Autoimmunity Reviews xxx (2014) xxx–xxx

AUTREV-01645; No of Pages 8

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Autoimmunity Reviews

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Review

Goodpasture's syndrome: A clinical update

Antonio Greco a, Maria Ida Rizzo b, Armando De Virgilio a,b,⁎, Andrea Gallo c, Massimo Fusconi a,Giulio Pagliuca c, Salvatore Martellucci c, Rosaria Turchetta d, Lucia Longo a, Marco De Vincentiis a

a Department Organs of Sense, ENT Section, 'Sapienza' University of Rome, Viale del Policlinico 155, 00100 Roma, Italyb Department of Surgical Science, 'Sapienza' University of Rome, Viale del Policlinico 155, 00100 Roma, Italyc Department of Medico-Surgical Sciences and Biotechnologies, Otorhinolaryngology Section, 'Sapienza' University of Rome, Corso della Repubblica, 79, 04100 Latina, LT, Italyd Department Organs of Sense, Audiology Section, 'Sapienza' University of Rome, Viale del Policlinico 155, 00100 Roma, Italy

49976803.E-mail address: armando.devirgilio@gmail.com (A. De

http://dx.doi.org/10.1016/j.autrev.2014.11.0061568-9972/© 2014 Published by Elsevier B.V.

Please cite this article as: Greco A, et al, Gj.autrev.2014.11.006

a b s t r a c t

a r t i c l e i n f o

Article history:Received 2 November 2014Accepted 9 November 2014Available online xxxx

Keywords:Goodpasture syndromeAnti-GBM diseaseCrescentic glomerulonephritisPulmonary-renal syndromeAnti-GBM antibodiesANCAs

Goodpasture's syndrome (GS) is a rare and organ-specific autoimmune disease that is mediated by anti-glomer-ular basement membrane (anti-GBM) antibodies and has pathology characterized by crescentic glomerulone-phritis with linear immunofluorescent staining for IgG on the GBM. It typically presents as acute renal failurecaused by a rapidly progressive glomerulonephritis, accompanied by pulmonary hemorrhage that may be life-threatening. It was first described as a distinctive syndrome by Pasture in 1919. Autoimmune Inner Ear Disease(AIED) may be associated. The etiology of GS is unknown. Researchers hypothesized a genetic predispositionHLA-associated. Complex immunological mechanisms are in the pathogenesis. The disease is caused by autoan-tibodies against the NC1 domain of the alpha 3 chain of type IV collagen. The limited presence of thismolecule inthe body explains the interest confined to specific target organs, such as the lung and kidney. It occurs when theimmune system attacks thewalls of the lungs and the tiny filtering units in the kidneys.Without prompt diagno-sis and treatment, the disease can lead to bleeding in the lungs, kidney failure, and even death.

© 2014 Published by Elsevier B.V.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03. Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 04. Symptomatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 05. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

5.1. Physical examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 05.2. Blood and urine testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 05.3. Anti-GBM antibody testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 05.4. Antineutrophil cytoplasmic antibody testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 05.5. Chest radiograph . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 05.6. Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 05.7. Lung hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

6. Differential diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 07. Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 08. Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

8.1. Immunosuppressive therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 08.2. Plasmapheresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 08.3. Renal transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 010. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

⁎ Corresponding author at: Department Organs of Sense, ENT Section, 'Sapienza' University of Rome, Viale del Policlinico 155, 00100 Roma, Italy. Tel.: +39 380 3408909; fax: +39 06

Virgilio).

oodpasture's syndrome: A clinical update, Autoimmun Rev (2014), http://dx.doi.org/10.1016/

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1. Introduction

Goodpasture's syndrome (GS) is a rare disease, identified by Dr.Ernest Goodpasture in 1919 [1,2]. It is an organ-specific autoimmunedisease that is mediated by anti-glomerular basement membrane(anti-GBM) antibodies and has pathology characterized by crescenticglomerulonephritis with linear immunofluorescent staining for IgG onthe GBM. It typically presents as acute renal failure caused by a rapidlyprogressive glomerulonephritis, accompanied by pulmonary hemor-rhage, that may be life-threatening [3–6].

