Levamisole in childhood idiopathic nephrotic syndrome: new promises, and advocacy for global access.

In the current issue of Kidney International, Sinha et al. present data from an open-label, noninferior, randomized controlled trial comparing 12-months of alternate-day prednisolone, given daily during infection, versus levamisole, in children with frequently relapsing or steroid-dependent nephrotic syndrome. This study suggests that both of these strategies are efficacious and safe. Results of this study should redefine the role of levamisole in future guidelines, and a call for global availability of levamisole should be advocated.

An open label non-inferiority randomized controlled trial evaluated alternate day prednisolone given daily during infections vs. levamisole in frequently relapsing nephrotic syndrome.

Initial therapies for children with frequently relapsing nephrotic syndrome include alternate-day prednisolone that is given daily during infections, or levamisole. In this open label, non-inferiority trial, 160 patients, 2 to 18-years-old with frequent relapses, were randomly assigned to receive either prednisolone (0.5-0.7 mg/kg/alternate-day, given daily during infections), or levamisole (2-2.5 mg/kg/alternate-days) for one-year. Patients with relapses on alternate day prednisolone at over 1 mg/kg, prior use of potent steroid-sparing therapies, eGFR under 60 ml/min/1.73 m2 and significant steroid toxicity were excluded. Primary outcome was the proportion of patients with frequent relapses, defined as three-relapses in one-year, or two-relapses within six-months if associated with significant steroid toxicity or loss to follow up. Eighty patients each were randomized to receive prednisolone and levamisole. Baseline features showed preponderance of young patients presenting within two-years of disease onset. On intention-to-treat analysis, frequent relapses were more common in patients administered prednisolone (40% versus 22.5%; risk difference 17.5%; 95% confidence interval 3.4-31.6%). Prednisolone was not non-inferior to levamisole in preventing frequent relapses. However, the two groups showed similar proportions of patients in sustained remission, comparable frequency of relapses, and low frequency of adverse events. The decline in steroid requirement from baseline was higher in the levamisole group. Per-protocol analysis showed similar results. These results have implications for choice of therapy for frequently relapsing nephrotic syndrome. Although therapy with alternate-day prednisolone was not non-inferior to levamisole in preventing frequent relapses, both therapies were effective in other outcome measures. Thus, levamisole was relatively steroid-sparing and may be preferred in patients at risk of steroid toxicity.

Antineutrophil cytoplasmic antibody in children with nephrotic syndrome treated with levamisole: a cross-sectional cohort study.

BACKGROUND: Levamisole is a commonly used steroid-sparing agent (SSA), but the reported incidence of antineutrophil cytoplasmic antibody (ANCA) positivity has been concerning. METHODS: Observational cross-sectional study wherein children aged 2 to 18 years with frequently relapsing/steroid dependent nephrotic syndrome (FRNS/SDNS) on levamisole for ≥ 12 months were tested for ANCA. RESULTS: A total of 210 children (33% female), median age of 7.3 (IQR: 5.6-9.6) years, and a median duration of levamisole exposure of 21 (IQR: 15-30) months were tested. ANCA was positive in 18% (n = 37): 89% (n = 33) perinuclear ANCA (pANCA), 3% (n = 1) cytoplasmic ANCA (cANCA), and 8% (n = 3) both. Of ANCA-positive children, none had reduced eGFR or abnormal urinalysis. The majority of these children were asymptomatic (81%, n = 30). Rash was more common among ANCA-positive children [6/37 (16%) vs. 3/173 (2%), p = 0.0001]. On multivariate analysis, higher age (OR = 1.02, [95th CI: 1.01 to 1.03], p = 0.007) and longer duration of levamisole exposure (OR = 1.05, [95th CI: 1.02 to 1.08], p = 0.0007) were associated with ANCA positivity. Levamisole was stopped in ANCA-positive children with the resolution of any clinical manifestations if present. Repeat ANCA testing was performed in 54% (20/37), and all were ANCA negative by 18 months. CONCLUSIONS: Children with FRNS/SDNS on longer duration of levamisole were associated with increasing prevalence of ANCA positivity, but most of these children were clinically asymptomatic. Prospective studies are required to determine the chronology of ANCA positivity and its clinical implication.

