Cyclosporine A or intravenous cyclophosphamide for lupus nephritis: the Cyclofa-Lune study.

Intravenous cyclophosphamide is considered to be the standard of care for the treatment of proliferative lupus nephritis. However, its use is limited by potentially severe toxic effects. Cyclosporine A has been suggested to be an efficient and safe treatment alternative to cyclophosphamide. Forty patients with clinically active proliferative lupus nephritis were randomly assigned to one of two sequential induction and maintenance treatment regimens based either on cyclophosphamide or Cyclosporine A. The primary outcomes were remission (defined as normal urinary sediment, proteinuria <0.3 g/24 h, and stable s-creatinine) and response to therapy (defined as stable s-creatinine, 50% reduction in proteinuria, and either normalization of urinary sediment or significant improvement in C3) at the end of induction and maintenance phase. Secondary outcomes were incidence of adverse events, and relapse-free survival. At the end of the induction phase, 24% of the 21 patients treated by cyclophosphamide achieved remission, and 52% achieved response, as compared with 26% and 43%, respectively of the 19 patients treated by the Cyclosporine A. At the end of the maintenance phase, 14% of patients in cyclophosphamide group, and 37% in Cyclosporine A group had remission, and 38% and 58% respectively response. Treatment with Cyclosporine A was associated with transient increase in blood pressure and reversible decrease in glomerular filtration rate. There was no significant difference in median relapse-free survival. In conclusion, Cyclosporine A was as effective as cyclophosphamide in the trial of sequential induction and maintenance treatment in patients with proliferative lupus nephritis and preserved renal function.(ClinicalTrials.gov identifier: NCT00976300)

EULAR points to consider for conducting clinical trials in systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a complex multi-organ disease, characterised by relapses and remissions. DESIGN: ng a high-quality randomised controlled trial poses many challenges. We have developed evidenced-based recommendations for points to consider in conducting clinical trials in patients with SLE. METHODS: The EULAR Task Force on SLE comprised 19 specialists and a clinical epidemiologist. Initially, the evidence for clinical trial end-points in SLE was evaluated and this has been reported separately. A consensus approach was developed by the SLE Task Force in formulating recommendations for points to consider when conducting clinical trials in SLE. RESULTS: The literature review revealed that most outcome measures used in phase 2/3 trials in SLE have not actually been validated in clinical trials, although other forms of validation have been undertaken. The final recommendations for points to consider for conducting clinical trials in SLE address the following areas: study design, eligibility criteria, outcome measures including adverse events, concomitant therapies for SLE and its complications. CONCLUSIONS: Recommendations for points to consider when conducting clinical trials in SLE were developed using an evidence-based approach followed by expert consensus. The recommendations should be disseminated, implemented and then reviewed in detail and revised using an evidence-based approach in about 5 years, by which time there will be further evidence to consider from current clinical trials.

EULAR points to consider for conducting clinical trials in systemic lupus erythematosus: literature based evidence for the selection of endpoints.

OBJECTIVE: To assess available evidence on the use of end-points (outcome measures) in clinical trials in systemic lupus erythematosus (SLE), as a part of the development of evidence-based recommendations for points to consider in clinical trials in SLE. METHODS: The European League Against Rheumatism (EULAR) Task Force on SLE comprised 19 specialists, a clinical epidemiologist and a research fellow. Key questions addressing the evidence for clinical trial end-points in SLE were compiled using the Delphi technique. A systematic search of the PubMed and Cochrane Library databases was performed using McMaster/Hedges clinical query strategies and an array of relevant terms. Evidence was categorised based on sample size and type of design, and the categories of available evidence were identified for each recommendation. The strength of recommendation was assessed based on the category of available evidence and agreement on the statements was measured across the 19 specialists. RESULTS: Eight questions were generated regarding end-points for clinical trials. The evidence to support each proposition was evaluated. The literature review revealed that most outcome measures used in phase 2/3 trials in SLE have not been formally validated in clinical trials, although some indirect validation has been undertaken. CONCLUSION: This systematic literature review forms the evidence base considered in the development of the EULAR recommendations for end-points in clinical trials in SLE.

EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a complex disease with variable presentations, course and prognosis. We sought to develop evidence-based recommendations addressing the major issues in the management of SLE. METHODS: The EULAR Task Force on SLE comprised 19 specialists and a clinical epidemiologist. Key questions for the management of SLE were compiled using the Delphi technique. A systematic search of PubMed and Cochrane Library Reports was performed using McMaster/Hedges clinical queries' strategies for questions related to the diagnosis, prognosis, monitoring and treatment of SLE. For neuropsychiatric, pregnancy and antiphospholipid syndrome questions, the search was conducted using an array of relevant terms. Evidence was categorised based on sample size and type of design, and the categories of available evidence were identified for each recommendation. The strength of recommendation was assessed based on the category of available evidence, and agreement on the statements was measured across the 19 specialists. RESULTS: Twelve questions were generated regarding the prognosis, diagnosis, monitoring and treatment of SLE, including neuropsychiatric SLE, pregnancy, the antiphospholipid syndrome and lupus nephritis. The evidence to support each proposition was evaluated and scored. After discussion and votes, the final recommendations were presented using brief statements. The average agreement among experts was 8.8 out of 10. CONCLUSION: Recommendations for the management of SLE were developed using an evidence-based approach followed by expert consensus with high level of agreement among the experts.

Magnetic resonance volumetry of pathological brain foci in patients with systemic lupus erythematosus.

OBJECTIVE: The aim of our study was to determine the volume of pathological foci in the brain tissue of patients suffering from systemic lupus erythematosus (SLE) with or without neuropsychiatric manifestations (NP), and also to find out if that volume depends on the study subjects' data and clinical records. Magnetic resonance (MR) scans of patients with SLE and, in particular, signs of neuropsychiatric involvement, show pathological foci in the cerebral white matter. METHODS: A total of 53 SLE patients, 29 with signs of neuropsychiatric syndromes (NPSLE), 24 without, and 16 healthy controls underwent prospective volumetric magnetic resonance imaging in a flow attenuated inversion recovery (FLAIR) sequence. The disease activity was expressed in terms of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). RESULTS: All the patients in this study were found to have a larger volume of pathological foci in the brain tissue than the healthy controls. The NPSLE subgroup had a larger volume of pathological foci than the SLE patients without NP (p<0.001). The largest volume of such foci was found in the patients with a history of cerebrovascular disease (p<0.05). These were also noted for a correlation between the duration of the disease and the period of time elapsed from the onset of the first signs of neuropsychiatric lupus (p<0.01). Correlation with SLEDAI-rated disease activity was found statistically significant in all the patients (p<0.05) and in those with NPSLE at a level of p<0.01. CONCLUSION: We found that the lesion load was significantly larger in NPSLE than in SLE patients free from NP and controls. Our measurement revealed a positive correlation between the lesion load and SLEDAI in the whole SLE patients group, particularly in the subgroup with NP manifestation. In the future, longitudinal volumetry might conceivably facilitate the therapeutical effect rating.

Prevalence of antinucleosome antibodies by enzyme-linked immunosorbent assays in patients with systemic lupus erythematosus and other autoimmune systemic diseases.

The objective was to report our experience with the detection of antinucleosome antibodies (anti-Ncs Ab) in a series of systemic lupus erythematosus (SLE) patients, and to compare these results with those of antihistone and anti-double-stranded (ds) DNA antibodies. For this we selected 128 patients (106 females, 22 males, mean age 40 years) including 52 patients with SLE without organ involvement, 14 with lupus nephritis, 8 with neuropsychiatric lupus (NPSLE), 39 with systemic sclerosis (SSc), 15 with Sjögren syndrome (SS), and 51 healthy controls (38 females, 13 males, mean age 42 years). The sera were assayed for the levels of anti-ds DNA (ELISA), antihistone (INNO LIA ANA Update), anti-Ncs Ab (ELISA) and antinuclear antibodies (ANA-indirect immunofluorescence (IIF) on Hep-2 cells). The frequencies of positive anti-Ncs Ab, anti-ds DNA, and antihistone antibodies were in group of patients with SLE: 73%, 63%, and 54%, with SSc: 18%, 8%, 5%, and with SS: 3%, 3% and 0%, respectively. Patients with SLE have significantly increased levels of anti-Ncs Ab in their sera compared to healthy controls, SSc patients, and patients with SS. The concentration of the anti-Ncs Ab was 76 IU/mL in the SLE patients, 139 IU/mL in cases with lupus nephritis, 117 IU in NPSLE patients, 15 IU/mL in the SSc and 8 IU/mL in the healthy controls. All the three autoantibodies were present more frequently in cases with lupus and this correlation was significant in statistical means. Antinucleosome IgG antibodies seem to be a more sensitive marker of SLE than anti-ds DNA.

