Autoimmunity Reviews 14 (2015) 246–253
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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, Italy Department of Surgical Science, 'Sapienza' University of Rome, Viale del Policlinico 155, 00100 Roma, Italy Department of Medico-Surgical Sciences and Biotechnologies, Otorhinolaryngology Section, 'Sapienza' University of Rome, Corso della Repubblica, 79, 04100 Latina, LT, Italy d Department Organs of Sense, Audiology Section, 'Sapienza' University of Rome, Viale del Policlinico 155, 00100 Roma, Italy b c
a r t i c l e
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Article history: Received 2 November 2014 Accepted 9 November 2014 Available online 15 November 2014 Keywords: Goodpasture syndrome Anti-GBM disease Crescentic glomerulonephritis Pulmonary-renal syndrome Anti-GBM antibodies ANCAs
a b s t r a c t Goodpasture's syndrome (GS) is a rare and organ-specific autoimmune disease that is mediated by anti-glomerular basement membrane (anti-GBM) antibodies and has pathology characterized by crescentic glomerulonephritis with linear immunofluorescent staining for IgG on the GBM. It typically presents as acute renal failure caused by a rapidly progressive glomerulonephritis, accompanied by pulmonary hemorrhage that may be lifethreatening. 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 predisposition HLA-associated. Complex immunological mechanisms are in the pathogenesis. The disease is caused by autoantibodies against the NC1 domain of the alpha 3 chain of type IV collagen. The limited presence of this molecule in the body explains the interest confined to specific target organs, such as the lung and kidney. It occurs when the immune system attacks the walls of the lungs and the tiny filtering units in the kidneys. Without prompt diagnosis and treatment, the disease can lead to bleeding in the lungs, kidney failure, and even death. © 2014 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . Symptomatology . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . 5.1. Physical examination . . . . . . . . . . . 5.2. Blood and urine testing . . . . . . . . . . 5.3. Anti-GBM antibody testing . . . . . . . . 5.4. Antineutrophil cytoplasmic antibody testing 5.5. Chest radiograph . . . . . . . . . . . . 5.6. Biopsy . . . . . . . . . . . . . . . . . 5.7. Lung hemorrhage . . . . . . . . . . . . 6. Differential diagnosis . . . . . . . . . . . . . . 7. Prognosis . . . . . . . . . . . . . . . . . . . 8. Treatments . . . . . . . . . . . . . . . . . . 8.1. Immunosuppressive therapy . . . . . . . 8.2. Plasmapheresis . . . . . . . . . . . . . 8.3. Renal transplantation . . . . . . . . . . 9. Conclusions . . . . . . . . . . . . . . . . . . 10. Search strategy . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .
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⁎ 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 49976803. E-mail address: [email protected] (A. De Virgilio).
http://dx.doi.org/10.1016/j.autrev.2014.11.006 1568-9972/© 2014 Elsevier B.V. All rights reserved.
A. Greco et al. / Autoimmunity Reviews 14 (2015) 246–253
1. Introduction Goodpasture's syndrome (GS) is a rare disease, identified by Dr. Ernest Goodpasture in 1919 [1,2]. It is an organ-specific autoimmune disease that is mediated by anti-glomerular basement membrane (anti-GBM) antibodies and has pathology characterized by crescentic glomerulonephritis with linear immunofluorescent staining for IgG on the GBM. It typically presents as acute renal failure caused by a rapidly progressive glomerulonephritis, accompanied by pulmonary hemorrhage, that may be life-threatening [3–6]. Other acronyms and names include Goodpasture's disease, antiGBM disease and crescentic glomerulonephritis type 1 [7–11]. Numerous reports of single patients with this disorder, as well as small case series, have been published [12–20]. There is the lack of systematic data on GS.
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in white populations. It is therefore clear that additional factors, either genetic or environmental, are required for disease expression [30–33]. While the exact cause of GS is unknown, certain behaviors and environmental factors are believed to put people at higher risk. Certain respiratory infections may trigger the disease. Exposure to hydrocarbon fumes, metallic dust, tobacco smoke, or substances such as cocaine may also increase risk. The recent literature shows that an initial insult to the pulmonary vasculature is required for exposure of the alveolar capillaries to the anti-GBM antibodies, and predisposing factors for such exposure include the following: association with HLA-DR15; exposure to organic solvents or hydrocarbons; smoking; infection (e.g., influenza A2); cocaine inhalation; exposure to metal dusts; and lymphocyte-depletion therapy, such as alemtuzumab [34–39]. 4. Symptomatology
2. Epidemiology The incidence of GS is estimated to be 1 case per million per year, but it is a cause of acute renal failure in approximately 20% of all cases of rapidly progressive or crescentic glomerulonephritis [21]. This disorder occurs more commonly in white people than in black people. The age distribution is bimodal, 20–30 years and 60–70 years. The prevalence of the disease is higher in men in the younger age group and women in the older age subgroup [22]. 3. Etiopathogenesis In the 1950s, Krakower and Greenspon [23] identified GBM as the antigen. In 1967, Lerner, Glassock, and Dixon [24] confirmed that the antibodies taken from the diseased kidneys produced nephritis in experimental animals. The discovery of anti-GBM antibodies led to the understanding of the pathogenesis of GS. GS or Anti-GBM disease is an autoimmune disorder characterized by autoantibodies directed against the glomerular/alveolar basement membrane. The autoantibodies bind to their reactive epitopes in the basement membranes and activate the complement cascade, resulting in tissue injury. This is a classic type II reaction in the Gell and Coombs classification of antigen–antibody reactions. This binding of antibodies can be visualized as the linear deposition of immunoglobulin along the glomerular basement membrane and, less commonly, the alveolar basement membranes, by direct immunofluorescent techniques. In most patients, the autoantibody in GS is directed against a 28-kd monomeric subunit