Is There a Role for TNF- in Anti-Neutrophil Cytoplasmic Antibody–Associated Vasculitis? Lessons from Other Chronic Inflammatory Diseases
Marc Feldmann* and
Charles D. Pusey
* Kennedy Institute of Rheumatology Division, Charing Cross Campus; and Renal Section, Division of Medicine, Hammersmith Campus, Imperial College London, United Kingdom
Address correspondence to: Prof. Charles D. Pusey, Renal Section, Division of Medicine, Imperial College London, Hammersmith Campus, London W12 0NN, UK. Phone: +44-20-8383-3152; Fax: +44-20-8383-2062; E-mail: c.pusey{at}imperial.ac.uk
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitisis the most common cause of rapidly progressive glomerulonephritisand immune-mediated pulmonary renal syndrome. Now that the acutemanifestations of the disease generally can be controlled withimmunosuppressive drugs, ANCA-associated vasculitis has becomea chronic and relapsing inflammatory disorder. The need to developsafer and more effective treatment has led to great interestin the mediators of chronic inflammation. There are many lessonsto be learned from studies of other chronic inflammatory diseases,particularly rheumatoid arthritis (RA). The identification ofa TNF-–dependent cytokine cascade in the in vitro culturesof synovium in joints of patients with RA led to studies ofTNF blockade in experimental models of arthritis and subsequentlyto clinical trials. These have culminated in the widespreadintroduction of anti-TNF therapy not only in RA but also inCrohn disease, ankylosing spondylitis, and several other chronicinflammatory disorders. Following a similar investigative pathway,studies that show the importance of TNF production by leukocytesand intrinsic renal cells in glomerulonephritis have been followedby the demonstration of the effectiveness of TNF blockade inseveral experimental models of glomerulonephritis and vasculitis.In experimental autoimmune vasculitis, improvement in diseasewas paralleled by a reduction in leukocyte transmigration, asdemonstrated by intravital microscopy. The benefit of infliximab(a mAb to TNF) in ANCA-associated vasculitis was recently reportedin a prospective open-label study. However, the use of etanercept(a soluble TNF receptor fusion protein) was not found to beof significant benefit in a randomized, controlled trial inpatients with Wegener granulomatosis. Therefore, there is aneed for further evaluation of the use of anti-TNF antibodiesin patients with ANCA-associated glomerulonephritis.
In the past 20 yr, the importance of the cytokine family ofmediators has been uncovered. This had to await the era of molecularbiology, because the necessary tools to establish that thesehighly potent mediators were in fact dominant signals in immunityand inflammation depended on their molecular cloning, with theirsubsequent production and evaluation in pure form. We now knowthat there are more than 200 large polypeptides, genericallycalled cytokines, that usually are released from cells to actas short-range mediators of inflammation, immunity, cell mobility,recruitment, fibrosis, and repair (1). Cytokines are known tobe important in all biologic processes, from organ developmentto host defense against pathogenic agents.
The cytokines are described according to their major properties.There are proinflammatory cytokines, anti-inflammatory cytokines,chemokines, and growth factors. Certain families were identifiedin different ways and so are termed interferons (antiviral proteins),interleukins (acting between leukocytes), or colony-stimulatingfactors (acting on hemopoietic cell growth). However, all ofthe colony-stimulating factors also have important functionsin inflammation, immunity, and repair and hence are not reallydistinct. These historical "families" are really misnomers;interleukins also act on other cell types, interferons act onhost defense and hemopoietic tissue, and so forth.
In any given acute or chronic inflammatory disease, a wide spectrumof cytokines will be detected in diseased tissue (2). This hasbeen documented most extensively in rheumatoid arthritis (RA),because in this condition, human tissue can be sampled at theheight of the disease process without causing injury to thepatient, during biopsy procedures early in disease or duringjoint replacement surgery late in disease (3). This work hasprovided several important insights into chronic inflammation.