Periorbital Pyoderma Gangrenosum Associated With a Cocaine-Induced Midline Destructive Lesion: Case Report and Review of the Literature.

A 72-year-old woman with a history of chronic cocaine use presented 9 months after a dog bite with a large facial ulceration and absent sinonasal structures. Biopsies were negative for infectious, vasculitic, or neoplastic pathologies. The patient was lost to follow up for 15 months and returned with a significantly larger lesion despite abstinence from cocaine. Additional inflammatory and infectious workup was negative. Intravenous steroids were administered with clinical improvement. Therefore, she was diagnosed with pyoderma gangrenosum and cocaine-induced midline destructive lesion due to cocaine/levamisole. Pyoderma gangrenosum is a rare dermatologic condition that uncommonly involves the eye and ocular adnexa. Diagnosis involves clinical examination, response to steroids, exclusion of infectious or autoimmune conditions, and identifying potential triggers including cocaine/levamisole. This report highlights a rare presentation of periorbital pyoderma gangrenosum causing cicatricial ectropion associated with concomitant cocaine-induced midline destructive lesion and reviews important aspects of clinical manifestations, diagnosis, and management of pyoderma gangrenosum and cocaine/levamisole autoimmune phenomenon.

[Cocaine-induced vasculitis and mimics of vasculitis]. / Kokain-induzierte Vaskulitiden und Vaskulitis-Mimics.

Cocaine is a psychotropic tropane alkaloid and stimulant drug. Nasal insufflation of cocaine powder is a common route of administration. In Germany, cocaine is frequently adulterated with levamisole, an anthelminthic drug with immunomodulatory effects. Both substances are linked to various autoimmune conditions. Cocaine-induced midline destructive lesions cause a progressive destruction of osteocartilaginous structures within the upper respiratory tract and can mimic localized granulomatosis with polyangiitis. In addition, systemic vasculitis due to cocaine and levamisole has been reported. Differentiation of these conditions from primary vasculitis can be challenging because antineutrophil cytoplasmic antibodies (ANCA) are commonly detected. Early diagnosis of these conditions is crucial as clinical improvement is closely related to drug cessation.

Cutaneous and Mucosal Conditions Associated With Cocaine Use. / Cuadros cutáneo-mucosos asociados al consumo de cocaína.

Cocaine and some of its main adulterants, such as levamisole, can cause multiple cutaneous and mucosal manifestations, including ischemic complications, neutrophilic dermatoses, midline destructive lesions, and vasculitis associated with antineutrophil cytoplasmic antibodies (ANCAs). Striking systemic symptoms are generally not seen. In all these conditions, positive test results may be observed for antinuclear antibodies, antiphospholipid antibodies, and various ANCAs, sometimes with characteristic staining patterns. Histology typically shows vascular changes, such as leukocytoclastic vasculitis, necrotizing vasculitis, and thrombi. We review the clinical, serologic, and histologic features of cutaneous and mucosal conditions associated with the use of cocaine and also look at pathophysiologic mechanisms, differential diagnoses, and treatments.

Safety and Efficacy of Levamisole in Loiasis: A Randomized, Placebo-controlled, Double-blind Clinical Trial.

