Review Of Refractory Lupus Nephritis - Open Access Journals
ReviewReview of refractory lupus nephritisDespite significant advances in the management of patients with lupus nephritis, a significant proportionof patients either do not respond to first-line immunosuppressive drugs, or relapse after having achievedinitial remission. Various factors including ethnicity, gender, genetics, clinical features, serology andhistology affect response to therapy and prognosis. The term ‘refractory nephritis’ is used for those patientswho have no or partial response to first-line therapies, which include cyclophosphamide and mycophenolatemofetil. Alternative therapies that are currently available include the ‘multitarget therapy’ and variousbiologics that target B cells, T cells or different cytokines. Among these, multitarget therapy, which includescyclosporine, mycophenolate mofetil and prednisolone, and the anti-CD20 antibody rituximab, alone orin combination with immunosuppressives, have demonstrated efficacy in treating refractory nephritis. Inthis review, we will discuss the definition of refractory nephritis and partial and complete responses,various factors associated with refractory nephritis, followed by an overview of the treatment of lupusnephritis, and finally on the various drugs currently available and potential new agents for the treatmentof refractory nephritis.Keywords: belimumab n lupus nephritis n refractory n rituximab n triple therapySystemic lupus erythematosus (SLE) is anextremely heterogeneous, multisystem, autoimmune disease, characterized by the presenceof multiple autoantibodies and deposition ofimmune complexes in various tissues. Nephritis,which is the most frequent serious manifestationof the disease, can affect up to 60% of adultsand 80–90% of children throughout the courseof illness [1,2] . Untreated it has a dismal prognosis, with 5-year survival rates varying from0 to 20%. The introduction of corticosteroidsand then immunosuppressive therapies, namelycyclophosphamide (CYP) and, more recently,mycophenolate mofetil (MMF), which is lesstoxic than CYP with regard to gonadal toxicity, have improved prognosis, such that 5-yearsurvival rates are approximately 95%, and at10 years 90% [3] . Rates of end-stage renal failure (ESRF) have, however, remained static at10–20% despite the effective therapies available[3] . Response to therapy is slow and often incomplete, with approximately 25–50% patients experiencing remission (both partial and complete) at2 years, and the majority having a relapse after5 years, despite continuous immunosuppressivetherapy [4] .The term ‘refractory nephritis’ is used for thosepatients with none or partial response to first-linetherapies, namely CYP or MMF. Response criteria for lupus nephritis clinical trials have beenestablished by the ACR, on the basis of the effectsof treatment on renal function, proteinuria andurinary sediments [5] . These have been endorsedby a European consensus statement in 2009 [6] .A complete response is defined as inactive urinarysediment, a decrease in proteinuria to 0.2 g/dayand normal or stable renal function. A sustainedresponse of 3–6 months is considered a remission, but cannot be judged to be complete remission in the absence of a biopsy. Partial responseis a level of improvement defined as an in activeurinary sediment, proteinuria 0.5 g/day, withnormal or stable renal function. Recently,the European League Against Rheumatism(EULAR)-European Dialysis and TransplantAssociation (EDTA) have published definitionsof response in lupus nephritis [7] . Complete renalresponse is defined as urine protein:creatinineratio 50 mg/mmol and normal or near normal(within 10% of normal glomerular filtration rate[GFR] if previously abnormal) GFR. Partial renalresponse is defined as 50% reduction in proteinuria to subnephrotic levels and normal or nearnormal GFR. This should be achieved preferably by 6 months and no later than 12 monthsfollowing treatment initiation. Improvement isdefined as any reduction in proteinuria and normalization or stabilization of GFR. Switching toan alternative agent is recommended for patientswho do not improve within 3–4 months, or those10.2217/IJR.12.80 2013 Future Medicine LtdInt. J. Clin. Rheumatol. (2013) 8(1), 61–72Shabina HabibiDepartment of Rheumatology, Nizam’sInstitute of Medical Sciences,Hyderabad, 500082, IndiaTel.: 91 040 23489000shabina.h@gmail.compart ofISSN 1758-427261
