated in various disease states and in response to inflammatory stimuli. Recently, alpha-defensins have been implicated in the pathogenesis of autoimmune diseases. In order to explore whether these defensins may have a role in the pathogenesis of systemic lupus erythematosus (SLE), we sought to determine whether altered expression can be found in SLE patients. Material and Methods: Serum and EDTA-blood of 50 SLE patients who fulfilled the American College of Rheumatology (ACR) criteria (aged 41.4 ± 13.3 years) and 28 age- and sex-matched healthy controls were collected. Real-time polymerase chain reaction with gene-specific primers for human neutrophil peptides (HNPs), human beta-defensin 2 and 3 (hBD2, 3) in isolated polymorphonuclear cells and enzyme-linked immunosorbent assay (ELISA) in serum samples were performed. Results of SLE patients were compared with the control group and correlated to routine laboratory parameters, clinical data and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Results: SLE patients were predominantly female (90%) with a mean SLEDAI of 5.7 ± 6.1. In sera, patients displayed higher amounts of hBD2 and HNPs when compared with healthy controls. Furthermore, hBD2 correlated with levels of anti-dsDNA antibodies, erythrocyte count and the SLEDAI. Elevated values were observed in patients with myositis (n = 4). Serum HNPs on the other hand correlated with the neutrophil count and was elevated in patients with a rash (n = 7). Lupus patients suffering from transverse myelitis (n = 3) had raised serum-values of both HNPs and hBD2. While no mRNA of hBD2 or hBD3 was detected in polymorphonuclear cells, HNP mRNA was found in both healthy controls and patients without significant difference. Lupus nephritis and rash were associated with higher amounts of HNP mRNA, and the relative amount of copies correlated positively with the SLEDAI and negatively with C3 measurements. Conclusions: Serum levels of hBD2 and HNPs are elevated in SLE. The correlations of hBD2 and HNPs to established disease activity parameters and distinct clinical situations suggest that innate immune mechanisms are activated. Defensins may be involved in SLE pathogenesis.

Clinical outcomes and safety of rituximab treatment for patients with systemic lupus erythematosus (SLE) - results from a nationwide cohort in Germany (GRAID)

Objective The objective of this article is to evaluate the safety and clinical outcome of rituximab treatment in systemic lupus erythematosus (SLE) patients refractory to standard of care therapy in a real-life setting in Germany. Methods The GRAID registry included patients with different autoimmune diseases who were given off-label treatment with rituximab. Data on safety and clinical response were collected retrospectively. In SLE patients, clinical parameters included tender and swollen joint counts, fatigue, myalgia, general wellbeing, Raynaud’s and the SLEDAI index. Laboratory tests included dsDNA antibody titres, complement factors, hematologic parameters and proteinuria. Finally, the investigators rated their patients as non-, partial or complete responders based on clinical grounds. Results Data from 85 SLE patients were collected, 69 female and 16 male, with a mean disease duration of 9.8 years. The mean follow-up period was 9.6 ± 7.4 months, resulting in 66.8 patient years of observation. A complete response was reported in 37 patients (46.8%), partial response in 27 (34.2%), no response in 15 (19.0%). On average, major clinical as well as laboratory efficacy parameters improved substantially, with the SLEDAI decreasing significantly from 12.2 to 3.3 points. Concerning safety, one infusion reaction leading to discontinuation of treatment occurred. Infections were reported with a rate of 19.5 (including six severe infections) per 100 patient years. Conclusion With the restrictions of a retrospective data collection, the results of this study confirm data of other registries, which suggest a favourable benefit-risk ratio of rituximab in patients with treatment-refractory SLE.

Renal Outcome in Patients with Lupus Nephritis Using a Steroid-free Regimen of Monthly Intravenous Cyclophosphamide: A Prospective Observational Study

Objective. Intravenous cyclophosphamide (IV CYC) in combination with high doses of corticosteroids is considered the “gold standard” of therapy for lupus nephritis (LN). However, the optimal dose of corticosteroids needed has not been defined. We evaluated the efficacy of a monotherapy with IV CYC in patients with a first episode of LN (duration ≤ 6 months). Methods. Forty patients with LN received IV CYC (12 pulses). Prednisone alone was administered and dose-adjusted to control extrarenal manifestations. Response after 24 months was defined as normalization of creatinine level, inactive urinary sediment, and proteinuria ≤ 0.2 g/day [complete response (CR)] or ≤ 0.5 g/day [partial response (PR)]. Results. CR was achieved in 25 (62.5%) and PR in 8 (20%) patients. Mean starting dose of prednisone was 23.9 ± 23.8 mg/day. In a posthoc analysis, we separately analyzed patients initially treated with prednisone doses ≥ 20 mg/day (Group A, n = 19) or < 20 mg/day (Group B, n = 21). CR was achieved in 52.6% (Group A) versus 71.4% (Group B; p = 0.37); and PR in 26.3% versus 14.3%, respectively (p = 0.58). During longterm followup (10.4 ± 3.1 yrs), 37.8% experienced a renal flare. Thirty patients (81%) still have normal renal function. Renal outcome was irrespective of initial prednisone doses (p = 0.46, Pearson chi-square test of independence). Conclusion. Our rates of CR and PR and longterm outcomes were comparable with rates after treatment with a combination of IV CYC with high doses of corticosteroids. These data warrant randomized controlled trials evaluating different doses of corticosteroids in LN.