Other acronyms and names include Goodpasture's disease, anti-GBM disease and crescentic glomerulonephritis type 1 [7–11].

Numerous reports of single patients with this disorder, as well assmall case series, have been published [12–20]. There is the lack of sys-tematic data on GS.

2. Epidemiology

The incidence of GS is estimated to be 1 case permillion per year, butit is a cause of acute renal failure in approximately 20% of all cases of rap-idly progressive or crescentic glomerulonephritis [21]. This disorder oc-curs more commonly in white people than in black people. The agedistribution is bimodal, 20–30 years and 60–70 years. The prevalenceof the disease is higher in men in the younger age group and womenin the older age subgroup [22].

3. Etiopathogenesis

In the 1950s, Krakower and Greenspon [23] identified GBM as theantigen. In 1967, Lerner, Glassock, and Dixon [24] confirmed that theantibodies taken from the diseased kidneys produced nephritis in ex-perimental animals. The discovery of anti-GBM antibodies led to the un-derstanding of the pathogenesis of GS.

GS or Anti-GBMdisease is an autoimmune disorder characterized byautoantibodies directed against the glomerular/alveolar basementmembrane. The autoantibodies bind to their reactive epitopes in thebasement membranes and activate the complement cascade, resultingin tissue injury. This is a classic type II reaction in the Gell and Coombsclassification of antigen–antibody reactions. This binding of antibodiescan be visualized as the linear deposition of immunoglobulin alongthe glomerular basement membrane and, less commonly, the alveolarbasement membranes, by direct immunofluorescent techniques.

In most patients, the autoantibody in GS is directed against a 28-kdmonomeric subunit present within the noncollagenous domain of thealpha 3 chain of type IV collagen (alpha3[IV]NC1) [22–25]. Two confor-mational epitopes of anti-GBM antibodies have been defined at residues17–31 and 127–141 of alpha3(IV)NC1,whichwere named as EA and EB,respectively [Fig. 1].

Although basement membranes are ubiquitous, only the alveolarand glomerular basementmembranes are affected clinically. The prefer-ential binding to the alveolar and glomerular basement membranesappears to be caused by greater accessibility of epitopes and greater ex-pansion of alpha 3 collagen units. Furthermore, the alpha 3 collagenchains of glomerular and basement membranes are structurallyintegrated in such a way that they are more accessible to the circulatingantibodies [26,27].

Strong evidence exists that genetics play an important role. Patientswith specific human leukocyte antigen (HLA) types are more suscepti-ble to disease and may have a worse prognosis.

There is an increased prevalence of HLA-DR15 (previously known asHLA-DR2) and DRB1*03, DRB1*04 and a decreased frequency ofDRB1*01 andDRB1*07 [28,29]. Goodpasture disease is strongly associatedwith the DRB1*1501 and to a lesser extent the DRB1*1502 allele.Although a strong association exists between anti-GBM disease and HLADRB1*1501, this allele is present in as many as one third of individuals

Please cite this article as: Greco A, et al, Goodpasture's syndrome: A cj.autrev.2014.11.006

in white populations. It is therefore clear that additional factors, eithergenetic or environmental, are required for disease expression [30–33].

While the exact cause of GS is unknown, certain behaviors andenvironmental factors are believed to put people at higher risk. Certainrespiratory infectionsmay trigger the disease. Exposure to hydrocarbonfumes, metallic dust, tobacco smoke, or substances such as cocaine mayalso increase risk.

The recent literature shows that an initial insult to the pulmonaryvasculature is required for exposure of the alveolar capillaries to theanti-GBM antibodies, and predisposing factors for such exposure in-clude the following: association with HLA-DR15; exposure to organicsolvents or hydrocarbons; smoking; infection (e.g., influenza A2); co-caine inhalation; exposure to metal dusts; and lymphocyte-depletiontherapy, such as alemtuzumab [34–39].