ReviewHabibiwho do not achieve partial remission within6–12 months or complete remission within2 years [7] .Flare is an increase in disease activity,requiring more aggressive immunosuppressivetherapy. A renal flare is indicated by an increasein proteinuria, serum creatinine, presence ofactive urine sediments or a decrease in creatinineclearance. It may be a proteinuric, nephriticor a severe nephritic flare. Nephritic flares arecommon, even in those patients who achievecomplete response [8] . Patients with nephriticflares have a higher risk of developing doublingof serum creatinine and ESRD over the long termas compared with those with proteinuric flares [9] .Factors affecting prognosisThe prognosis of nephritis is unpredictable.Various demographic, clinical, histological andserologic factors affect the outcome (Box 1) [10] .Individual risk factors are extremely heterogeneousand vary in their overall impact. Those patientswith the highest number of risk factors are likelyto have more aggressive disease with a worseprognosis.The incidence of nephritis is higher, and itsseverity greater, in African, Asian and LatinAmerican individuals, as compared withCaucasians [11–13] . Patients of African–Americanethnicity also have a less favorable responseto CYP with greater flares, both nephritic andproteinuric, compared with Caucasians [14] . Malegender and juvenile-onset SLE have also beenassociated with a higher incidence and moresevere nephritis [12,15–17] . Various other featuressuch as nephrotic syndrome, azotemia, presence ofantiphospholipid antibodies, high activity indexand marked chronic changes on histopathology,class III, IV and combined class IV/V, have alsoindicated adverse prognosis in different studies.Long-term follow-up of the Euro-Lupustrial concluded that early response to therapyBox 1. Factors associated with adverse prognosis in lupus nephritis.Demographic Black race, male gender, juvenile-onset diseaseClinical Hypertension, pregnancy, failure to achieve or a marked delay ( 2 years) toachieve remissionLaboratory Azotemia, nephritic urinary sediment, nephrotic syndrome, presence ofantiphospholipid antibodies, anemia, thrombocytopeniaHistologic Proliferative or mixed membranous and proliferative nephritis, high activity index,marked chronicity62Int. J. Clin. Rheumatol. (2013) 8(1)at 6 months, defined as a decrease in serumcreatinine and proteinuria 1 g/24 h, was thebest predictor of good long-term renal outcome[18,19] . Overall 10-year survival rates and renalsurvival rates are better in patients who attaincomplete remission (95 and 94%, respectively) ascompared to those who attain partial remission(76 and 45%, respectively) or no remission(45 and 19%, respectively) [20] . Similarly, failureto attain complete remission at 6 months predictsrenal relapse and ESRD in the long term [21] .Overview of the treatment of lupusnephritisTreatment of lupus nephritis is a challenge despiterecommendations published by the ACR and morerecently the EULAR/EDTA, due to overall poorresponse to recommended treatment. It is dividedinto two phases: induction of remission andmaintenance of remission. The recently publishedACR guidelines for the management of lupusnephritis have recommended that all patients withclinical evidence of nephritis, who were previouslyuntreated, undergo a renal biopsy to classify theglomerular disease by the ISN/RPS classificationand evaluate for activity, chronicity, vascularand tubular lesions [22] . The EULAR/EDTAalso recommend biopsy in patients with anysign of renal involvement, especially in thosewith reproducible proteinuria 0.5 g/24 h withglomerular hematuria and cellular casts [7] .In patients with proliferative nephritis, CYP,administered either as the modified NIH regimeor the Euro-Lupus regime, or MMF, are used forinducing remission [22] . A recent meta-analysisconsidered both these drugs to be of equivalentefficacy [23] . In certain situations, for example,African–American and Hispanic individuals andin certain patients to avoid premature ovarianfailure, MMF is preferred as the first choicefor induction of remission [14,24] . The EuroLupus regime of low dose CYP pulse therapyhas demonstrated the same efficacy as the NIHregime over 10 years, with better safety [19] . Thistrial included predominantly Caucasian andnot blacks or Hispanic individuals. Thus therecent ACR guidelines recommend this low-dosetherapy only for patients of western or southernEuropean backgrounds [22] .Either azathioprine or MMF is used asmaintenance therapy once remission is achieved[22] . The maintenance phase of the ALMS trialshowed superior efficacy of MMF to maintainremission [25] . The MAINTAIN nephritis trialon the other hand showed equivalent efficacy andsafety [26] . The ALMS trial included patients offuture science group