BACKGROUND: Individuals with high microfilarial densities (MFDs) of Loa loa are at risk of developing serious adverse events (SAEs) after ivermectin treatment. Pretreatment with drugs progressively reducing Loa MFDs below the risk threshold might help prevent these SAEs. We assessed the safety and efficacy of levamisole for this purpose. METHODS: A double-blind, randomized, placebo-controlled, MFD-ascending trial was conducted in the Republic of the Congo. Participants were treated in 3 cohorts defined by pretreatment MFD and levamisole dose (cohort 1: 1.0kg and 1.5mg/kg; cohorts 2 and 3: 2.5mg/kg). Safety outcomes were occurrence of SAE and adverse event frequency during the first week. The efficacy outcomes were MFD reduction from baseline and proportions of individuals with at least 40% and 80% MFD reduction at day 2 (D2), D7, and D30. RESULTS: The 2 lowest doses (1.0mg/kg and 1.5mg/kg) caused no SAEs but were ineffective. Compared with placebo, 2.5mg/kg levamisole caused more mild adverse events (10/85 vs. 3/85, P=.018), a higher median reduction from baseline to D2 (-12.9% vs. +15.5%, P<.001), D7 (-4.9% vs. +18.7%, P<.001), and D30 (-0.5% vs. +13.5%, P=.036) and a higher percentage of participants with >40% MFD reduction at D2 (17.5% vs. 1.2%, P<.001), D7 (11.8% vs. 6.3%, P=.269), and D30 (18.5% vs. 9.6%, P=.107). CONCLUSIONS: A single 2.5mg/kg levamisole dose induces a promising transient reduction in Loa loa MFDs and should encourage testing different regimens.

Adverse reactions with levamisole vary according to its indications and misuse: A systematic pharmacovigilance study.

Levamisole was initially prescribed for the treatment of intestinal worms. Because of immunomodulatory properties, levamisole has been used in inflammatory pathologies and in cancers in association with 5-fluorouracil. Levamisole is misused as a cocaine adulterant. Post-marketing reports have implicated levamisole in the occurrence of adverse drug reactions (ADRs) and its use is now limited in Europe and North America. In contrast, all other parts of the World continue to use single-dose levamisole as an anthelmintic. The aim of this study was to identify ADRs reported after levamisole exposure in VigiBase, the World Health Organisation's pharmacovigilance database, and analyse their frequency compared to other drugs and according to levamisole type of use. METHODS: All levamisole-related ADRs were extracted from VigiBase. Disproportionality analyses were conducted to investigate psychiatric, hepatobiliary, renal, vascular, nervous, blood, skin, cardiac, musculoskeletal and general ADRs associated with levamisole and other drugs exposure. In secondary analyses, we compared the frequency of ADRs between levamisole and mebendazole and between levamisole type of use. RESULTS: Among the 1763 levamisole-related ADRs identified, psychiatric disorders (reporting odds ratio with 95% confidence intervals: 1.4 [1.2-2.6]), hepatobiliary disorders (2.4 [1.9-4.3]), vasculitis (6.5 [4.1-10.6]), encephalopathy (22.5 [17.4-39.9]), neuropathy (4.3 [2.9-7.1]), haematological disorders, mild rashes and musculoskeletal disorders were more frequently reported with levamisole than with other drug. The majority of levamisole-related ADRs occurred when the drug was administrated for a non-anti-infectious indication. CONCLUSION: The great majority of the levamisole-related ADRs concerned its immunomodulatory indication and multiple-dose regimen. Our results suggest that single-dose treatments for anthelmintic action have a good safety profile.

Levamisole causes a transient increase in plasma creatinine levels but does not affect kidney function based on cystatin C.

