[Protocols in pediatric rheumatology (PROKIND): treat-to-target in polyarticular juvenile idiopathic arthritis]. / Protokolle in der Kinderrheumatologie (PROKIND): Treat-to-Target bei polyartikulärer juveniler idiopathischer Arthritis.

BACKGROUND: The aims of the PROKIND protocols are improvement and harmonization of the diagnostics, monitoring, treatment decision and prognosis. MATERIAL AND METHODS: This article reports the results of a prospective treat-to-target observational study of patients with polyarticular juvenile idiopathic arthritis (JIA) during the first year of treatment. Disease activity was assessed with the 10-joint juvenile arthritis disease activity score (JADAS-10), functional limitation with the childhood health assessment questionnaire disability index (CHAQ-DI) and with information on overall well-being, on pain, on fatigue and on global estimation of disease activity. RESULTS: Overall, 129 patients with polyarticular JIA (rheumatoid factor, RF, positive (+) polyarthritis n = 22, RF negative (-) polyarthritis n = 133 from 23 pediatric rheumatology institutions in Germany and Austria were recruited. Patients with initial treatment with methotrexate formed cohort 1, patients with additional repeated intravenous corticosteroid pulse therapy formed cohort 2 and patients with concomitant intra-articular corticosteroid administration in at least 5 joints formed cohort 3. The mean JADAS10 showed a decrease in disease activity from 16.4 ± 6.1 to 2.8 ± 3.6 and the decrease in the CHAQ-DI from 1.0 ± 0.8 to 0.3 ± 0.5 showed the improvement in functional capacity. Similarly, improvements in quality of life, pain and fatigue were demonstrable. A JADAS inactive disease was achieved by 18.1% at month 3, 47.7% at month 6 and 66.7% at month 12. In cohort 1 a JADAS remission was achieved by 72.4%, by 50% in cohort 2 and by 69.2% in cohort 3. An escalation to treatment with biologics was necessary in 38% of patients in cohort 1, 60% in cohort 2 and 46% in cohort 3. CONCLUSION: Using a treat-to-target approach a dramatic improvement in disease activity, functional capacity and quality of life in polyarticular JIA could be achieved. Even after 12 months an inactive disease was achieved in the majority of cases.

IL-6 blockade in systemic juvenile idiopathic arthritis - achievement of inactive disease and remission (data from the German AID-registry).

BACKGROUND: Systemic juvenile idiopathic arthritis (sJIA) is a complex disease with an autoinflammatory component of unknown etiology related to the innate immune system. A major role in the pathogenesis has been ascribed to proinflammatory cytokines like interleukin-6 (IL-6), and effective drugs inhibiting their signaling are being developed. This study evaluates sJIA patients treated with the IL-6 inhibitor tocilizumab (TCZ) concerning clinical response rate, disease course and adverse effects in a real-life clinical setting. METHODS: In 2009 a clinical and research consortium was established, including an online registry for autoinflammatory diseases (AID) ( https://aid-register.de ). Data for this retrospective TCZ study were documented by 13 centers. RESULTS: From 7/2009 to 4/2014, 200 patients with sJIA were recorded in the AID-registry. Out of these, 46 (19 m, 27 f, age 1-18 years) received therapy with TCZ. Long term treatment (median 23 months) has been documented in 24/46 patients who were evaluated according to Wallace criteria (active disease 6/24, inactive disease 5/24, remission 13/24 cases). Under observation co-medication were used in 40/46 cases. Adverse events were reported in 11/46 patients. The clinical response rate (no clinical manifestation, no increased inflammation parameters) within the first 12 weeks of treatment was calculated to be 35%. CONCLUSION: Out of 200 sJIA children reported in the German AID-registry, 46 were treated with TCZ, showing a clinical response rate of 35% during the first 12 weeks, and inactive disease and/or remission under medication in 75% after one year. Adverse events were seen in 24% and severe adverse events in 4%. TRIAL REGISTRATION: The AID-Registry is funded by the BMBF (01GM08104, 01GM1112D, 01GM1512D).

Food-induced anaphylaxis and cofactors - data from the anaphylaxis registry.