Review of refractory lupus nephritisdiverse ethnicity and different geographic regions,treated with either high-dose CYP (modifiedNIH protocol) or MMF in the induction phase,whereas the MAINTAIN trial was an extensionof the Euro-Lupus trial, which predominantlyincluded Caucasians with active nephritis whowere treated with low-dose CYP (Euro-Lupusregime) for induction of remission.Adjunctive therapy includes hydroxy chloro quine, which decreases flare rate and there issignificantly lesser damage accrual, includingrenal damage in patients on hydroxychloroquine[27–29] . For patients with proteinuria, angiotensinconverting enzyme inhibitors or angiotensinreceptor blockers are required. These agents reducethe intraglomerular pressure and delay doublingof serum creatinine and progression to end-stagerenal disease [25] . Control of hypertension withtarget values 130/80 mmHg, and hyperlipidemiain patients with LDL cholesterol 100 mg/dl withstatins is also essential [101,102] .Treatment of refractory lupusnephritisThere is no international consensus on thedefinition of refractory lupus nephritis. Accordingto NIH criteria refractory patients are those whoshow no response to treatment and those in whomproteinuria does not decrease to less than half ofpretreatment value or to 3 g/day and who havepersistent active urinary casts or deteriorationin serum creatinine level [30] . According to theEULAR consensus statement, nonresponders orpatients with treatment failure are those who donot achieve even a partial response [6] . Switchingto an alternative agent is recommended in patientswho fail to improve within 3–4 months, do notachieve partial response after 6–12 months orcomplete response after 2 years [7] . Switchingto another first-line drug, for example, MMFif the patient received CYP, and vice versa maybe attempted [22,31] . Additionally, alternativetreatments as given below may also be considered. Calcineurin inhibitorsCyclosporine (CsA) is a prodrug, which afterbinding to its cytoplasmic receptor cyclophyllin,subsequently binds to calcineurin, andinterferes with IL-2 production, which causesT-cell activation and thus it dampens T-cellcytokine production. It also causes cell arrest inG0–G1 phase of the cell cycle, thus decreasingT-cell proliferation [32] . It also stabilizes theactin skeleton of the podocytes and decreasesproteinuria [33] . Tacrolimus binds to a differentreceptor, FK-binding protein-12, which thenfuture science groupReviewinteracts with calcineurin, inhibiting IL-2production. These drugs have been successfullyused to treat refractory nephritis.An initial trial of 18 patients with proliferativenephritis, refractory to conventional therapy, whenadministered CsA at 5 mg/kg/day, demonstratedreduction in proteinuria, improvement in renalfunction and decrease in the dose of corticosteroids[34] . A trial that compared cyclosporine withCYP as induction and maintenance in patientswith active proliferative nephritis demonstratedcomparable efficacy of both the drugs [35] . Amulticenter randomized controlled trial of75 patients with diffuse proliferative nephritis,compared the efficacy of CsA versus azathioprineas maintenance therapy after induction ofremission with 3 months of prednisolone and oralCYP [36] . Treatment was continued for 4 years.The flare rates were comparable (7 in CsA groupversus 8 in the azathioprine group), and therewas no difference in the proteinuria and bloodpressure levels, with both the drugs being welltolerated. Significantly higher number of patientsin the CsA group had undetectable proteinuria(42 vs 15%). Another trial of ten patientsrandomized to receive prednisolone or CsAfor 1 year showed that proteinuria decreasedsignificantly in patients receiving CsA (i.e.,from 2.5 g/day to 0.14 g/day) [37] . Hence CsAis an effective option for patients with refractorynephritis, especially to decrease proteinuria andthe cumulative corticosteroid dose.A study compared multitarget therapy (MT)comprising tacrolimus, MMF and prednisolonewith intravenous (iv.) CYP in patients with biopsyproven combined class V