4. Symptomatology

Symptoms may start out slowly, gradually affecting the lungs andthe kidneys. Other times they may progress rapidly, becoming severein a matter of days. Constitutional symptoms like malaise, chills andfever, and/or arthralgias may precede or be concurrent with pulmonaryor renal manifestations. Initial symptoms may include fatigue, weak-ness, or lethargy nausea and/or vomiting, loss of appetite, unhealthy,pale appearance. Substantial variation exists in the clinical manifesta-tions of patients with anti-GBM disease. 60 to 80% of the patientshave clinically apparent manifestations of pulmonary and renal disease,20–40% have renal disease alone, and less than 10% have disease that islimited to the lungs [40–43].

If the disease moves to affect the lungs, hemoptysis is usually thepresenting symptom and the following symptoms like dry cough orcoughing up blood, shortness of breath or dyspnea may occur.Sometimes symptoms affecting the lungs can become life-threatening,if there is a massive pulmonary hemorrhage leading to respiratory fail-ure. Chest pain is present in less than half of the patients. Significantanemia may result from persistent intrapulmonary bleeding.

If the disease affects the kidneys, it may cause burning sensationduring urination, hematuria or foamy urine, swelling of the hands andfeet, high blood pressure, and back pain below the ribs. Other renalmanifestations include edema and eventually uremia.

Autoimmune Inner Ear Disease (AIED) is present in the samecases [44,45]. The symptoms of AIED are sudden hearing loss in oneear [46] progressing rapidly to the second ear. The hearing loss canprogress over weeks or months. Patients may feel fullness in the earand experience vertigo [47]. In addition, a ringing, hissing, or roaringsound in the ear may be experienced [44,45].

5. Diagnosis

Diagnosis of GS is made by detection of circulating anti-GBMantibodies, and more specifically, the anti-α3(IV) NC1 antibodies onsolid-phase immunoassays. Kidney biopsy provides definitive diagnosis.On light microscopy, the early changes are of a focal proliferative GN.This proliferative response usually progresses to necrosis and extensivecrescent formation with interstitial inflammation. The pathognomonicfinding on direct immunofluorescence is the linear deposition of immu-noglobulin G (IgG) along the GBM and sometimes along the distaltubular basement [48].

Diagnosis of AIED-Goodpasture-associated is difficult and AIED isoften mistaken for otitis media until the patient develops a loss in thesecond ear [44,45].

5.1. Physical examination

Physical examination findings in patients with anti-GBM disease in-clude the following: tachypnea; inspiratory crackles over lung bases;

linical update, Autoimmun Rev (2014), http://dx.doi.org/10.1016/

Fig. 1. Topology of the EA and EB regions in theα345 noncollagenous-1 hexamer, structural determinants for the binding of Alport alloantibodies andGoodpasture autoantibodies in vitro,and accessible surface area of the EA-α3 and EA-α5 regions of the noncollagenous-1 hexamer.From: Pedchenko V et al. Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis. N Engl J Med. 2010; 363: 343–54.

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Please cite this article as: Greco A, et al, Goodpasture's syndrome: A clinical update, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.11.006

Fig. 2. Hemorrhagic alveolitis. Chest X-ray: low density multiple opacities with gradientaspect, distributed in both lungs with a tendency to confluence, mainly distributed inthe central portions.From: Naticchia A et al. Sindromi pneumo-renali. G Ital Nefrol 2011; 28: 57–63.

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cyanosis; hepatosplenomegaly; hypertension; rash; and edema. First, itis necessary to check for high blood pressure, bleeding, abnormal heartand lung sounds, and medical history.

5.2. Blood and urine testing

Anemia may be observed secondary to iron deficiency caused byintrapulmonary bleeding. Leukocytosis is commonly present. A bloodtest can show a high level of waste products, whichmay indicate kidneyproblems. Elevated blood urea nitrogen (BUN) and serum creatininelevels secondary to renal dysfunction may be present. A blood testmay show the presence of antibodies that indicate the presence of thedisease.

Urinalysis findings are characteristic of acute glomerulonephritis,usually demonstrating low-grade proteinuria, gross or microscopichematuria, and red blood cell casts.