present within the noncollagenous domain of the alpha 3 chain of type IV collagen (alpha3[IV]NC1) [22–25]. Two conformational epitopes of anti-GBM antibodies have been defined at residues 17–31 and 127–141 of alpha3(IV)NC1, which were named as EA and EB, respectively [Fig. 1]. Although basement membranes are ubiquitous, only the alveolar and glomerular basement membranes are affected clinically. The preferential binding to the alveolar and glomerular basement membranes appears to be caused by greater accessibility of epitopes and greater expansion of alpha 3 collagen units. Furthermore, the alpha 3 collagen chains of glomerular and basement membranes are structurally integrated in such a way that they are more accessible to the circulating antibodies [26,27]. Strong evidence exists that genetics play an important role. Patients with specific human leukocyte antigen (HLA) types are more susceptible to disease and may have a worse prognosis. There is an increased prevalence of HLA-DR15 (previously known as HLA-DR2) and DRB1*03, DRB1*04 and a decreased frequency of DRB1*01 and DRB1*07 [28,29]. Goodpasture disease is strongly associated with the DRB1*1501 and to a lesser extent the DRB1*1502 allele. Although a strong association exists between anti-GBM disease and HLA DRB1*1501, this allele is present in as many as one third of individuals
Symptoms may start out slowly, gradually affecting the lungs and the kidneys. Other times they may progress rapidly, becoming severe in a matter of days. Constitutional symptoms like malaise, chills and fever, and/or arthralgias may precede or be concurrent with pulmonary or renal manifestations. Initial symptoms may include fatigue, weakness, or lethargy nausea and/or vomiting, loss of appetite, unhealthy, pale appearance. Substantial variation exists in the clinical manifestations of patients with anti-GBM disease. 60 to 80% of the patients have clinically apparent manifestations of pulmonary and renal disease, 20–40% have renal disease alone, and less than 10% have disease that is limited to the lungs [40–43]. If the disease moves to affect the lungs, hemoptysis is usually the presenting symptom and the following symptoms like dry cough or coughing 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 failure. Chest pain is present in less than half of the patients. Significant anemia may result from persistent intrapulmonary bleeding. If the disease affects the kidneys, it may cause burning sensation during urination, hematuria or foamy urine, swelling of the hands and feet, high blood pressure, and back pain below the ribs. Other renal manifestations include edema and eventually uremia. Autoimmune Inner Ear Disease (AIED) is present in the same cases [44,45]. The symptoms of AIED are sudden hearing loss in one ear [46] progressing rapidly to the second ear. The hearing loss can progress over weeks or months. Patients may feel fullness in the ear and experience vertigo [47]. In addition, a ringing, hissing, or roaring sound in the ear may be experienced [44,45]. 5. Diagnosis Diagnosis of GS is made by detection of circulating anti-GBM antibodies, and more specifically, the anti-α3(IV) NC1 antibodies on solid-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 extensive crescent formation with interstitial inflammation. The pathognomonic finding on direct immunofluorescence is the linear deposition of immunoglobulin G (IgG) along the GBM and sometimes along the distal tubular basement [48]. Diagnosis of AIED-Goodpasture-associated is difficult and AIED is often mistaken for otitis media until the patient develops a loss in the second ear [44,45]. 5.1. Physical examination Physical examination findings in patients with anti-GBM disease include the following: tachypnea; inspiratory crackles over lung bases;
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Fig. 1. Topology of the EA and EB regions in the α345 noncollagenous-1 hexamer, structural determinants for the binding of Alport alloantibodies and Goodpasture 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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cyanosis; hepatosplenomegaly; hypertension; rash; and edema. First, it is necessary to check for high blood pressure, bleeding, abnormal heart and lung sounds, and medical history. 5.2. Blood and urine testing Anemia may be observed secondary to iron deficiency caused by intrapulmonary bleeding. Leukocytosis is commonly present. A blood test can show a high level of waste products, which may indicate kidney problems. Elevated blood urea nitrogen (BUN) and serum creatinine levels secondary to renal dysfunction may be present. A blood test may show the presence of antibodies that indicate the presence of the disease. Urinalysis findings are characteristic of acute glomerulonephritis, usually demonstrating low-grade proteinuria, gross or microscopic hematuria, and red blood cell casts. 5.3. Anti-GBM antibody testing Serologic assays for anti-GBM antibodies are valuable for confirming the diagnosis and monitoring the adequacy of therapy. Radioimmunoassays or enzyme-linked immunosorbent assays (ELISAs) for antiGBM antibodies are highly sensitive (N 95%) and specific (N97%). Positive results should be confirmed by western blotting on collagenasesolubilized human GBM, especially if a kidney biopsy is not being performed. In a comparison study of 4 immunoassay-based anti-GBM antibody kits, all the assays showed comparably good sensitivity (94.7–100.0%), whereas specificity varied considerably (90.9–100.0%). The recombinant antigen fluorescence immunoassay demonstrated the best sensitivity/specificity [49]. Healthy individuals may have circulating antibodies against GBM belonging to IgG2 and IgG4 subclasses. With the onset of clinical disease, IgG1 and IgG3 subclasses increase and levels may correlate with disease severity [25,50]. A study by Yang et al. indicated that higher levels of circulating antiGBM antibodies against the epitopes EA and EB occurred in patients whose renal disease was more severe and that these patients had a worse prognosis. Correlation was noted between the levels of antiGBM antibodies and the serum creatinine at diagnosis and the presence of oliguria. Correlation existed between the percentage of crescents on biopsy and levels of antibodies, but it was significant only for anti-EA antibodies (P b .05) [51].