and IV LN for 6, or9 months if complete remission was not achieved[38] . Enrolled patients (n 40) had preservedrenal function, proteinuria 4.4 2.0 g/day and70% had previously been treated with MMF orCYP. Rates of complete remission were higherboth at 6 and 9 months with MT (50 and 65%,respectively) as compared with iv. CYP (5 and15%, respectively). Rates of partial remission at6 months were similar in both groups (40%). At9 months partial remission was observed in 30%in the MT group and 40% in the iv. CYP group.Adverse events were more frequent in the iv. CYPgroup, but new onset of hypertension was seen inthe MT group. This study highlighted the roleof MT in the treatment of mixed class IV andV LN, which responds less well to conventionalimmunosuppressives and has a poor prognosis.In another study of seven LN patientsrefractory to MMF, it was shown that whentacrolimus was added (dual therapy), one patientwww.futuremedicine.com63
ReviewHabibiachieved complete response, three attainedpartial response and one had a reduction inproteinuria [39] . However, toxicity limitedthe use of tacrolimus in five patients (diabeticketoacidosis in one, proteinuria in two andmuscle pain in two patients), but there was nosevere nephrotoxicity.The study concluded that MT is a goodoption in refractory cases, but patients must bemonitored for possible side effects.A recent study of 70 patients with proliferativeand membranous nephritis, who were treatedwith MMF, of whom 23 failed treatment and 17received tacrolimus in combination with MMF[40] . Twelve out of 17 (70%) responded (sixcomplete remission and six partial remission), fourof whom relapsed at 19 6 months. The studyconcluded that combination with tacrolimus isa safe and effective option for MMF-resistantpatients.Hence tacrolimus, either as monotherapy oras multitarget therapy is an option in patientsrefractory to CYP or MMF or both.Table 1 summarizes the results of various trialswith calcineurin inhibitors in refractory lupusnephritis. LeflunomideLeflunomide, which is currently used as a diseasemodifying drug in patients with rheumatoidarthritis, has demonstrated efficacy in patientswith lupus nephritis refractory or intolerantto standard drugs [41] . Nineteen patients withlupus nephritis, of whom 12 were refractory toCYP, were given a loading dose of leflunomideof 100 mg/day for 3 days followed by 20 mg/dayfor a mean of 52 weeks. Thirteen out of 17 (76%)patients achieved a response. Complete responsewas observed in five out of 17 (29%) and partialresponse in eight out of 17 (47%) patients.Another Chinese study of 51 nephritis patients,15 of whom had relapsing disease demonstratedtotal response in 60% and complete remissionin 6.7% of the patients when treated withleflunomide [42] . Intravenous immunoglobulinIn a small randomized trial, iv. immunoglobulin(400 mg/kg monthly for 18 months) was aseffective as iv. CYP pulse (1 g/m2 every 2 monthsfor 6 months and then every quarterly for 1 year) asmaintenance therapy in patients with proliferativenephritis [43] . Although there are reviews on theefficacy of this drug, controlled trials are required[44,45] . Adverse reactions have been reported in upto 20% of infusions, most of which are minorand transient, such as headache and transfusionrelated reactions [46] . Potential serious reactionsthat can occur in 2–6% of patients includehemolysis, thrombotic complications, asepticmeningitis and acute renal failure [47] .Biologic agentsVarious biologics have been tried in uncontrolledstudies in patients with relapsed or refractorylupus nephritis (Table 2) . However, the smallnumber of patients, short follow-up and differentregimes used warrant caution when interpretingthese studies. Biologics that target B cells, T cellsor cytokines and complement components havebeen tried. Among the various biologics, thereis much greater experience with B-cell directedtherapies, especially rituximab. B-cell directed therapiesB cells are central in the pathogenesis oflupus nephritis. These produce pathogenicautoantibodies, act as antigen presenting cellsfor autoreactive T cells, provide costimulatorysupport for T-cell activation and produce aTable 1. Trials with calcineurin inhibitors in refractory lupus nephritis.Study (year)Patients (n) DrugEffectivenessRef.Favre et al. (1989)18CsA 5 mg/kg/dayReduction in proteinuria, improvement in renal functionand decrease in the dose of corticosteroids[34]Zavada et al. (2010)40CsA vs CYP for inductionComparable efficacy of both drugs[35]Moroni et al. (2006)75CsA vs azathioprine formaintenanceNo difference in the proteinuria and blood pressureComparable flare rates[36]Balletta et al. (1992)10CsA vs prednisoloneProteinuria decreased significantly in patientsreceiving CsA[37]Bao et al. (2008)40MT vs intravenous CYPHigher rates of complete remission with MT at 6 and9 months[38]Lanata et al. (2010)7Tacrolimus added to MMFFive responded[39]CsA: Cyclosporine; CYP: Cyclophosphamide; MMF: Mycophenolate mofetil; MT: Multitarget therapy.64Int. J. Clin. Rheumatol. (2013) 8(1)future science group