BACKGROUND: In pediatric patients treated with levamisole to prevent relapses of idiopathic nephrotic syndrome (INS), a transient and non-progressive rise in creatinine levels has been observed. It has been suggested that levamisole affects tubular secretion of creatinine. However, other potential mechanisms - nephrotoxicity and interference with the analytical assay for creatinine - have never been thoroughly investigated. METHODS: In three steroid-sensitive nephrotic syndrome (SSNS) patients with elevated plasma creatinine levels, treated with levamisole 2.5 mg/kg every other day, serum cystatin C was determined. The glomerular filtration rate (GFR) was estimated using the full age spectrum for creatinine and the full age spectrum for cystatin C equations. Interference of levamisole with the enzymatic creatinine assay was tested using spare human plasma of different creatinine concentrations spiked with levamisole (4, 20, and 100 µM). RESULTS: Three patients who received levamisole with elevated plasma creatinine levels had normal serum cystatin C levels and corresponding estimated GFR. There was no assay interference. CONCLUSION: Levamisole increases plasma creatinine levels, which is most probably due to impaired tubular secretion of creatinine since there was no assay interference and patients had normal eGFR based on serum cystatin C. However, interference of metabolites of levamisole could not be excluded. To monitor GFR, cystatin C in addition to creatinine should be used and be measured before and during levamisole use.

Clinical efficacy of mycophenolate mofetil versus levamisole therapy in frequently relapsing and steroid dependent childhood nephrotic syndrome - A retrospective comparative analysis.

BACKGROUND: Children with frequently relapsing (FR) or steroid dependent (SD) nephrotic syndrome (NS) often develop side effects of corticosteroids. Various steroid-sparing agents are in practice, but only a few studies exist so far which have compared the safety and efficacy of these two commonly used agents. METHODS: We did a retrospective medical records review of children with FRNS or SDNS who had levamisole or mycophenolate mofetil (MMF) as a steroid-sparing agent with a minimum follow-up period of 12 months. The aim was to compare the course of our patients on MMF and levamisole. Our primary objective was to determine the number of children in sustained remission and those with the infrequently relapsing course on levamisole and MMF and, the median time to relapse in months in the two groups. The secondary objective was to compare time to first relapse and number of relapses in FRNS and SDNS group children on MMF and levamisole. RESULTS: A total of 88 children (34% female) with diagnosis FR/SDNS (44 each) were included in the study. Thirty-nine patients took levamisole, while 49 received MMF therapy. The median age of presentation at the relapsing course was 4.2 years. The proportion of children with sustained remission or infrequent relapsing (IFR) course on MMF was 73.6%, compared to 48.71% on levamisole (p-value .015). In addition, the median time to first relapse was 12 months (24, 1.5) and 4.5 months (24, 1) on respective medications. CONCLUSION: Clinical outcome was superior in the MMF group than levamisole, especially in SDNS patients, and also MMF was more efficacious in maintaining sustained remission.

Late Onset of ANCA Vasculitis as a Side Effect of Levamisole Treatment in Nephrotic Syndrome.

Levamisole is effectively used in steroid-dependent nephrotic syndrome and the more frequent side effects reported are cytopenia and liver enzymes alterations. Several studies have demonstrated that this drug can induce high titers of circulating perinuclear antineutrophil cytoplasmic autoantibodies (ANCA) and vasculitis, most of them occurring in the case of prolonged use. A four-year-old boy that was affected with steroid-dependent nephrotic syndrome was treated with Levamisole as a steroid-sparing agent at a dose of 2 mg/kg/48 h. After initiation of the treatment, the number of relapses drastically decreased, enabling a significant reduction in the cumulative steroid dose. Levamisole was well tolerated, and was therefore administered for several years. At the age of 15, he was also diagnosed with celiac disease. After nine years of continuous Levamisole treatment, he presented with a high fever, hand and foot joint arthritis, and increased levels of total and direct bilirubin. Since the symptoms started two days after the injection of the second dose of the COVID-19 vaccine, it was initially concluded that these manifestations were rare vaccination side effects. Therefore, he did not receive any specific treatments, and Levamisole was continued at the same dose. After an initial improvement, two months later, the patient presented with the same symptoms. Suspecting Levamisole-induced vasculitis, an ANCA titer was measured and this returned positive. Clinical manifestations and double positivity for both myeloperoxidase (MPO) and anti-proteinase 3 (PR3) antibodies argued against the fact that that these findings were secondary to vaccination, cocaine abuse, or celiac disease. Assuming that we were facing a rare drug reaction, Levamisole was promptly interrupted. This resulted in a rapid remission of fever and arthritis improvement, and a decrease in ANCA titers. By reporting this case, we want to raise awareness among clinicians regarding a rare complication of treatment with Levamisole that is often misdiagnosed due to the fact that the current literature lacks univocal guidelines regarding the precise timing of ANCA titrations and the duration of the treatment.