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as many as 18% of patients may have normal findings on chest radiographs. The consolidation resolves over 2–3 days, and it gradually progresses to an interstitial pattern as patients experience repeated episodes of hemorrhage. Pleural effusions are unusual. 5.6. Biopsy In patients with evidence of diffuse alveolar hemorrhage and renal involvement, kidney biopsy should be considered to identify the underlying cause and to help direct therapy. Percutaneous kidney biopsy is the preferred invasive procedure to substantiate the diagnosis of antiGBM disease. Renal biopsy provides a significantly higher yield than lung biopsy, but transbronchial or open lung biopsy may be performed in cases where renal biopsy cannot be performed. The biopsy tissue must be processed for light microscopy, immunofluorescence, and electron microscopy. Light microscopy demonstrates nonspecific features of a proliferative 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 bright linear deposits of immunoglobulin G (IgG), as seen in the Fig. 3b, and complement (C3) along the glomerular basement membranes. Subclass IgG-1 predominates [56] [Fig. 3]. Lung biopsy shows extensive hemorrhage with accumulation of hemosiderin-laden macrophages within alveolar spaces. Neutrophilic capillaritis, hyaline membranes, and diffuse alveolar damage may also be 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 urinary findings suggestive of an acute glomerulonephritis), the detection of circulating anti-glomerular basement membrane (anti-GBM) antibodies allows the clinician to make a firm diagnosis of anti-GBM disease. This obviates lung or kidney biopsy.
5.4. Antineutrophil cytoplasmic antibody testing At some time during the course of illness, as many as one third of patients with Goodpasture syndrome have circulating antineutrophil cytoplasmic antibodies (ANCAs) in addition to anti-GBM antibody [52]. In most cases, the ANCAs precede the development of anti-GBM antibodies by months to years [53]. It is postulated that the renal involvement in ANCA vasculitis leads to the exposure of antigens from the basement membrane and the formation of antibodies. These patients are referred to as double-positive. In majority of double-positive patients, 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 antibodies only. The renal survival in these patients is similar to antiGBM-positive patients and is worse compared with patients with MPO-ANCAs only. 5.5. Chest radiograph Characteristically, the chest film shows patchy parenchymal consolidations, which are usually bilateral, symmetric perihilar, and bibasilar [Fig. 2]. The apices and costophrenic angles are usually spared. However,
Fig. 2. Hemorrhagic alveolitis. Chest X-ray: low density multiple opacities with gradient aspect, distributed in both lungs with a tendency to confluence, mainly distributed in the central portions. From: Naticchia A et al. Sindromi pneumo-renali. G Ital Nefrol 2011; 28: 57–63.
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When the diagnosis remains in doubt, renal biopsy is the best method for detecting anti-GBM antibodies in tissues. Patients in whom the diagnosis of diffuse alveolar hemorrhage remains uncertain should undergo diagnostic bronchoscopy. 6. Differential diagnosis Conditions that affect the lung and kidney (pulmonary-renal syndromes) are important in the differential diagnosis. These include Wegener granulomatosis, systemic lupus erythematosus, microscopic polyangiitis, other forms of systemic vasculitides (Churg–Strauss syndrome, essential mixed cryoglobulinemia, Henoch–Schönlein purpura, microscopic polyarteritis, and undifferentiated connective-tissue disease), and other disorders (Pneumocystis carinii pneumonia, community-acquired, respiratory failure, and rheumatoid arthritis) [59,60]. Distinguishing Wegener granulomatosis from GS is particularly important. Interestingly, some patients with GS may present with antineutrophil cytoplasmic antibodies (ANCAs), which are predominantly observed in patients with Wegener granulomatosis [52,61]. Pulmonary-renal syndromes are less commonly a manifestation of IgA-mediated disorders (e.g., IgA nephropathy or Henoch–Schönlein purpura) and of immune complex-mediated renal disease (e.g., essential mixed cryoglobulinemia) [62]. Rarely, rapidly progressive glomerulonephritis alone can cause pulmonary-renal syndromes through a mechanism involving renal failure, volume overload, and pulmonary edema with hemoptysis. Careful attention to the medical history, physical examination, and targeted laboratory evaluation often suggests the underlying cause. 7. Prognosis Aggressive therapy with plasmapheresis, corticosteroids, and immunosuppressive agents has dramatically improved prognosis compared to the past, in which GS was fatal [63]. The 5-year survival rate exceeds 80% and fewer than 30% of patients require long-term dialysis. Patients presenting with serum creatinine levels greater than 4 mg/dL, oliguria, and more than 50% crescents on renal biopsy rarely recover. They usually progress to end-stage renal failure that requires long-term dialysis. In a retrospective analysis of patients with anti-GBM disease who started renal replacement therapy for end-stage renal disease (ESRD) in Australia and New Zealand (ANZDATA Registry), the median survival rate was 5.93 years with death predicted by older age and history of pulmonary hemorrhage [21]. In patients with both anti-GBM antibodies and MPO-ANCAs, histological findings differ from those of patients with anti-GBM antibodies only. The renal survival in these patients is similar to anti-
GBM-positive patients and is worse compared with patients with MPO-ANCAs only [64,65]. The prognosis depends on the timeline of diagnosis and treatment. Although some patients requiring dialysis may recover a good renal function, usually the higher the serum creatinine at presentation the worse the outcome. When treatment is initiated early, most patients obtain a complete or partial remission [7]. 8. Treatments Until today, no studies on the best treatment of the syndrome have been performed because of the rarity and also the sometimes late diagnosis of the syndrome. The correct diagnosis is the first important step for the correct treatment. Based on the hypothesis of being an autoimmune disease, treatment has to be immunosuppressive. High-dose corticosteroids and cyclophosphamide represent the standard therapy. The addition of plasma exchange is important, particularly in patients with massive alveolar hemorrhage. Anti-B monoclonal antibodies have also been used in some patients with crescentic GN, but their role in this particular area is still poorly established [7,66]. 