Review of refractory lupus nephritisvariety of cytokines such as IL-6 and TNF-a[48] . Biologics act by depleting B cells, inhibitingtheir activation and reducing B-cell and plasmacell survival. B-cell depletionRituximab is a chimeric mouse–humanmonoclonal antibody directed against theB-cell surface molecule CD20. This molecule isabsent on the pre-B cells and plasma cells. Thusit causes depletion of the peripheral B cells,without affecting regeneration of these cells orthe production of immunoglobulins [49,50] . Itdepletes B cells by antibody-dependent, cellmediated cytotoxicity (ADCC), apoptosis andcomplement-mediated cell lysis [51] . A number ofcase reports and case series have reported efficacyof this drug in refractory patients [52–59] . However,the LUNAR trial, which was a randomizeddouble-blind placebo-controlled trial comparingrituximab with placebo in addition to MMF andprednisolone in 144 patients (approximately halfwere refractory to conventional therapy) withclass III or IV nephritis, did not demonstratea superior response with rituximab [60] . Ratesof partial and complete responses were 57 and46% in patients treated with rituximab versusplacebo, respectively. There was, however, an11% difference in the absolute renal response atthe end of 1 year. Additionally, eight placebotreated patients and no patient who was givenrituximab required CYP rescue therapy. Acomplete response with respect to proteinuria wasalso higher in patients who received rituximab(32 vs 9%). This reduction in proteinuriapersisted through 78 weeks, raising thepossibility that a longer duration of observationmay be necessary to understand the impact ofrituximab. When renal response according torace and ethnicity was taken into account, thedifference in the treatment responses betweenthe two groups in black individuals was 25%.The failure to achieve the primary outcome byrituximab may be explained by the fact that thetrial included a heterogeneous population withrespect to ethnicity, unlike the case series, whichpredominantly comprised white individuals, andthese patients did not have very active disease,and were also concomitantly receiving otherimmunosuppressants, namely MMF, which mayhave masked any beneficial effect of rituximab.In a recently published systematic analysis ofpublished reports on the efficacy of rituximab inpatients with refractory nephritis, 300 patientsfollowed-up for 60 weeks reported complete andpartial response rates in 87, 76, 67 and 76% offuture science groupReviewTable 2. Biologics for refractory lupus nephritis.DrugTargetBiologics targeting B cellsB-cell depletion:Rituximab (chimeric mAb)Ocrelizumab (humanized mAb)Epratuzumab (humanized mAb)CD20CD20CD22B-cell survival factors:Belimumab (human mAb)Aticacept (TACI–Ig fusion protein)BLyS/BAFFBAFF/APRILTolerizing B cells:Abetimus (synthetic toleragen)dsDNA, BCRBiologics targeting T cellsBlocking costimulation:Abatacept (murine CTLA-4 Ig)RuplizumabTolarizumabCD28/B7CD40LCD40LCytokine & complement mabComplement-5BCR: B-cell receptor; mAb: Monoclonal antibody.patients with class III, IV, V and mixed class,respectively [61] . The analysis concluded thatrituximab effectively induces remission in thosepatients in whom standard therapies fail.In a systematic review of published reports onthe use of rituximab between 2002 and 2007, in188 SLE patients of which 103 had nephritis, theoverall rate of renal response was 91% [57] . Theresponse rates were 82, 98 and 100% in class III,IV and V nephritis, respectively.Another Mexican study of 52 treatmentrefractory SLE patients, 13 of whom had nephritis,38.4% each had complete and partial renalresponses [62] . The drug also allowed a reductionin prednisolone dose in the majority of patients.A French study assessed the long-term efficacyand safety ( 12 months) of rituximab