Food allergens are frequent causes of anaphylaxis. In particular in children and adolescents they are the most frequent elicitors of severe allergic reactions, and in adults food allergens rank third behind insect venom and drugs. Since July 2006 severe allergic reactions from Germany, Austria, and Switzerland are collected in the anaphylaxis registry. Currently 78 hospitals and private practises are connected. From July 2006 until February 2009 1,156 severe allergic reactions were registered. Among children and adolescents (n = 187, age range from 3 months to 17 years) food allergens were the most frequent triggers, comprising 58% of cases. In the adult group (n = 968, 18 - 85 years) food allergens were in the third position (16.3%) behind insect venom and drugs. In children legumes (31%) and in particular peanuts were frequently responsible food allergens, followed by tree nuts (25%) with hazelnut being the most frequent elicitor. In adults fruits (13.4%) most often induced severe food-dependent anaphylaxis, but also animal products (12.2%); among these most frequently crustaceans and molluscs. Cofactors were often suspected in food-dependent anaphylaxis, namely in 39% of the adult group and in 14% of the pediatric group. In adults drugs (22%) and physical activity (10%) were reported to be the most frequent cofactors, in children physical activity was suspected in 8.7% and drugs in 2.6%. Concomitant diseases like atopic dermatitis, allergic asthma, or allergic rhinoconjunctivitis were reported in 78% of children and adolescents and in 67% of the adults. In conclusion, food-induced anaphylaxis, its cofactors and concomitant diseases are age-dependent. The data offers to identify risk factors of anaphylaxis.

CXCR5 is critically involved in progression of lupus through regulation of B cell and double-negative T cell trafficking.

The recruitment of immune cells to sites of tissue inflammation is orchestrated by chemokine/chemokine receptor networks. Among these, the CXCL13/CXCR5 axis is thought to be involved critically in systemic lupus erythematosus (SLE) and lupus nephritis pathogenesis. Beyond B cell abnormalities, another hallmark of SLE disease is the occurrence of aberrant T cell responses. In particular, double-negative (DN) T cells are expanded in the peripheral blood of patients with SLE and in lupus-prone mice. DN T cells induce immunoglobulin production, secrete proinflammatory cytokines and infiltrate inflamed tissue, including kidneys. We aimed to investigate how CXCR5 deficiency changes immune cell trafficking in murine lupus. We therefore crossed CXCR5(-/-) mice with B6/lpr mice, a well-established murine lupus model. B cell numbers and B cellular immune responses were diminished in CXCR5-deficient B6/lpr mice. In addition, we observed reduced accumulation of DN T cells in spleen and lymph nodes, paralleled by reduced splenomegaly and lymphadenopathy. In-vivo migration assays revealed reduced migration of CXCR5-deficient DN T cells into lymph nodes, and ex-vivo-activated CXCR5-deficient DN T cells failed to infiltrate kidneys of recipients. Moreover, DN T cells and B cells of CXCR5-deficient B6/lpr mice failed to migrate towards CXCL13 in vitro. We propose that CXCR5 is involved critically in B cell trafficking and germinal cell (GC) formation in murine lupus and in guiding pathogenic DN T cells into lymphoid organs and kidneys, and we therefore describe new pathomechanisms for the CXCL13/CXCR5 axis in SLE.

[Regulatory T-cells in systemic lupus erythematosus. IL-2 is decisive for loss of tolerance]. / Regulatorische T-Zellen beim systemischen Lupus erythematodes. IL-2 entscheidend für Verlust der Toleranz.

Systemic lupus erythematosus (SLE) results from loss of immunological tolerance. Regulatory T­cells (Treg) are major gatekeepers of peripheral tolerance by suppression of autoreactive lymphocytes. Defects in Treg function are therefore possible pathogenetic mechanisms of SLE. Despite this fact published work about numbers and functions of Tregs in SLE are contradictory and the definitive role of Treg in SLE remains unclear. In this review we summarize the current literature about Treg subtypes and the phenotypic markers in human SLE. We also discuss data from mouse models and ex vivo experiments, which provide indications for possible mechanisms that contribute to loss of tolerance. We also discuss the role of interleukin 2 (IL-2), which is decisive for the function of Treg and has been used therapeutically in preliminary trials in human SLE. The identification of novel Treg markers and the development of novel therapeutic approaches, which restore the balance between Treg and autoreactive T­cells are future goals for research in SLE.

ß7-Integrin exacerbates experimental DSS-induced colitis in mice by directing inflammatory monocytes into the colon.