8.1. Immunosuppressive therapy Immunosuppressive therapy is required to inhibit antibody production and rebound hypersynthesis, which may occur following discontinuation of plasma exchange [67–69]. Initial therapy includes cyclophosphamide at 2 mg/kg orally, adjusted to maintain a white blood cell count of approximately 5000, and corticosteroids (e.g., prednisone at 1–1.5 mg/kg). Treatment of acute life-threatening alveolar hemorrhage in patients with Goodpasture syndrome is with pulse methylprednisolone at 1 g/day for 3 days, followed by a gradual corticosteroid taper. Intravenous cyclophosphamide has begun concomitantly at 1 g/m2 and repeated 3–4 weeks later, depending on the recovery of bone marrow. The duration of immunosuppressive therapy is not well established. Anti-GBM antibody levels must be monitored at regular intervals. In patients who achieve a prompt remission, immunosuppression with cyclophosphamide is continued for 2–3 months and steroids for 6 months. Patients with clinically or serologically active disease at 3–4 months need longer immunosuppression (6–9 months). Azathioprine may be substituted for cyclophosphamide to reduce adverse effects, especially in patients needing prolonged immunosuppression. Rituximab, a chimeric monoclonal antibody, effectively depletes CD20-positive B cells over 6–9 months and has been used in several case reports as an alternative approach in the treatment of anti-GBM antibody disease. In these reports, rituximab was used as either an initial or a second-line agent in patients in whom cyclophosphamide failed
Fig. 3. Light microscopy and immunofluorescent findings on renal biopsy. (a) Fibrinoid necrosis of GBM, cellular crescentic formation, and slight periglomerular limpho-monocytic infiltration (PAS, ×400) and (b) Immunofluorescence: fine linear pattern along GBM stained with anti IgG antibody (×200). From: Bogdanović R et al. Pulmonary renal syndrome in a child with coexistence of anti-neutrophil cytoplasmic antibodies and anti-glomerular basement membrane disease: case report and literature review. BMC Nephrol. 2013; 14:66.
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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.
or yielded adverse effects. The anti-GBM antibodies became undetectable in all these patients, but they had variable renal outcomes [70,71]. Pneumocystis jiroveci pneumonia has an annual incidence of 1% but is a potentially deadly complication of immunosuppressive therapy in patients with Goodpasture syndrome. Prophylaxis with trimethoprimsulfamethoxazole (160 mg trimethoprim and 800 mg sulfamethoxazole 3 times per week) may be a cost-effective method of prolonging life in these patients. 8.2. Plasmapheresis In published case series and one randomized trial, plasmapheresis has been shown to be beneficial in the treatment of GS by removal of anti-GBM antibodies [57,68,72–74]. Plasmapheresis is generally instituted after the diagnosis of GS is established either by renal biopsy or by detection of anti-GBM antibodies. When a patient presents in a life-threatening situation secondary to pulmonary hemorrhage, however, plasmapheresis may be initiated if the diagnosis appears very likely, even though confirmation is not available immediately. The extent and duration of plasmapheresis is not known, but 4-liter plasma exchanges daily or every other day is usually performed. The plasmapheresis is continued for 2–3 weeks or until the patient's clinical course has improved and serum anti-GBM antibodies are not detected. 8.3. Renal transplantation Renal transplantation has been used for end-stage renal disease secondary to GS [75]. It is optimal to delay renal transplantation until antiGBM antibodies are undetectable in the serum for 12 months and the disease has been in remission for at least 6 months without the use of cytotoxic agents. Many patients develop linear deposits of IgG along glomeruli of the renal allograft. However, this development does not cause histologic or functional damage to the transplanted kidney. Interestingly anti-GBM disease can occur in approximately 3–5% of male patients who have hereditary nephritis (Alport syndrome) undergoing renal transplantation, known as de novo anti-GBM disease. Patients receiving renal transplants must be informed that anti-GBM disease can recur in the transplanted kidney, although graft loss due to this is very rare. 9. Conclusions GS is a rare autoimmune disorder characterized by the association of pulmonary hemorrhage, glomerulonephritis and extracapillary antibodies against the glomerular basement membrane. The disease is caused by autoantibodies against the NC1 domain of the alpha 3 chain of type IV collagen. The limited presence of this molecule in the body explains the interest confined to specific target organs, such as the lung and kidney.
It occurs when the immune system attacks the walls of the lungs and the tiny filtering units in the kidneys. Without prompt diagnosis and treatment, 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 antibodies using immunosuppression with medications; and (c) to remove offending agents that may have initiated the antibody production. The therapy with corticosteroids, cyclophosphamide and plasmapheresis allows obtaining a survival of the 75% in one year. Severe renal impairment and pulmonary hemorrhage may require urgent dialysis and/or assisted ventilation. It is very important to avoid fluid overload and to treat infections quickly. The renal survival at one year is greater than 90% for patients treated early, while it is less than 10% for those undergoing dialysis since the beginning of the treatment. 10 .Search strategy PubMed, Google Scholar, and Scopus were databases. Keywords were “Goodpasture syndrome”; “Goodpasture disease”; “anti-GBM disease”; “crescentic glomerulonephritis”; and “pulmonary-renal syndrome”. Inclusion criteria were: original article, case report, and review, with particular focus on the last five years (range: 2009–2014). Take-home messages • Goodpasture's syndrome is a rare disease characterized by crescentic glomerulonephritis accompanied by pulmonary hemorrhage that may be life-threatening. • It is an organ-specific autoimmune disease, mediated by anti-GBM antibodies. It is a possible genetic predisposition HLA-associated. The disease is caused by autoantibodies against the NC1 domain of the alpha 3 chain of type IV collagen. • Constitutional symptoms like malaise, chills and fever, and/or arthralgias may precede or be concurrent with pulmonary or renal manifestations. Initial symptoms may include fatigue, weakness, or lethargy nausea 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 antiGBM antibodies are valuable for confirming the diagnosis and monitoring the adequacy of therapy. • The 3 principles of therapy are the following: (a) to rapidly remove circulating antibody, primarily by plasmapheresis; (b) to stop further production of antibodies using immunosuppression with medications; and (c) to remove offending agents that may have initiated the antibody production. The therapy with corticosteroids, cyclophosphamide and plasmapheresis allows obtaining a survival of the 75% in one year.