Use of levamisole-adulterated cocaine is associated with increased load of white matter lesions.

Background: Cocaine use has been associated with vascular pathologies, including cerebral white matter hyperintensities. Street cocaine is most often adulterated with levamisole, an anthelminthic drug that may also be associated with vascular toxicity. However, whether levamisole exposure from cocaine consumption further accelerates the development of white matter lesions remains unknown. Methods: We investigated the association of cocaine and levamisole exposure with white matter hyperintensities in 35 chronic cocaine users and 34 healthy controls. We measured cocaine and levamisole concentrations in hair samples, which reflected exposure up to 6 months previously. We assessed the number and total surface area of the white matter hyperintensities using structural MRI (FLAIR sequence). Using generalized linear models, we analyzed the contributions of cocaine and levamisole to the number and area of white matter hyperintensities, accounting for several confounding factors. Results: Analysis using generalized linear models revealed that cocaine users had more white matter hyperintensities in terms of total surface area, but not in terms of number. Further generalized linear models that included cocaine and levamisole hair concentrations (instead of group) as predictors indicated that levamisole exposure was strongly associated with more and larger white matter hyperintensities, suggesting that the elevated white matter hyperintensities in cocaine users were driven mainly by levamisole exposure. Finally, white matter hyperintensities in levamisole-exposed cocaine users were located primarily in the periventricular and juxtacortical white matter. Limitations: The sample size was moderate, and blood pressure was not systematically assessed. Conclusion: As an adulterant of cocaine, levamisole appears to increase the risk of white matter injury.

Levamisole induced toxic epidermal necrolysis: A case report.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening immune-mediated hypersensitivity reactions. Various drugs, such as Non Steroidal Anti-inflammatory drugs (NSAIDS), allopurinol, anticonvulsants and antibiotics, have been implicated as triggering agent of SJS/TEN. Levamisole is frequently used as an antihelminthic and as an immunomodulator in cases of nephrotic syndrome. However, levamisole has not been reported as a trigger for SJS/TEN. The current case describes levamisole-induced TEN in a 15-year-old male who presented to emergency with erythematous lesions, blistering and denudation of skin involving up to 30% of body surface area. Algorithm of drug causality for epidermal necrolysis scoring was applied for causality assessment and a relationship was found to be "possible". Immediate withdrawal of levamisole along with a short course of corticosteroids and cyclosporine led to improvement in signs and symptoms. Clinicians should be aware of the possible association of levamisole and SJS/TEN.

Levamisole and ANCA positivity in childhood nephrotic syndrome.

BACKGROUND: This study aimed to determine the prevalence of ANCA positivity in children managed with levamisole as a steroid-sparing agent for nephrotic syndrome (NS). METHODS: Medical records of children with steroid-sensitive NS managed with levamisole therapy at Sydney Children's Hospital between 1/1/2000 and 31/12/2018 were retrospectively reviewed. Main outcome measure was side effects of levamisole therapy including ANCA positivity. RESULTS: Seventy-one children, median age 3 years and 1 month (IQR 29-68 months) at first presentation, were subsequently managed with levamisole. 60.6% were male and 65% Caucasian. 47.9% had frequently relapsing (FR)NS and 52.1% steroid-dependent (SD)NS. Overall, there was a median reduction in relapses from 3 (IQR 1-5) to 0.4 relapses (IQR 0-1) per year after levamisole was commenced. Levamisole was successful in preventing relapse in 19 (29%) patients and was used for median 24 (22 to 25) months. Levamisole was discontinued due to relapse in 25 patients (38%) after median 12 (5-28) months. Side effects occurred in 28 patients (42.4%); the most common side effect was ANCA positivity in 12 patients. In eleven of these patients, levamisole was discontinued; in one patient, low-level titres were documented and spontaneously resolved without cessation of levamisole. Two patients developed ANCA-associated vasculitis. CONCLUSION: ANCA positivity is a common side effect of levamisole and was seen in 18.2% of our patients. Monitoring is required to determine side effects including ANCA positivity and treatment modified accordingly.