Age-specific prevalence of diagnosed systemic lupus erythematosus in Germany 2002 and projection to 2030.

Objective The objective of this report is to estimate the prevalence and future number of cases of systemic lupus erythematosus (SLE) in Germany. Methods Data from a representative sample of all insurants from the statutory health insurance in Germany comprising more than 2.3 million individuals have been screened for SLE diagnoses. The gender- and age-specific prevalence of SLE is calculated. The case definition is based on at least one recorded diagnosis of SLE during 2002. The stratum-specific prevalence is applied to the current and the future population of Germany in order to estimate and predict the number of people with SLE until 2030. Results The overall prevalence of diagnosed SLE in 2002 was 15.4 (95% CI: 13.1–17.9) and 55.4 (51.4, 59.8) per 100,000 in the male and female German population. This corresponds to an estimated 30,000 and 31,000 people with diagnosed SLE in 2002 and 2010, respectively. This number will slightly increase until 2020 and decrease thereafter. Conclusions Compared with health insurance data from France, the prevalence in our data is similar. Under the assumption that the gender- and age-specific prevalence of SLE in Germany will not change considerably, the number of cases in the next two decades will change only slightly.

Entwicklung von Mortalität und Morbidität beim systemischen Lupus erythematodes

ZusammenfassungDer systemische Lupus erythematodes stellt als chronisch verlaufende Multisystemerkrankung trotz optimierter Behandlungsregimes unverändert eine klinische Herausforderung dar. Langzeituntersuchungen konnten in der Vergangenheit eine Abnahme der Mortalität belegen. Dieser Trend setzt sich auch in den letzten beiden Jahrzehnten fort. Dennoch ist die Lebenserwartung im Vergleich zur Normalbevölkerung weiterhin deutlich eingeschränkt. Neben der Krankheitsaktivität sind Infektionen und kardiovaskuläre Erkrankungen die Haupttodesursachen. Während sowohl die durch die Erkrankung selbst als auch durch Infektionen bedingten Todesfälle aber über die Jahre rückläufig sind, imponiert eine Zunahme kardiovaskulärer Erkrankungen. Ersteres kann durch die individuell angepassten Therapiekonzepte und den vorsichtigeren Einsatz von Steroiden erklärbar sein; dagegen sind die kardiovaskulären Komplikationen auf das längere Überleben der Patienten und die beschleunigte Arteriosklerose zurückzuführen. Dieser Langzeitaspekt muss bereits in frühen Phasen der Erkrankung bei der Behandlung von Aktivität und Komorbiditäten berücksichtigt werden.AbstractSystemic lupus erythematosus (SLE) is a chronic multisystem disease and despite the improvements in treatment, long-term care still represents a clinical challenge. Previous long-running studies have demonstrated a continuous improvement in mortality and this trend has persisted over the last two decades. However, there still remains a significantly increased mortality in comparison to the normal population. Besides deaths caused by disease activity, cardiovascular and infectious diseases also play a major role. While deaths caused by SLE activity or infections have declined over the years, there has been a notable increase in cardiovascular diseases. As the improvement of SLE activity and infections can be traced back to individually optimized treatment regimes and the more cautious use of steroids, the cardiovascular complications are due to accelerated atherosclerosis and the improved survival with ageing of the patients. This long-term aspect needs to be taken into account in the early stages of disease when treating disease activity and comorbidities.Systemic lupus erythematosus (SLE) is a chronic multisystem disease and despite the improvements in treatment, long-term care still represents a clinical challenge. Previous long-running studies have demonstrated a continuous improvement in mortality and this trend has persisted over the last two decades. However, there still remains a significantly increased mortality in comparison to the normal population. Besides deaths caused by disease activity, cardiovascular and infectious diseases also play a major role. While deaths caused by SLE activity or infections have declined over the years, there has been a notable increase in cardiovascular diseases. As the improvement of SLE activity and infections can be traced back to individually optimized treatment regimes and the more cautious use of steroids, the cardiovascular complications are due to accelerated atherosclerosis and the improved survival with ageing of the patients. This long-term aspect needs to be taken into account in the early stages of disease when treating disease activity and comorbidities.