5.3. Anti-GBM antibody testing

Serologic assays for anti-GBM antibodies are valuable for confirmingthe diagnosis and monitoring the adequacy of therapy. Radioimmuno-assays or enzyme-linked immunosorbent assays (ELISAs) for anti-GBM antibodies are highly sensitive (N95%) and specific (N97%). Posi-tive results should be confirmed by western blotting on collagenase-solubilized human GBM, especially if a kidney biopsy is not beingperformed.

In a comparison study of 4 immunoassay-based anti-GBM antibodykits, all the assays showed comparably good sensitivity (94.7–100.0%),whereas specificity varied considerably (90.9–100.0%). The recombi-nant antigen fluorescence immunoassay demonstrated the best sensi-tivity/specificity [49].

Healthy individuals may have circulating antibodies against GBMbelonging to IgG2 and IgG4 subclasses.With the onset of clinical disease,IgG1 and IgG3 subclasses increase and levelsmay correlatewith diseaseseverity [25,50].

A study by Yang et al. indicated that higher levels of circulating anti-GBM antibodies against the epitopes EA and EB occurred in patientswhose renal disease was more severe and that these patients had aworse prognosis. Correlation was noted between the levels of anti-GBM antibodies and the serum creatinine at diagnosis and the presenceof oliguria. Correlation existed between the percentage of crescents onbiopsy and levels of antibodies, but it was significant only for anti-EAantibodies (P b .05) [51].

5.4. Antineutrophil cytoplasmic antibody testing

At some time during the course of illness, asmany as one third of pa-tients with Goodpasture syndrome have circulating antineutrophil cy-toplasmic antibodies (ANCAs) in addition to anti-GBM antibody [52].In most cases, the ANCAs precede the development of anti-GBM anti-bodies by months to years [53]. It is postulated that the renal involve-ment in ANCA vasculitis leads to the exposure of antigens from thebasement membrane and the formation of antibodies. These patientsare referred to as double-positive. In majority of double-positive pa-tients, the ANCAs have specificity for myeloperoxidase (MPO-ANCAs)[54,55]. In patients with both anti-GBM antibodies and MPO-ANCAs,histological findings differ from those of patients with anti-GBM anti-bodies only. The renal survival in these patients is similar to anti-GBM-positive patients and is worse compared with patients withMPO-ANCAs only.

5.5. Chest radiograph

Characteristically, the chest film shows patchy parenchymal consol-idations, which are usually bilateral, symmetric perihilar, and bibasilar[Fig. 2]. The apices and costophrenic angles are usually spared.However,

Please cite this article as: Greco A, et al, Goodpasture's syndrome: A cj.autrev.2014.11.006

as many as 18% of patients may have normal findings on chestradiographs.

The consolidation resolves over 2–3 days, and it gradually progressesto an interstitial pattern as patients experience repeated episodes ofhemorrhage. Pleural effusions are unusual.

5.6. Biopsy

In patients with evidence of diffuse alveolar hemorrhage and renalinvolvement, kidney biopsy should be considered to identify the under-lying cause and to help direct therapy. Percutaneous kidney biopsy isthe preferred invasive procedure to substantiate the diagnosis of anti-GBM disease.

Renal biopsy provides a significantly higher yield than lung biopsy,but transbronchial or open lung biopsy may be performed in caseswhere renal biopsy cannot be performed.

The biopsy tissue must be processed for light microscopy, immuno-fluorescence, and electron microscopy.

Light microscopy demonstrates nonspecific features of a prolifera-tive or necrotizing glomerulonephritis with cellular crescents [Fig. 3a].Over time, the crescents become fibrotic, and frank glomerulosclerosis,interstitial fibrosis, and tubular atrophy may be observed.

Immunofluorescence stains are confirmatory. These show brightlinear deposits of immunoglobulin G (IgG), as seen in the Fig. 3b, andcomplement (C3) along the glomerular basementmembranes. SubclassIgG-1 predominates [56] [Fig. 3].