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Anti-glomerular basement membrane antibodies in the diagnosis of Goodpasture syndrome: a comparison of different assays. Nephrol Dial Transplant 2006;21:397–401. Qu Z, Cui Z, Liu G, Zhao MH. The distribution of IgG subclass deposition on renal tissues from patients with anti-glomerular basement membrane disease. BMC Immunol 2013;14:19. Yang R, Hellmark T, Zhao J, et al. Levels of epitope-specific autoantibodies correlate with renal damage in anti-GBM disease. Nephrol Dial Transplant 2009;24:1838–44. Weber MF, Andrassy K, Pullig O, Koderisch J, Netzer K. Antineutrophilcytoplasmic antibodies and antiglomerular basement membrane antibodies in Goodpasture's syndrome and in Wegener's granulomatosis. J Am Soc Nephrol 1992;2:1227–34. Olson SW, Arbogast CB, Baker TP, et al. Asymptomatic autoantibodies associate with future anti-glomerular basement membrane disease. J Am Soc Nephrol 2011;22: 1946–52. Levy JB, Hammad T, Coulthart A, Dougan T, Pusey CD. 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New insights into Chlamydia and arthritis. Promise of a cure? Chlamydia trachomatis and Chlamydia pneumoniae together comprise the most frequent causative pathogens that elicit reactive arthritis (ReA). Advances in their understanding of the molecular biology/molecular genetics of these organisms have improved significantly the ability to detect chlamydiae in the joint for diagnostic purposes, as well as extending their current understanding of the pathogenic processes they elicit in the joint and elsewhere. An important aspect of the latter is that synovial chlamydiae infect the joint in an unusual but metabolically active state. While some standard treatments can provide a palliative effect on the ReA disease phenotype, many reports have indicated that standard antibiotic treatment does not provide a cure. Of critical importance, however, two recent reports of controlled clinical trials demonstrated that Chlamydia-ReA can be treated successfully using combination antibiotic therapy. These observations offer the opportunity of a cure for this disease, thereby increasing the practical importance of awareness and diagnosis of the spondyloarthritis caused by Chlamydia. In this viewpoint, Zeidler H. and Hudson AP. (Ann Rheum Dis. 2014; 73(4): 637-44) provide an overview of recent key findings in the epidemiology, pathophysiology, clinical manifestations, diagnosis and treatment of Chlamydia-induced arthritis. Their intention is for these insights to be translated rapidly into clinical practice to overcome misdiagnosis and under diagnosis of the disease, and for them to stimulate the continued development of a cure.
Contents lists available at ScienceDirect
Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
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, Italy Department of Surgical Science, 'Sapienza' University of Rome, Viale del Policlinico 155, 00100 Roma, Italy Department of Medico-Surgical Sciences and Biotechnologies, Otorhinolaryngology Section, 'Sapienza' University of Rome, Corso della Repubblica, 79, 04100 Latina, LT, Italy d Department Organs of Sense, Audiology Section, 'Sapienza' University of Rome, Viale del Policlinico 155, 00100 Roma, Italy b c
a r t i c l e
i n f o
Article history: Received 2 November 2014 Accepted 9 November 2014 Available online 15 November 2014 Keywords: Goodpasture syndrome Anti-GBM disease Crescentic glomerulonephritis Pulmonary-renal syndrome Anti-GBM antibodies ANCAs
a b s t r a c t Goodpasture's syndrome (GS) is a rare and organ-specific autoimmune disease that is mediated by anti-glomerular basement membrane (anti-GBM) antibodies and has pathology characterized by crescentic glomerulonephritis with linear immunofluorescent staining for IgG on the GBM. It typically presents as acute renal failure caused by a rapidly progressive glomerulonephritis, accompanied by pulmonary hemorrhage that may be lifethreatening. 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 predisposition HLA-associated. Complex immunological mechanisms are in the pathogenesis. The disease is caused by autoantibodies against the NC1 domain of the alpha 3 chain of type IV collagen. The limited presence of this molecule in the body explains the interest confined to specific target organs, such as the lung and kidney. It occurs when the immune system attacks the walls of the lungs and the tiny filtering units in the kidneys. Without prompt diagnosis and treatment, the disease can lead to bleeding in the lungs, kidney failure, and even death. © 2014 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . Symptomatology . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . 5.1. Physical examination . . . . . . . . . . . 5.2. Blood and urine testing . . . . . . . . . . 5.3. Anti-GBM antibody testing . . . . . . . . 5.4. Antineutrophil cytoplasmic antibody testing 5.5. Chest radiograph . . . . . . . . . . . . 5.6. Biopsy . . . . . . . . . . . . . . . . . 5.7. Lung hemorrhage . . . . . . . . . . . . 6. Differential diagnosis . . . . . . . . . . . . . . 7. Prognosis . . . . . . . . . . . . . . . . . . . 8. Treatments . . . . . . . . . . . . . . . . . . 8.1. Immunosuppressive therapy . . . . . . . 8.2. Plasmapheresis . . . . . . . . . . . . . 8.3. Renal transplantation . . . . . . . . . . 9. Conclusions . . . . . . . . . . . . . . . . . . 10. Search strategy . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .
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⁎ 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 49976803. E-mail address: [email protected] (A. De Virgilio).
http://dx.doi.org/10.1016/j.autrev.2014.11.006 1568-9972/© 2014 Elsevier B.V. All rights reserved.
A. Greco et al. / Autoimmunity Reviews 14 (2015) 246–253
1. Introduction Goodpasture's syndrome (GS) is a rare disease, identified by Dr. Ernest Goodpasture in 1919 [1,2]. It is an organ-specific autoimmune disease that is mediated by anti-glomerular basement membrane (anti-GBM) antibodies and has pathology characterized by crescentic glomerulonephritis with linear immunofluorescent staining for IgG on the GBM. It typically presents as acute renal failure caused by a rapidly progressive glomerulonephritis, accompanied by pulmonary hemorrhage, that may be life-threatening [3–6]. Other acronyms and names include Goodpasture's disease, antiGBM disease and crescentic glomerulonephritis type 1 [7–11]. Numerous reports of single patients with this disorder, as well as small case series, have been published [12–20]. There is the lack of systematic data on GS.
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in white populations. It is therefore clear that additional factors, either genetic or environmental, are required for disease expression [30–33]. While the exact cause of GS is unknown, certain behaviors and environmental factors are believed to put people at higher risk. Certain respiratory infections may trigger the disease. Exposure to hydrocarbon fumes, metallic dust, tobacco smoke, or substances such as cocaine may also increase risk. The recent literature shows that an initial insult to the pulmonary vasculature is required for exposure of the alveolar capillaries to the anti-GBM antibodies, and predisposing factors for such exposure include the following: association with HLA-DR15; exposure to organic solvents or hydrocarbons; smoking; infection (e.g., influenza A2); cocaine inhalation; exposure to metal dusts; and lymphocyte-depletion therapy, such as alemtuzumab [34–39]. 4. Symptomatology
2. Epidemiology The incidence of GS is estimated to be 1 case per million per year, but it is a cause of acute renal failure in approximately 20% of all cases of rapidly progressive or crescentic glomerulonephritis [21]. This disorder occurs more commonly in white people than in black people. The age distribution is bimodal, 20–30 years and 60–70 years. The prevalence of the disease is higher in men in the younger age group and women in the older age subgroup [22]. 3. Etiopathogenesis In the 1950s, Krakower and Greenspon [23] identified GBM as the antigen. In 1967, Lerner, Glassock, and Dixon [24] confirmed that the antibodies taken from the diseased kidneys produced nephritis in experimental animals. The discovery of anti-GBM antibodies led to the understanding of the pathogenesis of GS. GS or Anti-GBM disease is an autoimmune disorder characterized by autoantibodies directed against the glomerular/alveolar basement membrane. The autoantibodies bind to their reactive epitopes in the basement membranes and activate the complement cascade, resulting in tissue injury. This is a classic type II reaction in the Gell and Coombs classification of antigen–antibody reactions. This binding of antibodies can be visualized as the linear deposition of immunoglobulin along the glomerular basement membrane and, less commonly, the alveolar basement membranes, by direct immunofluorescent techniques. In most patients, the autoantibody in GS is directed against a 28-kd monomeric subunit present within the noncollagenous domain of the alpha 3 chain of type IV collagen (alpha3[IV]NC1) [22–25]. Two conformational epitopes of anti-GBM antibodies have been defined at residues 17–31 and 127–141 of alpha3(IV)NC1, which were named as EA and EB, respectively [Fig. 1]. Although basement membranes are ubiquitous, only the alveolar and glomerular basement membranes are affected clinically. The preferential binding to the alveolar and glomerular basement membranes appears to be caused by greater accessibility of epitopes and greater expansion of alpha 3 collagen units. Furthermore, the alpha 3 collagen chains of glomerular and basement membranes are structurally integrated in such a way that they are more accessible to the circulating antibodies [26,27]. Strong evidence exists that genetics play an important role. Patients with specific human leukocyte antigen (HLA) types are more susceptible to disease and may have a worse prognosis. There is an increased prevalence of HLA-DR15 (previously known as HLA-DR2) and DRB1*03, DRB1*04 and a decreased frequency of DRB1*01 and DRB1*07 [28,29]. Goodpasture disease is strongly associated with the DRB1*1501 and to a lesser extent the DRB1*1502 allele. Although a strong association exists between anti-GBM disease and HLA DRB1*1501, this allele is present in as many as one third of individuals
Symptoms may start out slowly, gradually affecting the lungs and the kidneys. Other times they may progress rapidly, becoming severe in a matter of days. Constitutional symptoms like malaise, chills and fever, and/or arthralgias may precede or be concurrent with pulmonary or renal manifestations. Initial symptoms may include fatigue, weakness, or lethargy nausea and/or vomiting, loss of appetite, unhealthy, pale appearance. Substantial variation exists in the clinical manifestations of patients with anti-GBM disease. 60 to 80% of the patients have clinically apparent manifestations of pulmonary and renal disease, 20–40% have renal disease alone, and less than 10% have disease that is limited to the lungs [40–43]. If the disease moves to affect the lungs, hemoptysis is usually the presenting symptom and the following symptoms like dry cough or coughing 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 failure. Chest pain is present in less than half of the patients. Significant anemia may result from persistent intrapulmonary bleeding. If the disease affects the kidneys, it may cause burning sensation during urination, hematuria or foamy urine, swelling of the hands and feet, high blood pressure, and back pain below the ribs. Other renal manifestations include edema and eventually uremia. Autoimmune Inner Ear Disease (AIED) is present in the same cases [44,45]. The symptoms of AIED are sudden hearing loss in one ear [46] progressing rapidly to the second ear. The hearing loss can progress over weeks or months. Patients may feel fullness in the ear and experience vertigo [47]. In addition, a ringing, hissing, or roaring sound in the ear may be experienced [44,45]. 5. Diagnosis Diagnosis of GS is made by detection of circulating anti-GBM antibodies, and more specifically, the anti-α3(IV) NC1 antibodies on solid-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 extensive crescent formation with interstitial inflammation. The pathognomonic finding on direct immunofluorescence is the linear deposition of immunoglobulin G (IgG) along the GBM and sometimes along the distal tubular basement [48]. Diagnosis of AIED-Goodpasture-associated is difficult and AIED is often mistaken for otitis media until the patient develops a loss in the second ear [44,45]. 5.1. Physical examination Physical examination findings in patients with anti-GBM disease include the following: tachypnea; inspiratory crackles over lung bases;