Validation and evaluation of the German Brief Index of Lupus Damage (BILD) – a self-reported instrument to record damage in systemic lupus erythematosus

Introduction Damage is a very important predictor for outcome in systemic lupus erythematosus (SLE) and should be routinely documented. Patient-reported assessments for damage are rare and neither the Lupus Damage Index Questionnaire (LDIQ) nor the Brief Index of Lupus Damage (BILD) is validated in German language. Our aim was to validate the BILD in German language and evaluate its use as a patient-administered instrument. Method We translated and adapted the BILD questionnaire to use it as a self-administered questionnaire for German-speaking SLE patients. It was applied to SLE outpatients at an academic centre and compared to the SLICC/SDI and other lupus outcome parameters. Results The German BILD showed as strong a correlation with the SLICC/SDI as the original version of the BILD and a superior correlation compared to the LDIQ. It scored significantly higher with an increase of age, disease duration or disease activity, with a lower functional status or overall health and a higher probability of receiving an incapacity pension. Conclusion The German version of the BILD shows a comparable validity to the original BILD with even higher correlation to physician-reported damage even when used as a self-administered questionnaire. Hence it represents a promising instrument to survey damage in clinical routine as well as in clinical and epidemiological studies.

Age-specific and sex-specific incidence of systemic lupus erythematosus: an estimate from cross-sectional claims data of 2.3 million people in the German statutory health insurance 2002

Objective To provide an estimate of age-specific incidence rate of physician-diagnosed systemic lupus erythematosus (SLE) for German men and women. Methods The age-specific and sex-specific prevalence of diagnosed SLE in claims data is used to estimate the incidence in the German male and female population. The claims data set stems from a representative sample of the statutory health insurance in 2002 and comprises 2.3 million people. The statutory health insurance covers >85% of the German population. Results The estimated incidence rates are 0.9 (95% CI 0.7 to 1.1) per 100 000 person-years for men and 1.9 (95% CI 1.7 to 2.2) per 100 000 person-years for women. The age-specific incidence rate of SLE in the male population has a maximum of 2.2 (95% CI 1.0 to 3.4) per 100 000 person-years at the age of 65–70 years. In women, the incidence is peaking at the rate of 3.6 (95% CI 2.9 to 4.3) cases per 100 000 person-years at the age of 20–25 years, but has a second local maximum (2.6, 95% CI 1.5 to 3.8) at menopausal age. Conclusions For the first time, representative data on the incidence of SLE in Germany are provided. The estimated incidence rates of SLE for men and women in Germany are at the lower end of other estimates from comparable European countries.

What matters for lupus patients

La Presse Medicale - In Press.Proof corrected by the author Available online since lundi 5 mai 2014

Factors associated with pain coping and catastrophising in patients with systemic lupus erythematosus: a cross-sectional study of the LuLa-cohort

Objective The aim of this study was to identify factors associated with pain coping and catastrophising in patients with systemic lupus erythematosus. Methods All patients were participants of the lupus erythematosus long-term study, which is based on patient-reported data assessed among members of the German Lupus Erythematosus Self-Help Organization. Assessments were performed by means of a questionnaire. Among self-reported clinical data the Pain-Related Self Statements Scale (PRSS) was included. To depict significant differences univariable analyses were carried out using non-parametrical rank tests. To examine factors influencing our outcome variables, we performed a multivariable stepwise regression model including variables that presented significantly in the univariable analysis. Results 447 cases (94.9% female) were analysed showing a mean catastrophising score of 1.1 (SD 0.8) and a mean coping score of 2.8 (SD 0.9) in the PRSS subscales. Higher catastrophising quartiles went along with higher experienced pain, lupus activity, fatigue, damage and decreased health related quality of life, whereas they presented inversely for coping. In our multivariable model, factors associated with catastrophising were: number of lupus-specific drugs (p value 0.004), pain in the last 7 days (p value 0.034), the Short Form 12 Health Survey Mental Component Summary (p value <0.001) and disease activity measured by the Systemic Lupus Activity Questionnaire (p value 0.042). Social participation reflected by performed leisure activities such as dancing or bowling had a positive association with coping (p value 0.006). In contrast, other health related physical activities and their extent had no impact on coping. A direct association between the amount of pain coping and catastrophising, as well as a great impact of the catastrophising, respectively, coping level on physical and mental functioning could be shown. Conclusions Reduction or increase of detected factors might lead to a modification of pain coping and catastrophising and offer an approach to more effective care in patients with SLE.