Leukocyte recruitment is pivotal for the initiation and perpetuation of inflammatory bowel disease (IBD) and controlled by the specificity and interactions of chemokines and adhesion molecules. Interactions of the adhesion molecules α4ß7-integrin and mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) promote the accumulation of pathogenic T-cell populations in the inflamed intestine. We aimed to elucidate the significance of ß7-integrin expression on innate immune cells for the pathogenesis of IBD. We demonstrate that ß7-integrin deficiency protects recombination-activating gene-2 (RAG-2)-deficient mice from dextran sodium sulfate (DSS)-induced colitis and coincides with decreased numbers of colonic effector monocytes. We also show that ß7-integrin is expressed on most CD11b(+)CD64(low)Ly6C(+) bone marrow progenitors and contributes to colonic recruitment of these proinflammatory monocytes. Importantly, adoptive transfer of CD115(+) wild-type (WT) monocytes partially restored the susceptibility of RAG-2/ß7-integrin double-deficient mice to DSS-induced colitis, thereby demonstrating the functional importance of ß7-integrin-expressing monocytes for the development of DSS colitis. We also reveal that genetic ablation of MAdCAM-1 ameliorates experimental colitis in RAG-2-deficient mice as well. In summary, we demonstrate a previously unknown role of α4ß7-integrin-MAdCAM-1 interactions as drivers of colitis by directing inflammatory monocytes into the colon.

Interleukin-2 treatment reverses effects of cAMP-responsive element modulator α-over-expressing T cells in autoimmune-prone mice.

Systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), are often characterized by a failure of self-tolerance and result in an uncontrolled activation of B cells and effector T cells. Interleukin (IL)-2 critically maintains homeostasis of regulatory T cells (T(reg)) and effector T cells in the periphery. Previously, we identified the cAMP-responsive element modulator α (CREMα) as a major factor responsible for decreased IL-2 production in T cells from SLE patients. Additionally, using a transgenic mouse that specifically over-expresses CREMα in T cells (CD2CREMαtg), we provided in-vivo evidence that CREMα indeed suppresses IL-2 production. To analyse the effects of CREMα in an autoimmune prone mouse model we introduced a Fas mutation in the CD2CREMαtg mice (FVB/Fas(-/-) CD2CREMαtg). Overexpression of CREMα strongly accelerated the lymphadenopathy and splenomegaly in the FVB/Fas(-/-) mice. This was accompanied by a massive expansion of double-negative (DN) T cells, enhanced numbers of interferon (IFN)-γ-producing T cells and reduced percentages of T(regs). Treatment of FVB/Fas(-/-) CD2CREMαtg mice with IL-2 restored the percentage of T(regs) and reversed increased IFN-γ production, but did not affect the number of DNTs. Our data indicate that CREMα contributes to the failure of tolerance in SLE by favouring effector T cells and decreasing regulatory T cells, partially mediated by repression of IL-2 in vivo.

[Pathogenesis and new therapeutic approaches for systemic lupus erythematosus]. / Pathogenese und neue Therapieansätze beim systemischen Lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus is a complex autoimmune disease that can affect multiple organs and is characterized by a loss of peripheral tolerance against nuclear antigens, pathogenic B and T cell responses and production of autoantibodies. The prevalence is estimated to be 40 per 100,000 in the population in Europe but can be as high as 150 patients per 100,000 among the Afro-Caribbean population. Although the 5-year survival rate in the 1950s was estimated to be only 50%, the 10-year survival rate is currently estimated to be 70-92%. This progress is particularly due to a better understanding of the pathogenesis that opened up better therapeutic possibilities in the past and now raises new perspectives for future therapy approaches. OBJECTIVE: The current knowledge on the pathogenesis and the current situation of new therapeutic approaches for SLE are presented. RESULTS AND DISCUSSION: This progress in the therapeutic options was made possible by a better understanding of the pathophysiology, which leads to the expectation of an improvement in the prognosis of patients due to reduction in the burden of the disease in the future. Several new therapeutic medications are currently awaiting approval and recently for the first time in more than 50 years a new medication for SLE was approved, a monoclonal antibody to the tumor necrosis factor (TNF)-like ligand, B-cell activating factor (BAFF) belonging to the TNF family also named B-cell lymphocyte stimulator (BLyS), BAFF/BLyS.

[Clinical features and therapy of rheumatic diseases and vasculitides in childhood]. / Klinik und Therapie rheumatischer Erkrankungen und Vaskulitiden im Kindesalter.