Recurrent Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Induced by Levamisole-Adulterated Cocaine.

ABSTRACT: Levamisole, an anthelmintic and immunomodulatory drug, was withdrawn from the US market in 1999 due to adverse effects, including agranulocytosis and vasculitis. In recent years, levamisole has been used as a common cocaine adulterant, and its use has led to an autoimmune syndrome characterized by an antineutrophil cytoplasmic antibody-associated vasculitis presenting with necrotic retiform purpura on the face and extremities. We present a case of recurrent levamisole-induced vasculitis initially misdiagnosed as systemic lupus erythematosus to highlight this easily misdiagnosed entity and to demonstrate re-exposure leading to recurrent vasculitis with more extensive clinical manifestations.

Cocaine Consumption and Antineutrophil Cytoplasmic Antibody-associated Glomerulonephritis: A Case Report.

ABSTRACT: Cocaine is often sold in a mixture with levamisole to increase the profit margin and potentiate the euphoric effect. Apart from an overdose, cocaine can induce a wide range of clinical symptoms. We present a case of cocaine/levamisole-induced pauci-immune glomerulonephritis. A 22-year-old patient was sent to the hospital after a laboratory result showed an unexpected acute kidney injury, with an estimated glomerular filtration rate of 34 mL/min/1.73 m2. The medical history included cocaine abuse. Renal biopsy showed a pauci-immune necrotizing glomerulonephritis. Antineutrophil cytoplasmic antibodies were positive with a perinuclear staining pattern and target specificity for leucocyte myeloperoxidase (antimyeloperoxidase). Despite treatment, the kidney function did not show significant improvement. The forensic implication of this case is that even if the toxicological values are not high enough to suggest a lethal intoxication, an idiosyncratic reaction on cocaine and/or levamisole has to be taken into account.

Pyoderma gangrenosum associated with levamisole-adulterated cocaine in a c-ANCA positive patient.

Pyoderma gangrenosum (PG) is an inflammatory, ulcerative condition that is characterized by painful ulcers that commonly present on the lower extremities. Up to half of PG cases are associated with underlying systemic disease, including inflammatory bowel disease, various autoimmune conditions, and malignancy. Another well-known association is the manifestation of PG with recreational cocaine use, especially cocaine contaminated with the adulterant agent levamisole. Once utilized for its immunomodulatory capabilities, levamisole was withdrawn from the market in 2002. It has since been repurposed to potentiate the amphetamine-like effects and duration of cocaine and has reduced preparation cost. We present a 52-year-old woman with chronic maxillary sinusitis and cocaine use disorder presenting with a two-week history of painful ulcers on bilateral lower extremities, each with a purulent base and undermined, violaceous borders. Urine toxicology was positive for cocaine and serologic studies were positive for cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) and lupus anticoagulant. Underlying conditions, especially that of granulomatosis with polyangiitis, were considered and ultimately ruled out. The patient's lesions exhibited a marked response with a short course of oral corticosteroids, typical of PG associated with levamisole. This case highlights the crucial role that drug abstinence plays in the prevention of recurrence.

Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children.