Lung biopsy shows extensive hemorrhage with accumulation ofhemosiderin-laden macrophages within alveolar spaces. Neutrophiliccapillaritis, hyaline membranes, and diffuse alveolar damage may alsobe found. Medium-vessel or large-vessel vasculitis is not a feature [57].Immunofluorescence staining may be diagnostic [Fig. 4].

5.7. Lung hemorrhage

Diffuse alveolar hemorrhage represents a medical emergency [58].In the appropriate clinical setting (i.e., alveolar hemorrhage and urinaryfindings suggestive of an acute glomerulonephritis), thedetection of cir-culating anti-glomerular basement membrane (anti-GBM) antibodiesallows the clinician to make a firm diagnosis of anti-GBM disease. Thisobviates lung or kidney biopsy.

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When the diagnosis remains in doubt, renal biopsy is the best meth-od for detecting anti-GBM antibodies in tissues. Patients in whom thediagnosis of diffuse alveolar hemorrhage remains uncertain should un-dergo diagnostic bronchoscopy.

6. Differential diagnosis

Conditions that affect the lung and kidney (pulmonary-renal syn-dromes) are important in the differential diagnosis. These include We-gener granulomatosis, systemic lupus erythematosus, microscopicpolyangiitis, other forms of systemic vasculitides (Churg–Strausssyndrome, essential mixed cryoglobulinemia, Henoch–Schönlein pur-pura, microscopic polyarteritis, and undifferentiated connective-tissuedisease), and other disorders (Pneumocystis carinii pneumonia,community-acquired, respiratory failure, and rheumatoid arthritis)[59,60].

Distinguishing Wegener granulomatosis from GS is particularly im-portant. Interestingly, some patients with GS may present withantineutrophil cytoplasmic antibodies (ANCAs), which are predomi-nantly observed in patients with Wegener granulomatosis [52,61].

Pulmonary-renal syndromes are less commonly a manifestation ofIgA-mediated disorders (e.g., IgA nephropathy or Henoch–Schönleinpurpura) and of immune complex-mediated renal disease (e.g., essen-tial mixed cryoglobulinemia) [62]. Rarely, rapidly progressive glomeru-lonephritis alone can cause pulmonary-renal syndromes through amechanism involving renal failure, volume overload, and pulmonaryedema with hemoptysis. Careful attention to the medical history,physical examination, and targeted laboratory evaluation often suggeststhe underlying cause.

7. Prognosis

Aggressive therapywith plasmapheresis, corticosteroids, and immu-nosuppressive agents has dramatically improved prognosis comparedto the past, in which GS was fatal [63]. The 5-year survival rate exceeds80% and fewer than 30% of patients require long-term dialysis.

Patients presentingwith serumcreatinine levels greater than 4mg/dL,oliguria, andmore than 50% crescents on renal biopsy rarely recover. Theyusually progress to end-stage renal failure that requires long-term dialy-sis. In a retrospective analysis of patients with anti-GBM disease whostarted renal replacement therapy for end-stage renal disease (ESRD) inAustralia and New Zealand (ANZDATA Registry), the median survivalrate was 5.93 years with death predicted by older age and history ofpulmonary hemorrhage [21].

In patients with both anti-GBM antibodies and MPO-ANCAs,histological findings differ from those of patients with anti-GBM anti-bodies only. The renal survival in these patients is similar to anti-

Fig. 3. Light microscopy and immunofluorescent findings on renal biopsy. (a) Fibrinoid necrinfiltration (PAS, ×400) and (b) Immunofluorescence: fine linear pattern along GBM stained wFrom: Bogdanović R et al. Pulmonary renal syndrome in a child with coexistence of anti-neutroand literature review. BMC Nephrol. 2013; 14:66.

Please cite this article as: Greco A, et al, Goodpasture's syndrome: A cj.autrev.2014.11.006

GBM-positive patients and is worse compared with patients withMPO-ANCAs only [64,65].

The prognosis depends on the timeline of diagnosis and treatment.Although some patients requiring dialysis may recover a good renalfunction, usually the higher the serum creatinine at presentation theworse the outcome.When treatment is initiated early,most patients ob-tain a complete or partial remission [7].