First, in a chronic disease, cytokines that are produced experimentallyin a short-term, transient manner are continuously present (3).This observation indicated that the processes in a chronic diseaseare somewhat different from those studied with short-term stimuliand, not surprising, that chronic disease shows long-term sustainedproduction of cytokines. How these events are related is aninteresting question, which is being actively studied.
Second, anti-inflammatory cytokines are upregulated in chronicinflammation as well as proinflammatory cytokines (4). Thissuggested the concept of a dysregulated equilibrium, as illustratedin Figure 1. This concept was testable in vitro, using culturesof human disease tissue from rheumatoid synovium, by neutralizingthe inhibitory cytokines; for example, blocking IL-10 augmentedTNF and IL-1 production two-fold (4), and blocking both IL-10and IL-11 augmented TNF and IL-1 a dramatic five- to 20-fold(5).
Figure 1. Disordered equilibrium. In a chronic disease, both proinflammatory and anti-inflammatory cytokines are upregulated, but the proinflammatory side is dominant. Illustration by Josh Gramling—Gramling Medical Illustration.
Third, there is marked "redundancy" in the cytokine network,which means overlap of biologic properties of the cytokinesthat are found in the joints in active RA. IL-1, TNF, IL-6,and GM-CSF are all present in signaling quantities in activedisease tissue. They do much the same things on target cells.Which are the critical, rate-limiting factors that are goodtherapeutic targets? This was a major problem, as the new therapeuticapproaches of "biotechnology," making mAb and receptor fusionproteins against specific targets, could be used only experimentallyas a single target in clinical trials, so determining whichwas the best therapeutic target was of critical importance.
Complex biologic systems need to have alarms to detect problemsin homeostasis and initiate their resolution. This clearly isthe case in multicellular organisms such as human. Stress ofany type (e.g., burns, ultraviolet irradiation, x-rays, viruses,bacteria) induces the rapid release and production of TNF- (6).This acts as the body’s "fire alarm" and induces the rapidarrival of the "firefighters"—leukocytes from the blood.This interpretation is based on several lines of knowledge.The first clue came from the effects of TNF blockade. In humanRA cultures in vitro, blocking TNF downregulates all other proinflammatorymediators: cytokines (IL-1, IL-6, IL-8, and GM-CSF), destructiveenzymes such as matrix metalloproteinases (MMP), and prostaglandins(3,7). In mice that were given bacteria, a natural challengeto the immune system, TNF is the most rapidly detected cytokinein blood, before IL-1 or IL-6. When anti-TNF antibody is administered,it not only neutralizes the TNF but also diminishes IL-1 andIL-6 levels by four- to five-fold (8). These experiments werereported in 1989 and supported the concept of a TNF-dependentcytokine cascade (Figure 2).
Figure 2. Cytokine cascade. A TNF-dependent cytokine cascade was described in rheumatoid synovium cultures, confirmed in mice that received injections of Gram-negative bacteria, and subsequently proved in patients. Illustration by Josh Gramling—Gramling Medical Illustration.
The concept of a TNF-dependent proinflammatory cytokine cascaderesolved the dilemma of which cytokine was a potential therapeutictarget, but this hypothesis had to be tested in vivo. Animalmodels of arthritis in the late 1980s had a poor reputationas predictors of clinical success, after the failure of anti-CD4mAb, which had been effective in mouse models (in the preventivemode) but was not effective in patients with late-stage RA (9).However, the most relevant animal model of human RA, collagen-inducedarthritis in DBA/1 mice, was predictive. We consider this modelrelevant because it demonstrates genetic susceptibility andbecause these mice develop arthritis spontaneously as they age(10). Furthermore, the MHC genes involved have similar propertiesin that mouse I-Aq in the DBA/1 mouse resembles human HLA-DR4(associated with RA) in peptide selection (11). Hamster anti-mouseTNF antibody that was injected after disease onset was foundto ameliorate arthritis and reduce joint damage in this model(12), and this helped to establish the rationale for anti-TNFtherapy in RA.