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Fig. 1. Topology of the EA and EB regions in the α345 noncollagenous-1 hexamer, structural determinants for the binding of Alport alloantibodies and Goodpasture 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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cyanosis; hepatosplenomegaly; hypertension; rash; and edema. First, it is necessary to check for high blood pressure, bleeding, abnormal heart and lung sounds, and medical history. 5.2. Blood and urine testing Anemia may be observed secondary to iron deficiency caused by intrapulmonary bleeding. Leukocytosis is commonly present. A blood test can show a high level of waste products, which may indicate kidney problems. Elevated blood urea nitrogen (BUN) and serum creatinine levels secondary to renal dysfunction may be present. A blood test may show the presence of antibodies that indicate the presence of the disease. Urinalysis findings are characteristic of acute glomerulonephritis, usually demonstrating low-grade proteinuria, gross or microscopic hematuria, and red blood cell casts. 5.3. Anti-GBM antibody testing Serologic assays for anti-GBM antibodies are valuable for confirming the diagnosis and monitoring the adequacy of therapy. Radioimmunoassays or enzyme-linked immunosorbent assays (ELISAs) for antiGBM antibodies are highly sensitive (N 95%) and specific (N97%). Positive results should be confirmed by western blotting on collagenasesolubilized human GBM, especially if a kidney biopsy is not being performed. In a comparison study of 4 immunoassay-based anti-GBM antibody kits, all the assays showed comparably good sensitivity (94.7–100.0%), whereas specificity varied considerably (90.9–100.0%). The recombinant antigen fluorescence immunoassay demonstrated the best sensitivity/specificity [49]. Healthy individuals may have circulating antibodies against GBM belonging to IgG2 and IgG4 subclasses. With the onset of clinical disease, IgG1 and IgG3 subclasses increase and levels may correlate with disease severity [25,50]. A study by Yang et al. indicated that higher levels of circulating antiGBM antibodies against the epitopes EA and EB occurred in patients whose renal disease was more severe and that these patients had a worse prognosis. Correlation was noted between the levels of antiGBM antibodies and the serum creatinine at diagnosis and the presence of oliguria. Correlation existed between the percentage of crescents on biopsy and levels of antibodies, but it was significant only for anti-EA antibodies (P b .05) [51].
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as many as 18% of patients may have normal findings on chest radiographs. The consolidation resolves over 2–3 days, and it gradually progresses to an interstitial pattern as patients experience repeated episodes of hemorrhage. Pleural effusions are unusual. 5.6. Biopsy In patients with evidence of diffuse alveolar hemorrhage and renal involvement, kidney biopsy should be considered to identify the underlying cause and to help direct therapy. Percutaneous kidney biopsy is the preferred invasive procedure to substantiate the diagnosis of antiGBM disease. Renal biopsy provides a significantly higher yield than lung biopsy, but transbronchial or open lung biopsy may be performed in cases where renal biopsy cannot be performed. The biopsy tissue must be processed for light microscopy, immunofluorescence, and electron microscopy. Light microscopy demonstrates nonspecific features of a proliferative 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 bright linear deposits of immunoglobulin G (IgG), as seen in the Fig. 3b, and complement (C3) along the glomerular basement membranes. Subclass IgG-1 predominates [56] [Fig. 3]. Lung biopsy shows extensive hemorrhage with accumulation of hemosiderin-laden macrophages within alveolar spaces. Neutrophilic capillaritis, hyaline membranes, and diffuse alveolar damage may also be 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 urinary findings suggestive of an acute glomerulonephritis), the detection of circulating anti-glomerular basement membrane (anti-GBM) antibodies allows the clinician to make a firm diagnosis of anti-GBM disease. This obviates lung or kidney biopsy.
5.4. Antineutrophil cytoplasmic antibody testing At some time during the course of illness, as many as one third of patients with Goodpasture syndrome have circulating antineutrophil cytoplasmic antibodies (ANCAs) in addition to anti-GBM antibody [52]. In most cases, the ANCAs precede the development of anti-GBM antibodies by months to years [53]. It is postulated that the renal involvement in ANCA vasculitis leads to the exposure of antigens from the basement membrane and the formation of antibodies. These patients are referred to as double-positive. In majority of double-positive patients, 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 antibodies only. The renal survival in these patients is similar to antiGBM-positive patients and is worse compared with patients with MPO-ANCAs only. 5.5. Chest radiograph Characteristically, the chest film shows patchy parenchymal consolidations, which are usually bilateral, symmetric perihilar, and bibasilar [Fig. 2]. The apices and costophrenic angles are usually spared. However,
Fig. 2. Hemorrhagic alveolitis. Chest X-ray: low density multiple opacities with gradient aspect, distributed in both lungs with a tendency to confluence, mainly distributed in the central portions. From: Naticchia A et al. Sindromi pneumo-renali. G Ital Nefrol 2011; 28: 57–63.