in 20 patientswith severe proliferative (n 15) and membranousnephritis (n 5) [63] . Twelve patients receivedrituximab for refractory, and six for relapsingnephritis. After a median follow-up of 22 months,seven and five patients had complete and partialrenal remission, respectively. Among the patientswith class IV nephritis, 66% responded, with fiveachieving complete and five achieving partialremission. Two out of five patients with class Vnephritis had complete remission. The injectionswere overall well tolerated.Studies have also demonstrated the effectivenessof rituximab in improving the histological class.A study involving seven female patients withwww.futuremedicine.com65
ReviewHabibiCYP-resistant proliferative nephritis who weretreated with rituximab, repeat renal biopsiesduring follow-up demonstrated improvementin the majority of patients, and a decrease inthe activity index was noted (from 6 to 3) [58] .Clinical improvement as indicated by a decreasein SLEDAI, decreases in anti-dsDNA antibodiesand decrease in anti-c1q antibodies was seen.Another report of two patients with CYPrefractory proliferative nephritis, who were givenfour infusions of rituximab and two additionalCYP pulses, a reduction in activity was noted onrepeat biopsy [59] . One patient was subsequentlymaintained on low-dose prednisolone alone.Rituximab is thus an option in patients refractoryto first-line immunosuppressants, namely CYPand MMF. It can be given as an add-on therapyto MMF or CYP, or as monotherapy [7] .Rituximab has an overall acceptabletolerability and safety profile. Reported adverseeffects are usually mild and either self-limitedor responsive to conventional therapy. Thereare, however, reports of progressive multifocalleukoencephalopathy developing in patients whowere administered the drug, and the US FDA hasissued a warning with regard to this complication[64,65] . It is usually administered at dosesrecommended for lymphoma (375 mg/m2 BSAweekly for four doses) or in rheumatoid arthritis(two 1000 mg doses separated by 2 weeks).Ocrelizumab is a fully human monoclonalantibody directed against the CD20 molecule onthe B cells. This molecule has been occasionallyused in patients with severe refractory lupusnephritis [66] . However, a Phase III trial(BELONG trial) was prematurely discontinueddue to severe infections [103] .Epratuzumab is a humanized monoclonalantibody that targets the CD22 molecule onthe surface of B cells, and is present from thepre-B-cell stage to mature cells, but is absent onthe plasma cells. It induces depletion of naiveand transitional B cells, and also inhibits B-cellactivation and proliferation [67,68] .In an initial open-label trial on 14 patientswith moderately active SLE, significant efficacyof epratuzumab was demonstrated, as evidencedby reduction in BILAG scores by at least 50% in77% of the patients by 18 weeks [67] . Tolerabilityof the drug was satisfactory. However, none ofthe patients had renal involvement. Preliminaryresults from Phase III trials showed that patientsgiven epratuzumab had sustained improvementin BILAG scores, significant improvementin quality of life and less corticosteroid usecompared with those given placebo [69,70] .66Int. J. Clin. Rheumatol. (2013) 8(1) B-cell survival factorsAmong the various cytokines and growthfactors essential for B-lymphocyte survivaland maturation, the B-lymphocyte stimulatorprotein, also called B-cell activation factor(BAFF), and a proliferation-inducing ligand(APRIL), is the most important. It is a memberof the TNF ligand superfamily and binds to threedifferent receptors: transmembrane activator andcalcium-modulating cytophilin ligand interactor(TACI), the B-cell maturation antigen (BCMA)and the BAFF receptor (BAFF-R).Belimumab is a human monoclonal IgG1antibody that binds to and inhibits solubleB-lymphocyte stimulator protein. It has beenfound to be superior compared with placebo intwo Phase III placebo-controlled trials; BLISS52 and BLISS-76 [71,72] . These trials comparedtwo doses of belimumab, 1 mg/kg and 10 mg/kgversus placebo, in addition to standard therapyin more than 1500 serologically positive SLEpatients, using the SLE responder index as theprimary end point. There was a statisticallysignificant positive result for the primary endpoint with belimumab 10 mg/kg and standardof care as compared with placebo, as well as adecrease in the anti-dsDNA antibody levels andincrease in serum complement