BACKGROUND: About 80% of children with steroid-sensitive nephrotic syndrome (SSNS) have relapses. Of these children, half relapse frequently, and are at risk of adverse effects from corticosteroids. While non-corticosteroid immunosuppressive medications prolong periods of remission, they have significant potential adverse effects. Currently, there is no consensus about the most appropriate second-line agent in children who are steroid sensitive, but who continue to relapse. In addition, these medications could be used with corticosteroids in the initial episode of SSNS to prolong the period of remission. This is the fourth update of a review first published in 2001 and updated in 2005, 2008 and 2013. OBJECTIVES: To evaluate the benefits and harms of non-corticosteroid immunosuppressive medications in SSNS in children with a relapsing course of SSNS and in children with their first episode of nephrotic syndrome. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 10 March 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs were included if they involved children with SSNS and compared non-corticosteroid immunosuppressive medications with placebo, corticosteroids (prednisone or prednisolone) or no treatment; compared different non-corticosteroid immunosuppressive medications or different doses, durations or routes of administration of the same non-corticosteroid immunosuppressive medication. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility, risk of bias of the included studies and extracted data. Statistical analyses were performed using a random-effects model and results expressed as risk ratio (RR) for dichotomous outcomes or mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). The certainty of the evidence was assessed using GRADE. MAIN RESULTS: We identified 43 studies (91 reports) and included data from 2428 children. Risk of bias assessment indicated that 21 and 24 studies were at low risk of bias for sequence generation and allocation concealment respectively. Nine studies were at low risk of performance bias and 10 were at low risk of detection bias. Thirty-seven and 27 studies were at low risk of incomplete and selective reporting respectively. Rituximab (in combination with calcineurin inhibitors (CNI) and prednisolone) versus CNI and prednisolone probably reduces the number of children who relapse at six months (5 studies, 269 children: RR 0.23, 95% CI 0.12 to 0.43) and 12 months (3 studies, 198 children: RR 0.63, 95% CI 0.42 to 0.93) (moderate certainty evidence). At six months, rituximab resulted in 126 children/1000 relapsing compared with 548 children/1000 treated with conservative treatments. Rituximab may result in infusion reactions (4 studies, 252 children: RR 5.83, 95% CI 1.34 to 25.29). Mycophenolate mofetil (MMF) and levamisole may have similar effects on the number of children who relapse at 12 months (1 study, 149 children: RR 0.90, 95% CI 0.70 to 1.16). MMF may have a similar effect on the number of children relapsing compared to cyclosporin (2 studies, 82 children: RR 1.90, 95% CI 0.66 to 5.46) (low certainty evidence). MMF compared to cyclosporin is probably less likely to result in hypertrichosis (3 studies, 140 children: RR 0.23, 95% CI 0.10 to 0.50) and gum hypertrophy (3 studies, 144 children: RR 0.09, 95% CI 0.07 to 0.42) (low certainty evidence). Levamisole compared with steroids or placebo may reduce the number of children with relapse during treatment (8 studies, 474 children: RR 0.52, 95% CI 0.33 to 0.82) (low certainty evidence). Levamisole compared to cyclophosphamide may make little or no difference to the risk for relapse after 6 to 9 months (2 studies, 97 children: RR 1.17, 95% CI 0.76 to 1.81) (low certainty evidence). Cyclosporin compared with prednisolone may reduce the number of children who relapse (1 study, 104 children: RR 0.33, 95% CI 0.13 to 0.83) (low certainty evidence). Alkylating agents compared with cyclosporin may make little or no difference to the risk of relapse during cyclosporin treatment (2 studies, 95 children: RR 0.91, 95% CI 0.55 to 1.48) (low certainty evidence) but may reduce the risk of relapse at 12 to 24 months (2 studies, 95 children: RR 0.51, 95% CI 0.35 to 0.74), suggesting that the benefit of the alkylating agents may be sustained beyond the on-treatment period (low certainty evidence). Alkylating agents (cyclophosphamide and chlorambucil) compared with prednisone probably reduce the number of children, who experience relapse at six to 12 months (6 studies, 202 children: RR 0.44, 95% CI 0.32 to 0.60) and at 12 to 24 months (4 studies, 59 children: RR 0.20, 95% CI 0.09 to 0.46) (moderate certainty evidence). IV cyclophosphamide may reduce the number of children with relapse compared with oral cyclophosphamide at 6 months (2 studies, 83 children: RR 0.54, 95% CI 0.34 to 0.88), but not at 12 to 24 months (2 studies, 83 children: RR 0.99, 95% CI 0.76 to 1.29) and may result in fewer infections (2 studies, 83 children: RR 0.14, 95% CI 0.03 to 0.72) (low certainty evidence). Cyclophosphamide compared to chlorambucil may make little or no difference in the risk of relapse after 12 months (1 study, 50 children: RR 1.31, 95% CI 0.80 to 2.13) (low certainty evidence). AUTHORS' CONCLUSIONS: New studies incorporated in this review indicate that rituximab is a valuable additional agent for managing children with steroid-dependent nephrotic syndrome. However, the treatment effect is temporary, and many children will require additional courses of rituximab. The long-term adverse effects of this treatment are not known. Comparative studies of CNIs, MMF, levamisole and alkylating agents have demonstrated little or no differences in efficacy but, because of insufficient power; clinically important differences in treatment effects have not been completely excluded.