[Prolactin response to stress in patients with systemic lupus erythematodes (SLE), rheumatoid arthritis (RA) and in healthy controls]. / Stresová odezva prolaktinu u nemocnych se systémovým lupus erythematodes (SLE), revmatoidní artritidou (RA) a u zdravých kontrol.

Prolactin is a one of the stress hormones, like the growth hormone, ACTH, cortisol and catecholamins. Among its wide range of functions is the important role of controlling the immune response which is, unlike in the case of cortisol, of stimulatory nature. For this activity, it is monitored as a factor influencing the progress and course of autoimmune diseases. The authors of the paper monitored prolactin response to stress in a normal stress situation, i.e. blood collection. A significant difference was detected between the levels of prolactin in 3 successive blood collections in 30 minute intervals (P < 0.001). Prolactin responded by a prompt increase in the serum level, followed by a relatively fast linear decrease. There was no difference in the response between the SLE and RA patient groups and the healthy population. Therefore we conclude that this is a normal reaction of the organism because acute response to stress in patients with autoimmune diseases is the same as in healthy persons.

Epidemiology of rheumatoid arthritis, juvenile idiopathic arthritis and gout in two regions of the Czech Republic in a descriptive population-based survey in 2002-2003.

OBJECTIVE: To estimate the annual incidence and prevalence of rheumatoid arthritis (RA), juvenile arthritis (JIA) and gout in a population based study in two regions of the Czech Republic with total population of 186,000 inhabitants. METHODS: The study was conducted in the Town of Ceske Budejovice and district of Cheb in the Czech Republic (with a total population of 186,000 inhabitants) in the years 2002 and 2003. Incident cases were registered on condition that the definite diagnosis was confirmed according to existing classification criteria during the study period. Prevalence was studied on the basis of identification of established diagnosis from registers of patients of participating rheumatologists and other specialists. They were asked to report all living patients who had been diagnosed before 1st March 2002. Patients were only included in the study if their permanent address was in the selected study area. RESULTS: Overall, we found 48 incident and 947 prevalent cases of RA among adults (16+ years), 4 incident and 43 prevalent cases of JIA among children (less than 16 years old), and 64 incident and 425 prevalent cases of gout among adults (16+ years). The total annual incidence of RA was 31/100,000 in the adult population aged 16 years and more (95% CI 20 to 42/100,000). The prevalence of RA was 610/100,000 (95% CI 561 to 658/100,000) in the adult population. An annual incidence of gout in adults was 41/100,000 (95% CI 28 to 53/100,000). The prevalence of gout was 300/100,000 (95% CI 266 to 334/100,000). The annual incidence of JIA was 13/100,000 in children less than 16 years old (95%CI 1 to 20/100,000). The prevalence of JIA in children was 140/100,000 (95% CI 117 to 280/100,000). CONCLUSION: This study estimates the annual incidence and prevalence rates of RA, gout and JIA in the first population-based survey in the Czech Republic. The rates of RA and JIA compare well with figures reported from other countries; figures in gout seem to be lower than reported elsewhere.

[Antiphospholipid syndrome--the description of two cases]. / Antifosfolipidový syndrom--popisy dvou prípadu.