TNF now is recognized as the prototype of a gene superfamilythat is important in regulating many biologic functions. Membrane-boundor soluble TNF- reacts with two receptors, known as TNFR1 (p55)and TNFR2 (p75). These receptors themselves form part of theTNFR superfamily. Research in this field has identified approximately40 members of the TNF/TNFR superfamilies, and knowledge abouttheir function is rapidly emerging. Detailed consideration ofthe biology of the TNF/TNFR superfamilies is outside the scopeof this article and was reviewed recently (13).
TNF blockade in human medicine has had a checkered career. Evidencethat TNF was pivotal in animal models of sepsis (14) led tothe concept that TNF blockade would be therapeutic in sepsis,which is the cause of death of approximately 300,000 patientswith severe underlying diseases in the United States each year.However, extensive trials of anti-TNF antibodies or TNF receptorfusion proteins in thousands of patients with sepsis were notsuccessful. Benefit was seen in subsets of patients who stillhad elevated cytokine levels, but in the great majority, therewas no benefit and sometimes deterioration (15).
Although this result was unfortunate for the bioscience industry,many lessons were learned from the experience. For the therapyof chronic diseases such as RA, this presented a wonderful opportunity,because specific TNF-inhibiting agents had been produced andtested. When arthritis research identified TNF as a promisingtherapeutic target, there were multiple antibodies and TNF receptorfusion proteins, available as a legacy from the sepsis work,to be tested in this disease. The clinical trials in RA, initiatedfirst with a chimeric antibody, infliximab, were an instantsuccess (16).
Because TNF is an important host defense molecule (6), therewas a school of thought that TNF blockade for RA was unethical,because it was too dangerous. Nevertheless, via Jim Woody atCentocor, an open-label clinical trial in RA multidrug treatmentfailures was initiated (16) with Ravinder Maini and Marc Feldmannas principal investigators. This showed a remarkable responseto the chimeric anti-TNF antibody, infliximab (now sold as Remicade).There was rapid onset of benefit in all 20 patients, to a variabledegree, but with a median swollen joint reduction of 60 to 70%at 6 to 8 wk. There was very rapid symptomatic benefit, reductionin fatigue within hours, and reduction in stiffness and painin days, but eventually all patients relapsed by 18 wk. Thiswas amelioration, not a cure (Figure 3).
Figure 3. Initial clinical results of TNF blockade in patients with late-stage, treatment-refractory rheumatoid arthritis (RA) using infliximab. (A) Sequential swollen joint count. (B) Sequential measurements of C-reactive protein (CRP). Adapted from reference (16). Illustration by Josh Gramling—Gramling Medical Illustration.
This trial, with a clear response in an unmet medical need,opened the way to the rapid development of multiple TNF inhibitors,with the introduction of etanercept, a p75 TNFR-Ig fusion protein,being particularly efficient (17). Despite clinical trials onthe fusion protein that started after those that used the antibody(infliximab), etanercept obtained Food and Drug Administrationapproval first. From these studies, much was learned about theway to use anti-TNF therapy, how to minimize immunogenicity(18), and the mechanisms of action (19). This knowledge hasbeen particularly helpful in the development of TNF blockadefor other important disease indications in medicine and in understandinghow to use most effectively such powerful, expensive, and potentiallydangerous therapeutic agents (20) in a safe and cost-effectivemanner.
The degree of benefit in patients with RA is highly variable.Although few, if any, have no evidence of benefit, many (20to 40%) do not have a 20% improvement in swollen and tenderjoints, needed to qualify as American College of Rheumatologyresponders, depending on the stage of the disease. Late-stagetreatment failures, as entered in phase III studies, have a60% response rate (21), whereas patients in the first monthof diagnosis and within 6 mo of the onset of symptoms have a90% response rate (22). It is important to note that a markedreduction in joint damage occurs in the majority, and in a substantialproportion, there is evidence of bone and cartilage repair (21,23).The important mechanistic insights from these studies have beento verify that the TNF-dependent cytokine cascade that is detectedin rheumatoid synovial cultures in vitro is operative in patientswith RA in vivo (24) and to show that TNF blockade diminishesleukocyte recruitment (25).