A Unique Presentation of Levamisole-Induced Antineutrophil- Cytoplasmic-Antibody-Positive Vasculitis Presenting as Inflammatory Orbitopathy.

A 35-year-old woman with a history of cocaine abuse presented with progressively worsening OS pain. Neuroimaging revealed a 3-cm ill-defined left orbital lesion involving the intraconal and extraconal spaces. The orbital mass was biopsied via an anterior orbitotomy approach. Pathology demonstrated prominent angiocentric granulomatous and lymphoplasmacytic inflammation consistent with vasculitis. Laboratory tests were significant for neutropenia, positive perinuclear antineutrophil cytoplasmic antibodies with high titer, and positive myeloperoxidase antibodies, consistent with levamisole-induced vasculitis. To the authors' knowledge, this is the first reported case of cocaine-levamisole-induced vasculitis presenting as orbitopathy.

Cocaine Use and Levamisole-Induced Vasculitis: A Multiple Case Study.

BACKGROUND: Levamisole is an immunomodulatory medication previously used to treat rheumatoid arthritis and some types of cancers; it was banned for use in humans in 2000 owing to its harmful side effects. Use of levamisole-laced cocaine is associated with a life-threatening syndrome characterized by a necrotizing purpuric rash leading to tissue destruction and necrotic wounds. This Clinical Challenges article summarizes our experience with the care of 2 adult women diagnosed with levamisole-related vasculitis. CASE: Case 1 is a 46-year-old woman who presented with joint pain in her hands and legs, along with bilateral ear pain, swelling, and bleeding. She was initially diagnosed with vasculitis and possible systemic lupus erythematosus. She experienced multiple recurrences and exacerbation of her condition over a period of months. She was ultimately diagnosed with levamisole-related vasculitis from recurrent cocaine use resulting in bilateral above the knee amputations. The second case is a 50-year-old woman who presented to our emergency department with redness and swelling of her bilateral lower extremities. She developed blisters and pustules that rapidly evolved into abscesses and red lesions over the course of several months. Her wounds also deteriorated despite topical therapy that occurred in a context of recurring use of cocaine. CONCLUSIONS: Our experience with these cases suggests that WOC nurses should consider levamisole-induced vasculitis in all patients presenting with unexplained vasculitis-type lesions, and particularly when these lesions occur in the context of known or suspected use of illicit substances such as cocaine. Given the absence of clinical guidelines for this increasingly prevalent condition, we recommend wound care based on principles of moist wound healing, combined with judicious use of therapies with antimicrobial activity and nonadherent dressings to reduce pain. Finally, we strongly recommend that care of these patients occurs as one part of a multidisciplinary care approach that focuses on cessation of the use of cocaine and all other illicit substances.