Antiphospholipid syndrome (APS) often occurs in young people, it is defined by the presence of venous or arterial thromboses, repeated miscarriages, thrombocytopenias and increased levels of antiphospholipid antibodies. Clinical symptoms are different, there is often experienced the phlebothrombosis of lower limbs, miscarriages or neurological symptoms characterized by transient ischemic attacks (TIA). If APS is associated with other system disease, most often with systemic lupus erythematosus (SLE), it is called secondary APS. We present two cases of secondary APS in the work. In first case we describe synchronous occurrence of SLE with secondary APS, which was clinically manifested by phlebothrombosis of veins of crus. At another elder patient there was stated the diagnosis of non-differentiated disease of bonding agent with secondary APS with cardial, pneumonic and neurological clinical symptoms.

Effects of stress on serum prolactin levels in patients with systemic lupus erythematosus.

The results of a study of effects of stress on serum prolactin (PRL) levels in patients with SLE reveal statistically significant differences in serum PRL level readings in samples taken over a short period of time, thus corroborating the need to take into account PRL stress induction during sample withdrawals and to interpret the values obtained, especially where moderate idiopathic hyperprolactinemia was detected. To eliminate any external stress factors, it is advisable to take PRL samples repeatedly and in perfectly resting patients.

Hyperprolactinaemia in patients with systemic lupus erythematosus.

OBJECTIVE: To verify the presence of hyper-PRL in SLE patients, its association with high disease activity, specific organ involvement or presence of anti-ds-DNA antibodies. METHODS: The group under study consisted of 80 patients with systemic lupus erythematosus (SLE), 28 patients with rheumatoid arthritis (RA) and 27 healthy controls. PRL serum levels were assayed using standard commercial kits (Immunotech Prague) with the radioimmunometric method for testing three samples of each of the subjects. The samples were taken in the morning hours (9-11 a.m.) of absolute rest 30 minutes after the introduction of the cannula at 30-minute intervals. RESULTS: A significantly higher rate of elevated PRL levels was found in SLE patients (40.0%) compared with the healthy controls (14.8%, p < 0.017). No proof was found of association with the presence of anti-ds-DNA or with specific organ involvement. Similarly, elevated PRL levels were found in RA patients (39.3%). The PRL elevation tended to decline from the 1st to the 3rd sample in the group of patients with SLE and RA but not in healthy controls. CONCLUSION: As follows from our measurements of prolactin serum values in SLE patients they are varriable by definition. According to our opinion further investigations are needed.

Wegener's granulomatosis with bilateral necrotizing scleritis, polyarthritis and renal failure efficiently treated with immunosuppressive therapy.

A case report of a female patient with Wegener's granulomatosis is presented. After an initial involvement of the upper respiratory tract in the form of a sinusitis, there followed a severe necrotizing bilateral scleritis necessitating the enucleation of the left eye ball. Renal involvement developed as late as 24 months after the onset of the disease and led to renal failure within three months. Throughout the duration of her disease, the patient had joint symptoms in the form of episodes of migratory nondeforming polyarthritis. The administration of corticosteroids alone in daily doses up to 60 mg prednisone failed to control the progression of the disease, while immunosuppressive therapy with cyclophosphamide combined with methylprednisolone pulse therapy and haemodialysis resulted in a marked improvement of renal function and in the subsidence of the ocular and articular symptoms.

[Rheumatology today and yesterday. Modern advances and future trends]. / Revmatologie dnes a zítra. Soucasné pokroky a budoucí smery.

The author mentions some recent advances from the sphere of clinical medicine and associated theoretical disciplines which may closely influence the future development of rheumatology. In addition to technical advances as regards visualization of tissue structures such as magnetic resonance and the development of artificial prostheses of damaged joints, molecular biology and genetics are the greatest advance as regards knowledge of the aetiopathogenesis of disease in particular those which have an immunopathological background.

[Systemic lupus erythematosus and pregnancy. Present status]. / Systémový lupus erytematodes a tehotenstvt. Soucasný stav problému.