There have been extensive studies of how anti-TNF therapy mediatesclinical benefit in RA. Multiple cytokines are rapidly downregulatedin vivo, within a few hours, indicating a direct effect of TNFinhibition. Effects that are measured at a few weeks may bevery indirect. IL-6 levels in blood are rapidly reduced, asare IL-1, IL-8, monocyte chemoattractant protein-1, and vascularendothelial growth factor. Cytokine levels in joints also arediminished in biopsy samples, including IL-1 and IL-6. Acute-phaseprotein levels, including C-reactive protein, serum amyloidA (SAA), and fibrinogen, are reduced. There also are rapid changesin hematologic indices. Elevated levels of granulocytes andmonocytes are reduced, low hemoglobin is restored, and highplatelet levels normalize. Lymphocyte changes are complex. Thereare more IFN-–producing cells in blood, diminished mitogenand recall responses normalize, and poorly functioning regulatorycells are restored. Elevated serum levels of MMP (e.g., MMP-1,MMP-3) normalize, providing a partial reason for reduced jointdamage. Synovial cellularity is diminished within 2 to 4 wk,probably as a result of reduced influx of inflammatory cells,but there are no data on changes in egress. Possible changesin apoptosis are controversial. These studies have been reviewedthoroughly (19,23–26).
With the extensive improvement in the acute-phase response,including reductions in atherosclerotic risk factors such asfibrinogen, high platelets, and high C-reactive protein, itwas of interest to ascertain whether cardiac complications,augmented in RA, would diminish. This was indeed the case forboth heart failure (27) and atherosclerotic complications (28).The side effects of anti-TNF therapy are relatively modest,and there is no doubt that the benefits outweigh the risks (29,30).Infection is the most predictable, because a major host defensemolecule is compromised, but numbers are comparatively low.The most common opportunistic infection is tuberculosis, withthe risk for infection augmented four-fold, if precautions (screening,etc) are not taken (20). With screening now routine and prophylaxisgiven if in doubt, this problem is dramatically reduced. Otheropportunistic infections are much more rare. There still isdispute about the risk for respiratory infections, such as pneumonia.A survey of fewer than 1000 German patients suggested that itwas augmented two-fold, but a larger British survey so far hasfailed to show an increased risk for pneumonia.
Initially, there was a concern about increased numbers of lymphomasin anti-TNF–treated patients, despite the fact that itwas known that the risk for lymphomas in RA was proportionalto duration and disease activity. Whole population databasesin Sweden have clarified that there is in fact no increasedrisk (31). It long has been recognized that anti-TNF–treatedpatients have no overall increased risk for cancer.
Role of TNF Blockade in Other Chronic Inflammatory Diseases
With the success of TNF blockade in RA, as a result of downregulationof the proinflammatory cytokine cascade in the synovium of theinflamed joint, this approach subsequently was tested in otherchronic diseases in which TNF was implicated (25). The firstsuccess was in Crohn disease; patients who had steroid-resistantCrohn disease and were in flares responded well. Not only werethe symptoms relieved, as judged by the Crohn disease activityindex (32), but also the major complication of fistula formationresponded in the majority of cases (33). Infliximab thereforewas approved for short-term use in Crohn disease in 1998, andsubsequent trials have permitted long-term use. Trials in otherdiseases then were initiated, and there currently is approvalin six: RA, Crohn disease, juvenile RA, ankylosing spondylitis(34), psoriasis (35), and psoriatic arthritis (36).
Successful trials and case studies now have been reported inmany other diseases, as listed in Table 1, but there also havebeen interesting and intriguing failures. Etanercept, just aseffective as infliximab in RA, is not effective in Crohn disease(37,38). Various hypotheses may be suggested for this—aninadequate dose is one, and a lack of apoptosis induction isanother—but none is established. It is interesting thatadalimumab, a fully human anti-TNF antibody, also is effectivein Crohn disease (39). Lenercept, a p55 TNFR-Ig fusion protein,was tested in multiple sclerosis but was not successful (40),probably because it did not penetrate the central nervous system.More recently, a short-term trial of infliximab in chronic obstructivepulmonary disease (41), was not successful, but a trial in severesteroid-resistant asthma showed benefit (42).