Rheumatic diseases are the second most common autoimmune disease in childhood after diabetes mellitus. Because cutaneous findings are so common, a dermatologist is often the first physician these children and their parents see. The most common rheumatic disease is juvenile idiopathic arthritis. Except for the systemic form and psoriatic arthritis JIA usually does not show cutaneous symptoms. However, there are many rheumatic diseases that start with skin manifestations such as Henoch-Schönlein purpura, systemic lupus erythematosus and Kawasaki syndrome. Knowledge of these diseases and their symptoms is therefore of importance for the dermatologist.

Activated STING in a vascular and pulmonary syndrome.

BACKGROUND: The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation. METHODS: We analyzed the DNA of an index patient with early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary inflammation. We sequenced a candidate gene, TMEM173, encoding the stimulator of interferon genes (STING), in this patient and in five unrelated children with similar clinical phenotypes. Four children were evaluated clinically and immunologically. With the STING ligand cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), we stimulated peripheral-blood mononuclear cells and fibroblasts from patients and controls, as well as commercially obtained endothelial cells, and then assayed transcription of IFNB1, the gene encoding interferon-ß, in the stimulated cells. We analyzed IFNB1 reporter levels in HEK293T cells cotransfected with mutant or nonmutant STING constructs. Mutant STING leads to increased phosphorylation of signal transducer and activator of transcription 1 (STAT1), so we tested the effect of Janus kinase (JAK) inhibitors on STAT1 phosphorylation in lymphocytes from the affected children and controls. RESULTS: We identified three mutations in exon 5 of TMEM173 in the six patients. Elevated transcription of IFNB1 and other gene targets of STING in peripheral-blood mononuclear cells from the patients indicated constitutive activation of the pathway that cannot be further up-regulated with stimulation. On stimulation with cGAMP, fibroblasts from the patients showed increased transcription of IFNB1 but not of the genes encoding interleukin-1 (IL1), interleukin-6 (IL6), or tumor necrosis factor (TNF). HEK293T cells transfected with mutant constructs show elevated IFNB1 reporter levels. STING is expressed in endothelial cells, and exposure of these cells to cGAMP resulted in endothelial activation and apoptosis. Constitutive up-regulation of phosphorylated STAT1 in patients' lymphocytes was reduced by JAK inhibitors. CONCLUSIONS: STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by gain-of-function mutations in TMEM173. (Funded by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases; ClinicalTrials.gov number, NCT00059748.).

Basophil activation test for the diagnosis of hymenoptera venom allergy in childhood: a pilot study.

INTRODUCTION: Cellular in vitro tests such as the CD63-based basophil activation test (BAT) have been successfully used to diagnose hymenoptera venom sensitization in adult patients while this has not been investigated in children so far. METHODS: 15 children (9 male, 6 female; 12.7±3.5 years) with suspected allergy to vespula (VE) or honey bee (HB) venom entered this study. Besides serum tryptase (ST) levels, sensitisation against VE and HB was assessed by titrated skin testing and determination of venom-specific serum IgE (sIgE) in all patients. After stimulation with 50 ng of insect venom, CD63-expression of activated basophils was measured by flow cytometry. RESULTS: Skin testing permitted identification of the culprit insect in 7 patients, 3 cases were diagnosed by additional sIgE measurements. In addition, BAT identified mono-sensitization in 3 further patients with double sensitization upon skin and sIgE testing. Test sensitivity was lower for the BAT (67-75%) than for skin testing (89-100%) and sIgE determination (100%). Neither basophil activation nor sIgE serum levels were identified as reliable predictors of sting reaction severity. In all patients, ST measurements yielded values below the upper reference value. CONCLUSION: The current pilot study suggests a possible clinical benefit of BAT analysis in the diagnostic workup of pediatric insect venom allergy. However, further large-scale trials are required to investigate whether the BAT reliably contributes to the correct identification of the culprit insect venom. Due to its comparatively low sensitivity, the BAT should currently not be used in isolation from, but only in combination with established diagnostic instruments.

G/A polymorphism at -258 of the hepatic glucokinase promoter is not associated with decreased birth weight in preterm neonates.