levels. Overall,the drug was well tolerated and was safe.However, these trials excluded patients withCNS involvement and severe nephritis. The drugwas recently approved (2011) by the FDA to treatantibody-positive SLE, in combination withstandard therapies. The trial results as well asthe FDA approval have raised hopes that it maybe the long-awaited therapy for SLE, includingfor severe CNS and renal manifestations.Aticacept is a decoy recombinant fusionprotein comprising the extracellular domainof the TACI receptor and Fc region of humanIgG1. TACI binds both BAFF and APRIL,thereby affecting memory cells, plasma cellsand immunoglobulin production [73] . In an earlyphase trial involving 24 patients with SLE, thedrug demonstrated some effect with good overalltolerability [74] . A Phase II trial was prematurelyterminated due to concerns of severe infections.Currently it is under investigation. Tolerizing B cellsAbetimus sodium (LJP 394) is a tetramericoligonucleotide that binds to circulating antidsDNA, forming soluble drug–antibody immunecomplexes, which are rapidly eliminated. Amore prolonged effect is related to tolerizinganti-dsDNA-specific B cells. A randomizedfuture science group
Review of refractory lupus nephritisplacebo-controlled Phase III trial involving 317SLE patients with a history of renal flare and antidsDNA antibodies 15I U/ml, using 100 mg/weekof abetimus for 22 months did not meet its primaryend point, in other words, prolong the time torenal flare [75] . There was, however, 25% fewerrenal flares in the abetimus group as comparedwith the placebo group. In addition, abetimustreatment decreased anti-dsDNA antibody andincreased complement levels. Significantly morepatients in the abetimus group had a decreaseof 50% proteinuria. Those patients who hadimpaired renal function at baseline had a trendtowards reduced rates of renal and SLE flares.The drug was well tolerated overall. Anotherplacebo-controlled trial involving 230 patientswith SLE revealed that there was no differencein time to renal flare among patients receivingabetimus compared with placebo [76] . The drug,however, prolonged the time needed to add highdose corticosteroids or immunosuppressants,and 41% required fewer treatments withimmunosuppressants. In addition, patients withworse renal function (creatinine 1.5 mg/dl) had50% lesser flares. T-cell directed therapiesT cells are also involved in the pathogenesisof lupus nephritis. Antibodies in patients withSLE are class switched (IgG isotype) and haveundergone somatic hypermutation. Both theseindicate that the autoreactive B cells have receivedinput from cognate T cells. T cells in additiondirectly infiltrate the renal parenchyma causingdamage by direct cytotoxicity, and facilitatingthe recruitment and activation of macrophages. Blocking costimulationOptimal activation of T cells requires, in additionto antigen presentation in the context of the majorhistocompatibility complex proteins, a secondsignal by costimulatory molecules on the surfaceof T cells and antigen-presenting cells, the mostimportant of which is CD28 on the T cells andB7 (CD80/86) on the antigen-presenting cells.Cytotoxic T-lymphocyte activation-4 (CTLA-4),which is expressed on activated T cells, bi
Review of refractory lupus nephritis Systemic lupus erythematosus (SLE) is an extremely heterogeneous, multisystem, auto-immune disease, characterized by the presence of multiple autoantibodies and depo
Draft Evidence Report - Voclosporin and Belimumab for Lupus Nephritis Return to ToC Executive Summary Systemic lupus erythematosus (SLE) is an autoimmune disease that affects between 300,000 and 1.5 million Americans.1 It is more common in women (90% of diagnosed cases) and in non-Whites
CCLE (DLE, lupus panniculitis [LEP], lupus tumidus [LET]), enrolled in the longitudinal Georgia Organized Against Lupus (GOAL) cohort. GOAL is a population-based cohort of predominantly Black individuals with lupus from the Southeast U.S. Details of recruitment and data collection have been published previously [24]. GOAL initially enrolled .
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Overcoming Barriers to Drug Development in Lupus Final Report 9-09 2 PCDocs # 493207 infection, damage the liver, and may contribute to the higher incidence of certain cancers experienced by lupus patients (e.g., a three- to four-fold increase in non-Hodgkin lymphoma).5
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