With the medical and commercial success of TNF blockade withantibodies or TNF receptor fusion proteins, many pharmaceuticalcompanies have started to work on drugs to block TNF. The mostpopular approach has been to try to block p38 mitogen-activatedprotein kinase (43). This is involved in mRNA stability andtranslational efficiency (44), and p38 blockade markedly reducesTNF production in vivo in animal models, as well as reducingTNF signaling. This target has been the subject of considerableresearch, but so far the drugs studied in trials have been tootoxic for routine clinical use. However, there still are numerousactive drug discovery programs, and this approach may yet besuccessful. As an alternative, NF-B blockade would provide inhibitionboth of TNF production (although not in all circumstances) andof TNF signaling. Attempts to develop drugs that block the inducersof NF-B kinase (IKK), especially IKK2, have not yet been successful,although work still is in progress (45).
Several alternative approaches may be safer than the above andso may reach clinical use sooner. Some possibilities that wehave examined include phosphodiesterase type 4 (PDE4) inhibition(46), nonpsychoactive cannabinoids, and blockade of the Brutontyrosine kinase (btk)/tec tyrosine kinases (47). PDE4 enzymesregulate cAMP in both T cells and macrophages, and this leadsto reduced production of both T cell cytokines (IL-12 and IFN-)and macrophage cytokines (TNF). In animal models, PDE4 blockadeis effective in arthritis (46), but in humans, problems withnausea and emesis have been limiting. Newer compounds that lackthese adverse effects may prove effective in future. Cannabinoidshave anti-immune and anti-inflammatory properties. Cannabidiolis a nonpsychoactive cannabinoid, without significant capacityto bind to CB1 or CB2 receptors, which in vitro is inactivebut which in vivo is effective in animal models of RA, multiplesclerosis, and Crohn disease (48). Cytokine blockade is demonstrablein tissues that are taken from the treated animals; therefore,this family of drugs is a potential therapeutic candidate. Asurprise in RA treatment in recent years has been the considerablebenefit of the anti-CD20 antibody rituximab, which kills matureB cells (49) but not plasma cells. btk is defective in X-linkedagammaglobulinemia, in which B cells do not mature. btk alsois important in TNF production, so btk and its close relativetec are interesting targets, as their inhibition would blocktwo pathways of importance in RA: B cells and TNF (47).
As in the other chronic inflammatory diseases described above,there now is considerable evidence that TNF- plays an importantrole in glomerular inflammation and scarring. TNF productionhas been demonstrated within the glomeruli in both experimentaland human glomerulonephritis (50), including that associatedwith anti-neutrophil cytoplasmic antibody (ANCA) (51). Althoughit is clear that infiltrating macrophages are an important sourceof TNF, several intrinsic renal cell types (including mesangialcells and epithelial cells) also contribute. Experiments inthe late 1980s revealed that systemic administration of TNFwas able to induce glomerular damage in normal rabbits (52).More interesting, a small dose of TNF greatly increased glomerulardamage in rats with nephrotoxic nephritis that was induced byadministration of rabbit anti-rat glomerular basement membraneantibodies (nephrotoxic serum) (53).
Several studies now have confirmed the importance of TNF- inglomerular inflammation by using a variety of blocking strategies.TNF-binding protein, a dimeric form of the soluble receptor,reduced renal injury in rat nephrotoxic nephritis and also wasfound to decrease serum levels of macrophage migration inhibitoryfactor (MIF) (54). A soluble fragment of the extracellular domainof TNFR1 (p55 TNFR-Ig) was effective in reducing glomerularinjury in a short-term model of LPS-enhanced nephrotoxic nephritis.This was accompanied by reduction in glomerular IL-1 expression(55). Both of these experiments suggest that TNF blockade canmodulate production of other "downstream" proinflammatory cytokines,which may contribute to the therapeutic effect.