8. Treatments

Until today, no studies on the best treatment of the syndrome havebeen performed because of the rarity and also the sometimes late diag-nosis of the syndrome. The correct diagnosis is the first important stepfor the correct treatment. Based on the hypothesis of being an autoim-mune disease, treatment has to be immunosuppressive.

High-dose corticosteroids and cyclophosphamide represent thestandard therapy. The addition of plasma exchange is important, partic-ularly in patientswithmassive alveolar hemorrhage. Anti-Bmonoclonalantibodies have also been used in some patients with crescentic GN, buttheir role in this particular area is still poorly established [7,66].

8.1. Immunosuppressive therapy

Immunosuppressive therapy is required to inhibit antibody produc-tion and rebound hypersynthesis, whichmay occur following discontin-uation of plasma exchange [67–69].

Initial therapy includes cyclophosphamide at 2 mg/kg orally, adjust-ed to maintain a white blood cell count of approximately 5000, andcorticosteroids (e.g., prednisone at 1–1.5 mg/kg). Treatment of acutelife-threatening alveolar hemorrhage in patients with Goodpasturesyndrome is with pulse methylprednisolone at 1 g/day for 3 days,followed by a gradual corticosteroid taper. Intravenous cyclophospha-mide has begun concomitantly at 1 g/m2 and repeated 3–4 weekslater, depending on the recovery of bone marrow. The duration of im-munosuppressive therapy is not well established. Anti-GBM antibodylevels must be monitored at regular intervals. In patients who achievea prompt remission, immunosuppression with cyclophosphamide iscontinued for 2–3months and steroids for 6months. Patients with clin-ically or serologically active disease at 3–4 months need longer immu-nosuppression (6–9 months). Azathioprine may be substituted forcyclophosphamide to reduce adverse effects, especially in patientsneeding prolonged immunosuppression.

Rituximab, a chimeric monoclonal antibody, effectively depletesCD20-positive B cells over 6–9 months and has been used in severalcase reports as an alternative approach in the treatment of anti-GBMan-tibody disease. In these reports, rituximab was used as either an initialor a second-line agent in patients in whom cyclophosphamide failed

osis of GBM, cellular crescentic formation, and slight periglomerular limpho-monocyticith anti IgG antibody (×200).phil cytoplasmic antibodies and anti-glomerular basementmembrane disease: case report

linical update, Autoimmun Rev (2014), http://dx.doi.org/10.1016/

Fig. 4. Light microscopy and immunofluorescent findings on lung biopsy. (a) Pulmonary hemorrhage showing intra-alveolar fibrin and hemosiderin highly loaded alveolar macrophages.(b) An immunofluorescence micrograph showing linear IgG deposits in the GBM. Discontinuity is observed indicating rupture.From: Otero RRO et al. Síndrome de Goodpasture: Un enfoque pulmonar. de Goodpasture: Un enfoque pulmonar. Neumología y Cirugía De Tórax, Vol. 65(4):178–185, 2006.

6 A. Greco et al. / Autoimmunity Reviews xxx (2014) xxx–xxx

or yielded adverse effects. The anti-GBM antibodies became undetect-able in all these patients, but they had variable renal outcomes [70,71].

Pneumocystis jirovecipneumonia has an annual incidence of 1% but isa potentially deadly complication of immunosuppressive therapy in pa-tients with Goodpasture syndrome. Prophylaxis with trimethoprim-sulfamethoxazole (160mg trimethoprim and 800mg sulfamethoxazole3 times per week) may be a cost-effective method of prolonging life inthese patients.

8.2. Plasmapheresis

In published case series and one randomized trial, plasmapheresishas been shown to be beneficial in the treatment of GS by removal ofanti-GBM antibodies [57,68,72–74]. Plasmapheresis is generally insti-tuted after the diagnosis of GS is established either by renal biopsy orby detection of anti-GBM antibodies.

When a patient presents in a life-threatening situation secondary topulmonary hemorrhage, however, plasmapheresis may be initiated ifthe diagnosis appears very likely, even though confirmation is not avail-able immediately.