The authors summarize contemporary views on the relationship between pregnancy and systemic lupus erythematosus (SLE) in women of reproductive age. It is known that pregnancy influences in a marked way the basic disease and conversely the disease has an impact on the course of pregnancy. Risks ensuing from these in errelations for women--mothers with SLE and the foetus are exacerbation (flare-up) of the basic disease, loss of the foetus and damage of the foetus by so-called "lupus neonatorum" with skin symptoms and complete cardiac A-V block. The contemporary state of knowledge makes it possible under certain conditions to achieve by therapeutic interventions the development and delivery of a healthy foetus. Among these views it is most important for conception to occur in these patients with SLE during a period without signs of active SLE. To ensure a successful course of pregnancy in women with SLE is the task of a team of appropriate specialists.

[Antibodies against deoxyribonucleoproteins in circulating immune complexes in the blood of patients with autoimmune diseases]. / Protilátky proti deoxyribonukleoproteinu v cirkulujících imunitních komplexech a sérech nemocných s nekterými autoimunitními chorobami.

In 40 patients with various autoimmune diseases antibodies against desoxyribonucleoprotein (DNP) were assessed by enzyme immunoanalysis (ELISA) in serum and after dissociation of the isolated precipitate of circulating immune complexes (CIC) in the presence of polyethylene glycol. The results indicate that antibodies against DNP are not specific for systemic lupus erythematosus (SLE) and can be detected in serum and in particular in CIC in various autoimmune conditions. In SLE they may be important for evaluation of the activity of the disease, in particular if estimated concurrently in serum and in CIC.

[Clinical spectrum of the antiphospholipid syndrome]. / Klinické spektrum antifosfolipidového syndromu.

Antiphospholipid syndrome (APS) is characterized by multiple arterial and venous thromboses, repeated spontaneous abortions and thrombocytopenia, together with the presence of antiphospholipid antibodies in serum. We present three patients, two men and a woman, at the age of 43, 24 and 23 years respectively. The younger man and the woman had secondary APS and systemic lupus erythematosus, the older man had primary APS. The symptoms and course of the disease were different. The older man lives 17 years after the onset of first symptoms with multiple neurologic disorders, the younger man is symptomless. The woman died several months after the acute onset of the disease.

[Soluble cytokinin receptors in renal vasculitis and lupus nephritis]. / Solubilní receptory pro cytokiny u renální vaskulitidy a lupoidní nefritidy.

BACKGROUND: Activation of various cytokines, e.g. TNF alpha, IL-1 and/or IL-6 may play important role in the pathogenesis of renal vasculitis and lupus nephritis (LN). Systemic effects of these cytokines may be modulated by their circulating soluble receptors. Plasma levels of cytokine receptors may thus be also markers of the activation of these cytokines. METHODS AND RESULTS: Plasma levels of TNF alpha, its soluble receptor p75 (sTNF-RII), IL-6 and soluble IL-6 receptor (sIL-6R) were measured using ELISA in 17 pts with ANCA-positive renal vasculitis (12 active-ANCA-A, 7 in remission ANCA-R), 9 pts with active lupus nephritis (LN) and 5 healthy subjects. Pts with LN had in comparison with controls increased plasma levels of TNF alpha, sTNF-RII, IL-6 and sIL-6R. Pts with ANCA-A had also in comparison with controls increased plasma levels of TNF alpha, sTNF-RII and sIL-6R, but plasma levels of IL-6 were not significantly increased dut to great standard deviation. Pts with ANCA-R had in comparison with controls increased plasma levels of sTNF-RII, but plasma levels of TNF alpha were in ANCA-R significantly lower than in ANCA-A. While the ratio TNF alpha/sTNF-RII was significantly lower in all groups of pts than in controls, the ratio IL-6R/sIL-6R was in comparison with controls significantly increased only in LN. CONCLUSIONS: While increased plasma levels of TNF alpha may be nonspecific marker of the activity of ANCA-positive renal vasculitis and LN, plasma levels of sTNF-RII are increased also in pts with ANCA-positive renal vasculitis in remission. Increased plasma levels of sTNF-RII may interfere with systemic effects of TNF alpha, but may also prolong the lifetime of its active form. Plasma levels of sIL-6R are increased both in ANCA-A and in LN, but their increase is, however, much less pronounced than that of sTNF-RII and cannot effectively block systemic effects of IL-6.