More recent studies in our laboratory examined the effect ofTNF- blockade in both prevention and treatment of nephrotoxicnephritis in the WKY rat. This strain is particularly susceptibleto glomerular injury and consistently develops severe crescenticnephritis within 2 wk of the administration of nephrotoxic serum.This is followed by glomerular and interstitial scarring, withrenal impairment, by 4 wk (56). Soluble p55 TNFR-Ig was of benefitin both prevention and treatment of the early stage of the disease(57). A mAb to rat TNF- also was effective in the treatmentof established disease because, when started at day 4 (maximumglomerular hypercellularity), there was a marked reduction increscent formation and improvement in renal function by day14. This effect was sustained to day 28, when there was significantlyless renal scarring in treated animals (Figure 4). It is interestingthat when treatment was started at the peak of crescent formationat day 14 and continued until day 28, there still was a significantreduction in tubulointerstitial scarring and preservation ofrenal function (58). This work suggests that TNF- is importantnot only in the acute inflammatory response but also in thesubsequent renal fibrosis. As an alternative approach to TNFblockade, we have examined the effect of rolipram, an inhibitorof PDE4 (as discussed above). Rolipram was effective in bothprevention and treatment of nephrotoxic nephritis, and thiswas associated with a reduction in renal production of TNF-(59).
Figure 4. Delayed treatment with anti-TNF antibody in experimental crescentic nephritis. (A) Histology from control animal showing marked glomerular scarring with fibrous crescents, together with tubulointerstitial inflammation and tubular atrophy. (B) Histology from a treated animal showing reduced glomerular and tubulointerstitial scarring. Reprinted with permission from reference (58).
The effects of TNF- in glomerular inflammation and scarringalso have been investigated using various knockout mice. TNF-knockout mice showed a reduction in crescent formation in amodel of nephrotoxic nephritis (60). Bone marrow transplantationhas been used to create chimeric mice to distinguish the roleof bone marrow–derived versus intrinsic renal cell productionof TNF. The work of Tipping and colleagues (61) demonstratesthat intrinsic renal cells are the major source of TNF- contributingto renal injury in murine crescentic glomerulonephritis. Therole of TNF in renal fibrosis has been examined in the modelof unilateral ureteric obstruction. Mice that were deficientin either TNFR1 or TNFR2 showed a reduction in interstitialscarring, as compared with wild-type mice, although deficiencyof TNFR1 seemed to have a greater effect (62).
Most recently, the role of TNF was investigated in rodent modelsof ANCA-associated vasculitis. The model described by Jennette’sgroup is induced by transfer of anti-myeloperoxidase (anti-MPO)antibodies raised in MPO knockout mice to naïve recipients.This results in development of pauci-immune necrotizing glomerulonephritisin the recipient mice (63). A further study showed that theseverity of renal injury that was induced by anti-MPO antibodiescould be enhanced by administration of LPS, a finding that isconsistent with the observation that intercurrent infectioncan induce relapse in patients with systemic vasculitis. Theadministration of LPS transiently induced circulating TNF, anda mAb to TNF attenuated the severity of glomerular injury (64).In a different mouse model, involving the transfer of anti–proteinase3 (anti-PR3) antibodies raised in PR3-deficient mice, intradermalinjection of TNF- triggered local inflammation. This work demonstratesthat an additional stimulus, such as TNF-, is required for thepathogenic effects of ANCA (65).
We have developed a different model of systemic vasculitis byimmunizing WKY rats with MPO. These animals develop circulatinganti-MPO antibodies, accompanied by a pauci-immune crescenticnephritis and alveolar hemorrhage (66). This has been termedexperimental autoimmune vasculitis (EAV) and is effectivelya model of ANCA-associated microscopic polyangiitis. Using intravitalmicroscopy, we have demonstrated that anti-MPO antibodies inEAV are capable of inducing leukocyte adhesion and transmigrationin vivo and furthermore that they can induce microvascular hemorrhage.The administration of a blocking mAb to TNF in this model virtuallyabolishes crescent formation and reduces lung hemorrhage. Thesebeneficial effects are accompanied by a reduction in leukocytetransmigration, as demonstrated by intravital microscopy (Figure 5)(67). This work, in an autoimmune model that is highly relevantto human systemic vasculitis, further illustrates the importanceof TNF in recruitment of leukocytes to inflammatory sites.