BACKGROUND: A high percentage of preterm neonates are born small for gestational age (SGA). These children show a high morbidity and mortality after birth and often develop insulin resistance with ensuing impaired glucose metabolism in adulthood. Since insulin is important for intrauterine growth, fetal insulin resistance might also influence birth weight of preterm neonates. OBJECTIVES: A common polymorphism in the promoter region of the human hepatic glucokinase (-258) is associated with a decreased promoter activity, an enhanced insulin secretion, and hypertension and hepatic insulin resistance in adults. In this pilot study we wanted to investigate whether the G/A polymorphism at -258 of the hepatic glucokinase promoter has an effect on birth weight of preterm neonates and therefore might constitute a genotype leading to low birth weight and metabolic defects. METHODS: We enrolled 106 preterm neonates in our study. 44 of them were SGA and 62 AGA neonates. We extracted DNA from a buccal swab and identified the polymorphism by PCR-ARMS. RESULTS: We found no difference in the prevalence of the polymorphism in either groups. CONCLUSION: The polymorphism at -258 of the fetal hepatic glucokinase promoter is most probably not of a major relevance in the pathophysiology of low birth weight in preterm neonates.

Altered signal transduction in SLE T cells.

T cells from patients with systemic lupus erythematosus display numerous signalling abnormalities. The T cell receptor complex is rewired with the common FcRgamma chain replacing the CD3 zeta chain while the T cell surface membrane lipid rafts are aggregated. These two aberrations result in enhanced early signalling events and altered downstream signalling events. These are in turn responsible for an altered expression of cytokines such as interleukin-6 (IL-6), IL-10, IL-2, IFNy and CD40 ligand. While some of these abnormalities explain the enhanced ability of T cells to help B cells to produce autoantibodies, decreased IL-2 production results in enhanced susceptibility to infections, reduced activation-induced cell death and prolonged survival of autoreactive T cells, which promote help to autoreactive B cells.

Type I IgE receptor, interleukin 4 receptor and interleukin 13 polymorphisms in children with nephrotic syndrome.

Polymorphisms in the genes encoding the high-affinity IgE receptor, the interleukin 4 (IL4) receptor and IL13 can be associated with the development of asthma and allergy. Although several studies have described an association between atopy and idiopathic childhood nephrotic syndrome (NS), it is not clear whether this association is of a causal nature. Furthermore, it is not known whether these polymorphisms are associated with the clinical course of NS. A total of 84 children (52 male and 32 female; mean age 12.1 years) with NS were included in the present study. Of these, 78 could be classified as either atopic or non-atopic. Atopy was defined by elevated IgE levels (>100 k-units/l) and/or a positive history of atopy (33 of 78 patients). DNA was extracted from blood collected in EDTA tubes, and polymorphisms at positions 50 and 551 of the IL4 receptor, position 110 of IL13 and position 181 of the high-affinity IgE receptor were investigated by sequence-specific PCR or direct sequencing. Although we noted a strong tendency towards a higher allele frequency of polymorphisms in children with atopy and NS compared with children with NS but without atopy (IL4 50, 30% compared with 18%; IL4 551, 39% compared with 31%; IL13 110, 45% compared with 33%; IgE 181, 12% compared with 13%), these differences did not reach statistical significance. There were no differences in the frequency of polymorphisms between the different clinical courses of NS (frequent relapsers, steroid-dependent or steroid-resistant NS). We conclude that polymorphisms in the IL4 receptor, the high-affinity IgE receptor and IL13 do not seem to predict the clinical course of NS, despite the fact that serum IgE elevations are more frequent in patients with NS than in normal control subjects. The investigated polymorphisms may contribute to the IgE switch in patients with NS.

Analysis of muscle strength and bone structure in children with renal disease.

Bone structure and muscular strength of 30 children with renal disease were investigated by peripheral computed tomography and grip strength. Sixteen children suffered from nephrotic syndrome (NS) and had previously been treated with corticosteroids. Fourteen children suffered from chronic renal failure (CRF) ranging from mild renal failure to end-stage renal disease. Six children had received kidney transplants and corticosteroids for immunosuppression. There was a significant decrease in grip strength of children with NS (SD -0.91+/-1.5; P=0.042) and children with CRF (SD -1.38+/-1.4; P<0.001) compared with normal children. Furthermore, there was a significant correlation between cortical area and grip strength in all children with renal disease (r=0.92; P<0.0001). Trabecular bone mineral density did not correlate well with grip strength. These findings resemble results found in healthy children. Trabecular bone mineral density was significantly elevated in children with CRF compared with normal children (SD 1.14+/-1.4; P=0.008). Grip strength as a marker of muscle mass and cortical area as a marker of bone strength correlate well in children with renal disease, similar to the correlation in healthy children. Grip strength is significantly lower in children with NS and CRF compared with normal children. These data suggest that muscular impairment could be involved in renal osteopathy.