The extent and duration of plasmapheresis is not known, but 4-literplasma exchanges daily or every other day is usually performed. Theplasmapheresis is continued for 2–3 weeks or until the patient's clinicalcourse has improved and serum anti-GBM antibodies are not detected.

8.3. Renal transplantation

Renal transplantation has been used for end-stage renal disease sec-ondary to GS [75]. It is optimal to delay renal transplantation until anti-GBM antibodies are undetectable in the serum for 12 months and thedisease has been in remission for at least 6 months without the use ofcytotoxic agents.Many patients develop linear deposits of IgG along glo-meruli of the renal allograft. However, this development does not causehistologic or functional damage to the transplanted kidney. Interesting-ly anti-GBM disease can occur in approximately 3–5% of male patientswho have hereditary nephritis (Alport syndrome) undergoing renaltransplantation, known as de novo anti-GBM disease. Patients receivingrenal transplants must be informed that anti-GBM disease can recur inthe transplanted kidney, although graft loss due to this is very rare.

9. Conclusions

GS is a rare autoimmune disorder characterized by the association ofpulmonary hemorrhage, glomerulonephritis and extracapillary anti-bodies against the glomerular basement membrane. The disease iscaused by autoantibodies against the NC1 domain of the alpha 3 chainof type IV collagen. The limitedpresence of thismolecule in the body ex-plains the interest confined to specific target organs, such as the lungand kidney.

Please cite this article as: Greco A, et al, Goodpasture's syndrome: A cj.autrev.2014.11.006

It occurswhen the immune system attacks thewalls of the lungs andthe tiny filtering units in the kidneys. Without prompt diagnosis andtreatment, the disease can lead to bleeding in the lungs, kidney failure,and even death.

The 3 principles of therapy in anti-glomerular basement membrane(anti-GBM) disease are (a) to rapidly remove circulating antibody,primarily by plasmapheresis; (b) to stop further production of antibod-ies using immunosuppression with medications; and (c) to removeoffending agents that may have initiated the antibody production.

The therapy with corticosteroids, cyclophosphamide and plasma-pheresis allows obtaining a survival of the 75% in one year. Severerenal impairment and pulmonary hemorrhagemay require urgent dial-ysis and/or assisted ventilation. It is very important to avoid fluid over-load and to treat infections quickly. The renal survival at one year isgreater than 90% for patients treated early, while it is less than 10% forthose undergoing dialysis since the beginning of the treatment.

10 .Search strategy

PubMed, Google Scholar, and Scopus were databases. Keywordswere “Goodpasture syndrome”; “Goodpasture disease”; “anti-GBM dis-ease”; “crescentic glomerulonephritis”; and “pulmonary-renal syn-drome”. Inclusion criteria were: original article, case report, andreview, with particular focus on the last five years (range: 2009–2014).

Take-home messages

• Goodpasture's syndrome is a rare disease characterized by crescenticglomerulonephritis accompanied by pulmonary hemorrhage thatmay be life-threatening.

• It is an organ-specific autoimmunedisease,mediated by anti-GBMan-tibodies. It is a possible genetic predisposition HLA-associated. Thedisease is caused by autoantibodies against the NC1 domain of thealpha 3 chain of type IV collagen.

• Constitutional symptoms likemalaise, chills and fever, and/or arthral-gias may precede or be concurrent with pulmonary or renal manifes-tations. Initial symptoms may include fatigue, weakness, or lethargynausea and/or vomiting, loss of appetite, unhealthy, pale appearance.Autoimmune Inner Ear Disease is present in the same cases.

• Kidney biopsy provides definitive diagnosis. Serologic assays for anti-GBM antibodies are valuable for confirming the diagnosis and moni-toring the adequacy of therapy.

• The 3 principles of therapy are the following: (a) to rapidly removecirculating antibody, primarily by plasmapheresis; (b) to stop furtherproduction of antibodies using immunosuppression with medica-tions; and (c) to remove offending agents that may have initiatedthe antibody production. The therapywith corticosteroids, cyclophos-phamide and plasmapheresis allows obtaining a survival of the 75% inone year.

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