Current management of ANCA-associated systemic vasculitis andfocal necrotizing glomerulonephritis is based on the use ofprednisolone and cyclophosphamide (68–70). However, theregimens used carry considerable drug-related adverse effectsand are associated with a high incidence of relapse. New, moreeffective, and less toxic approaches to treatment clearly areneeded (71). Because of the beneficial effects of TNF blockadein other chronic inflammatory disorders and because of the evidencesupporting the role of TNF in experimental glomerulonephritis,it was logical to attempt this approach in human glomerulonephritis.Several small pilot studies suggested a benefit of anti-TNFantibody (infliximab) (72–74) or soluble p75 receptor(etanercept) (75) in ANCA-associated systemic vasculitis.
A larger, prospective, open-label study of infliximab, involving32 patients with biopsy-proven ANCA-associated vasculitis (bothWegener granulomatosis and microscopic polyangiitis), was reportedrecently (76). Two groups of patients were studied: (1) Thosewho presented with acute disease and (2) those with persistentor "grumbling" disease despite immunosuppressive treatment.In group 1, anti-TNF antibodies were used in addition to conventionaltherapy, but in group 2, the addition of anti-TNF antibodieswas the only change in therapy. In both groups, there was arapid response in the great majority (88%) of patients at amean time of 6.4 wk (Figure 6). Although it is difficult tointerpret the additional effect of infliximab in group 1 patients,there was a rapid clinical response and a significant steroid-sparingeffect when compared with standard regimens. In group 2 patients,in which infliximab was the only change in therapy, the resultssuggest that TNF- blockade was responsible for the observedremissions. However, it should be noted that relapse occurredin 18% of patients and that adverse events, particularly infection,were seen in 21% of patients.
Figure 6. Study of TNF blockade with infliximab in anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis. (A) Sequential Birmingham Vasculitis Activity Scores. (B) Sequential measurements of CRP. , study 1 (active disease); , study 2 (persistent disease). Adapted from reference (76). Illustration by Josh Gramling—Gramling Medical Illustration.
A randomized, controlled trial of the use of etanercept in Wegenergranulomatosis was published recently by the Wegener GranulomatosisEtanercept Trial (WGET) Research Group (77). In this study,patients with active Wegener granulomatosis were randomly assignedto receive standard therapy, together with either etanercept25 mg twice weekly or placebo. Of 174 patients analyzed, 72%developed sustained remission, but there was no significantdifference between the etanercept and control arms. Diseaseflares were common in both arms and were not significantly differentaccording to treatment (118 etanercept, 134 control). However,only approximately 50% of cases in both arms had evidence ofrenal involvement, with a mean serum creatinine of 1.85 mg/dlin the etanercept group and 1.62 mg/dl in the control group.Because renal disease was not analyzed separately, it is difficultto comment directly on the effect of etanercept on ANCA-associatedglomerulonephritis. It is notable that >50% of patients inboth groups experienced at least one severe adverse event. Sixsolid cancers were noted in the etanercept group, although itwas reported that a higher proportion of these patients hada history of failed treatment before enrollment.