[Practical results of monitoring pregnancy in women with systemic lupus erythematosus]. / Praktické výsledky sledování tehotenství u zen se systémovým lupus erythematodes.

BACKGROUND: The authors dealt with the urgent problem under what conditions it is possible to achieve in a woman with systemic lupus erythematosus (SLE) or another collagenosis, or secondary antiphospholipid syndrome (APS) a favourable outcome of pregnancy and the delivery of a healthy infant. METHODS AND RESULTS: The investigation comprised 23 women incl. 20 with SLE, two with the mixed form of a diffuse connective tissue disease (MCTD) and one with Sjögren's syndrome of the primary type. From the total number of 20 pregnancies six were consulted in advance with a doctor (group I-s-called planned pregnancies) and all terminated by a successful delivery. Of 11 pregnancies which were not consulted with a doctor in advance (group II-so-called unplanned pregnancies) 9 were terminated in term, however, only 5 with a successful delivery (55.5%), two women are still pregnant. Exacerbation of the basic disease during pregnancy was recorded only once and did not lead to discontinuation of the pregnancy. CONCLUSIONS: The authors provide evidence that desired pregnancy of informed women suffering from SLE or another collagenosis when assisted by a specialized medical team can lead to a successful delivery of an infant.

[Cytokines and adhesion molecules in renal vasculitis and lupus nephritis]. / Cytokiny a adhezní molekuly u renální vaskulitidy a lupoidní nefritidy.

BACKGROUND: Plasma levels and urinary excretion of proinflammatory cytokines and soluble adhesion molecules may be useful parameters of the activity of ANCA-positive renal vasculitis and lupus nephritis. METHODS AND RESULTS: Plasma levels and urinary excretion of TNF alpha, IL-6, IL-8, ICAM-1 and VCAM-1 were measured by ELISA in 14 patients (pts) with ANCA-positive renal vasculitis (8 active-ANCA-A, 6 in remission ANCA-R), 6 pts with active lupus nephritis (L.N), 15 pts with IgA nephropathy (IgAN) 10 pts with autosomal dominant polycystic kidney disease and 9 healthy subjects (Co). Fractional excretion (FE) of selected cytokines and adhesion molecules was also calculated. Pts with LN had in comparison with controls increased plasma levels of ICAM-1, VCAM-1, IL-6, IL-8 and TNF alpha, increased urinary excretion of VCAM-1, IL-8 and TNF alpha and increased fractional excretion of VCAM-1 and IL-8. Patients with ANCA-A had in comparison with controls increased plasma concentrations of ICAM-1 and VCAM-1, increased urinary excretion of VCAM-1, IL-6 and TNF alpha and increased fractional excretion of VCAM-1, IL-6, IL-8 and TNF alpha. Patients with ANCA-R had in comparison with controls higher plasma levels of ICAM-1, VCAM-1, IL-6 and TNF alpha, increased urinary excretion of VCAM-1 and TNF alpha and increased fractional excretion of VCAM-1, IL-6 and TNF alpha. CONCLUSIONS: Patients with ANCA-positive renal vasculitis had in contradistinction to pts with active LN increased fractional excretion of IL-6 and TNF alpha. Both cytokines are probably produced in renal vasculitis locally in the kidney. Increased plasma levels of soluble adhesion molecules and increased plasma levels and fractional excretion of proinflammatory cytokines in patients with ANCA-positive renal vasculitis in clinical remission may explain the strong propensity of these patients to develop relapses of the diseases on withdrawal of immunosuppressive treatment.

[The antiphospholipid syndrome]. / Antifosfolipidový syndrom.

The author summarized contemporary findings on anti-phospholipid autoantibodies, their different types and probable site of action. This autoimmune phenomenon produces some typical clinical symptoms which made it necessary to describe them as the so-called anti-phospholipid syndrome. If concurrently some autoimmune disease is present, in particular lupus erythematosus , this syndrome is considered "secondary". If this is not the case, it is assumed that the "primary form" is involved. The author suggests diagnostic criteria and in large groups of patients suffering from SLE the true prevalence of different symptoms of this syndrome is tested with participation of anti-phospholipid antibodies.