Intravenous iron treatment of renal anemia in children on hemodialysis.

Treatment of anemia in children with end-stage renal disease (ESRD) has been greatly facilitated by the introduction of recombinant human erythropoietin (rHuEPO). A major limiting factor in the treatment of renal anemia is sufficient iron supplementation. Eight children (aged 10-17 years) receiving hemodialysis were treated with intravenous iron (1 mg/kg per week) for 3 months. Hemoglobin (Hb), hematocrit (Hct), and serum ferritin levels were measured regularly. The mean Hct increased from 25% to 30%, the mean Hb increased from 7. 8 g/dl to 9.2 g/dl, and the mean ferritin level from 200 to 395 mg/dl. The mean EPO dosage could be tapered from 6,500 IU to 6,150 IU. No adverse side-effects were noted. Hence, in this uncontrolled study intravenous iron was an effective treatment for iron deficiency during rHuEPO therapy in children with ESRD on hemodialysis.

Absence of Oxalobacter formigenes in cystic fibrosis patients: a risk factor for hyperoxaluria.

BACKGROUND: Patients with cystic fibrosis have an increased risk of hyperoxaluria, and of subsequent nephrocalcinosis and calcium-oxalate urolithiasis. Oxalate homoeostasis is controlled, in part, by the intestinal bacterium, Oxalobacter formigenes. The loss of this bacterium from the gut flora is associated with an increased risk of hyperoxaluria and calcium-oxalate urolithiasis. We investigated whether the absence of O. formigenes and the presence of hyperoxaluria are correlated in cystic fibrosis (CF) patients. METHODS: Stool specimens from 43 patients with CF aged 3-9 years and from 21 similarly aged healthy volunteers were examined for O. formigenes by culture and DNA analysis. At the same time, 24 h urine samples were collected and analysed for oxalate and other factors that promote or inhibit stone formation. FINDINGS: 15 (71%) of 21 healthy volunteers but only seven (16%) of 43 CF patients were colonised with O. formigenes. Detection of O. formigenes in six of these seven patients required DNA-based identification, suggesting low numbers of colony-forming units, and the CF patient with normal numbers of O. formigenes was the only one of the 43 patients who had not been treated with antibiotics. All seven CF patients colonised with O. formigenes had normal urinary oxalate levels, but 19 (53%) of 36 patients not colonised with O. formigenes were hyperoxaluric, with the most severe hyperoxaluria occurring in young patients. INTERPRETATION: Absence of O. formigenes from the intestinal tract of CF patients appears to lead to increased absorption of oxalate, thereby increasing the risk of hyperoxaluria and its complications (eg, nephrocalcinosis, urolithiasis). Prolonged widespread use of antibiotics, and alterations of the gastrointestinal tract that occur in CF, may induce a permanent decolonisation in CF patients.

Levamisole treatment in steroid-sensitive and steroid-resistant nephrotic syndrome.

Since 1992 we have treated 11 children with frequently relapsing steroid-sensitive (n=6) or steroid-resistant (n=5) nephrotic syndrome with levamisole. All had been non-responsive to other immunosuppressive medication before levamisole treatment. All steroid-sensitive patients had signs of steroid toxicity. At least 1 kidney biopsy had been performed prior to study in each patient. Five children had minimal glomerular changes and the other 6 focal segmental glomerular sclerosis. The patients were treated with levamisole (2.5 mg/kg per 48 h) for at least 2 months (up to 18 months, median 10 months). Two patients had additional immunosuppression (cyclosporine A) during levamisole treatment. All patients with steroid-sensitive nephrotic syndrome became free of proteinuria within 2 months and have remained in remission after discontinuation of levamisole (follow-up time 8-50 months, median 24 months). None of the children with steroid-resistant nephrotic syndrome experienced a remission. Side effects were observed in 2 patients and included a granulocytopenia and a severe psoriasis-like cutaneous reaction; both were reversible after discontinuation of levamisole. We conclude that levamisole is of benefit in steroid-sensitive nephrotic syndrome but not in steroid-resistant nephrotic syndrome.