It is not appropriate to make direct comparisons between theresults that were obtained in the open-label study of infliximaband the much larger randomized, controlled trial of etanercept.However, these are different approaches to treatment, used indifferent patient groups, so it is appropriate to consider reasonsfor the apparently contrasting results. First, it is possiblethat the dose of etanercept that was used in WGET was not sufficient.Second, it may be that etanercept is less effective in granulomatousdisease, which was a major clinical feature in WGET; similarfindings have been reported in Crohn disease and sarcoidosis.Third, there are important biologic differences in the effectsof etanercept and infliximab; for example, etanercept also bindsto LT, and infliximab can bind directly to cell membrane–expressedTNF and induce apoptosis in activated cells in vitro. Whetherthis effect is important in vivo is controversial, as apoptosisnoted during therapy of Crohn disease with infliximab correlateswith clinical success, but this is not seen in RA. In consideringfuture trials of TNF blockade in vasculitis, thought also shouldbe given to the high incidence of adverse events in these studiesand whether anti-TNF therapy might allow a reduction in theuse of other immunosuppressive agents.
We have reviewed the role of TNF- in chronic inflammation anddescribed how TNF blockade was taken from human in vitro systemsto murine models of arthritis in vivo and then into clinicalpractice in patients with RA. The use of anti-TNF therapy nowis approved in RA and several other chronic inflammatory disorders.In renal disease, preclinical studies in experimental modelshave revealed clearly an important role for TNF- in glomerularinflammation. In certain mouse models of glomerulonephritis,there is a major role for intrinsic renal cell production ofTNF-, as opposed to that produced by infiltrating leukocytes.Blocking mAb to TNF has proved to be effective in several modelsof crescentic nephritis in rats, and the benefit in EAV waslinked to reduced leukocyte transmigration in vivo. Althoughthere are encouraging reports of the use of infliximab in open-labelstudies of patients with systemic vasculitis, enthusiasm forthis approach must be tempered by the lack of effectivenessof etanercept in a controlled trial of patients with Wegenergranulomatosis. Overall, we believe that mAb to TNF- may havea role in the treatment of ANCA-associated glomerulonephritisand suggest that this approach be further evaluated.
Acknowledgments
Portions of this work were funded by grants from the ArthritisResearch Campaign, the Medical Research Council, the WellcomeTrust, and Kidney Research UK.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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in Anti-Neutrophil Cytoplasmic Antibody–Associated Vasculitis? Lessons from Other Chronic Inflammatory Diseases
–dependent cytokine cascade in the in vitro cultures of synovium in joints of patients with RA led to studies of TNF blockade in experimental models of arthritis and subsequently to clinical trials. These have culminated in the widespread introduction of anti-TNF therapy not only in RA but also in Crohn disease, ankylosing spondylitis, and several other chronic inflammatory disorders. Following a similar investigative pathway, studies that show the importance of TNF production by leukocytes and intrinsic renal cells in glomerulonephritis have been followed by the demonstration of the effectiveness of TNF blockade in several experimental models of glomerulonephritis and vasculitis. In experimental autoimmune vasculitis, improvement in disease was paralleled by a reduction in leukocyte transmigration, as demonstrated by intravital microscopy. The benefit of infliximab (a mAb to TNF) in ANCA-associated vasculitis was recently reported in a prospective open-label study. However, the use of etanercept (a soluble TNF receptor fusion protein) was not found to be of significant benefit in a randomized, controlled trial in patients with Wegener granulomatosis. Therefore, there is a need for further evaluation of the use of anti-TNF antibodies in patients with ANCA-associated glomerulonephritis. 
–producing cells in blood, diminished mitogen and recall responses normalize, and poorly functioning regulatory cells are restored. Elevated serum levels of MMP (e.g., MMP-1, MMP-3) normalize, providing a partial reason for reduced joint damage. Synovial cellularity is diminished within 2 to 4 wk, probably as a result of reduced influx of inflammatory cells, but there are no data on changes in egress. Possible changes in apoptosis are controversial. These studies have been reviewed thoroughly (19,23–26). 
B blockade would provide inhibition both of TNF production (although not in all circumstances) and of TNF signaling. Attempts to develop drugs that block the inducers of NF-
expression (55). Both of these experiments suggest that TNF blockade can modulate production of other "downstream" proinflammatory cytokines, which may contribute to the therapeutic effect. 
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Abstract
Cytokines: Protein Mediators of...
, anti-TNF antibody; 
, controls. (B) Transmigration of leukocytes assessed using intravital microscopy. 