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When the diagnosis remains in doubt, renal biopsy is the best method for detecting anti-GBM antibodies in tissues. Patients in whom the diagnosis of diffuse alveolar hemorrhage remains uncertain should undergo diagnostic bronchoscopy. 6. Differential diagnosis Conditions that affect the lung and kidney (pulmonary-renal syndromes) are important in the differential diagnosis. These include Wegener granulomatosis, systemic lupus erythematosus, microscopic polyangiitis, other forms of systemic vasculitides (Churg–Strauss syndrome, essential mixed cryoglobulinemia, Henoch–Schönlein purpura, microscopic polyarteritis, and undifferentiated connective-tissue disease), and other disorders (Pneumocystis carinii pneumonia, community-acquired, respiratory failure, and rheumatoid arthritis) [59,60]. Distinguishing Wegener granulomatosis from GS is particularly important. Interestingly, some patients with GS may present with antineutrophil cytoplasmic antibodies (ANCAs), which are predominantly observed in patients with Wegener granulomatosis [52,61]. Pulmonary-renal syndromes are less commonly a manifestation of IgA-mediated disorders (e.g., IgA nephropathy or Henoch–Schönlein purpura) and of immune complex-mediated renal disease (e.g., essential mixed cryoglobulinemia) [62]. Rarely, rapidly progressive glomerulonephritis alone can cause pulmonary-renal syndromes through a mechanism involving renal failure, volume overload, and pulmonary edema with hemoptysis. Careful attention to the medical history, physical examination, and targeted laboratory evaluation often suggests the underlying cause. 7. Prognosis Aggressive therapy with plasmapheresis, corticosteroids, and immunosuppressive agents has dramatically improved prognosis compared to the past, in which GS was fatal [63]. The 5-year survival rate exceeds 80% and fewer than 30% of patients require long-term dialysis. Patients presenting with serum creatinine levels greater than 4 mg/dL, oliguria, and more than 50% crescents on renal biopsy rarely recover. They usually progress to end-stage renal failure that requires long-term dialysis. In a retrospective analysis of patients with anti-GBM disease who started renal replacement therapy for end-stage renal disease (ESRD) in Australia and New Zealand (ANZDATA Registry), the median survival rate was 5.93 years with death predicted by older age and history of pulmonary hemorrhage [21]. In patients with both anti-GBM antibodies and MPO-ANCAs, histological findings differ from those of patients with anti-GBM antibodies only. The renal survival in these patients is similar to anti-
GBM-positive patients and is worse compared with patients with MPO-ANCAs only [64,65]. The prognosis depends on the timeline of diagnosis and treatment. Although some patients requiring dialysis may recover a good renal function, usually the higher the serum creatinine at presentation the worse the outcome. When treatment is initiated early, most patients obtain a complete or partial remission [7]. 8. Treatments Until today, no studies on the best treatment of the syndrome have been performed because of the rarity and also the sometimes late diagnosis of the syndrome. The correct diagnosis is the first important step for the correct treatment. Based on the hypothesis of being an autoimmune disease, treatment has to be immunosuppressive. High-dose corticosteroids and cyclophosphamide represent the standard therapy. The addition of plasma exchange is important, particularly in patients with massive alveolar hemorrhage. Anti-B monoclonal antibodies have also been used in some patients with crescentic GN, but their role in this particular area is still poorly established [7,66]. 8.1. Immunosuppressive therapy Immunosuppressive therapy is required to inhibit antibody production and rebound hypersynthesis, which may occur following discontinuation of plasma exchange [67–69]. Initial therapy includes cyclophosphamide at 2 mg/kg orally, adjusted to maintain a white blood cell count of approximately 5000, and corticosteroids (e.g., prednisone at 1–1.5 mg/kg). Treatment of acute life-threatening alveolar hemorrhage in patients with Goodpasture syndrome is with pulse methylprednisolone at 1 g/day for 3 days, followed by a gradual corticosteroid taper. Intravenous cyclophosphamide has begun concomitantly at 1 g/m2 and repeated 3–4 weeks later, depending on the recovery of bone marrow. The duration of immunosuppressive therapy is not well established. Anti-GBM antibody levels must be monitored at regular intervals. In patients who achieve a prompt remission, immunosuppression with cyclophosphamide is continued for 2–3 months and steroids for 6 months. Patients with clinically or serologically active disease at 3–4 months need longer immunosuppression (6–9 months). Azathioprine may be substituted for cyclophosphamide to reduce adverse effects, especially in patients needing prolonged immunosuppression. Rituximab, a chimeric monoclonal antibody, effectively depletes CD20-positive B cells over 6–9 months and has been used in several case reports as an alternative approach in the treatment of anti-GBM antibody disease. In these reports, rituximab was used as either an initial or a second-line agent in patients in whom cyclophosphamide failed
Fig. 3. Light microscopy and immunofluorescent findings on renal biopsy. (a) Fibrinoid necrosis of GBM, cellular crescentic formation, and slight periglomerular limpho-monocytic infiltration (PAS, ×400) and (b) Immunofluorescence: fine linear pattern along GBM stained with anti IgG antibody (×200). From: Bogdanović R et al. Pulmonary renal syndrome in a child with coexistence of anti-neutrophil cytoplasmic antibodies and anti-glomerular basement membrane disease: case report and literature review. BMC Nephrol. 2013; 14:66.
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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.
or yielded adverse effects. The anti-GBM antibodies became undetectable in all these patients, but they had variable renal outcomes [70,71]. Pneumocystis jiroveci pneumonia has an annual incidence of 1% but is a potentially deadly complication of immunosuppressive therapy in patients with Goodpasture syndrome. Prophylaxis with trimethoprimsulfamethoxazole (160 mg trimethoprim and 800 mg sulfamethoxazole 3 times per week) may be a cost-effective method of prolonging life in these patients. 8.2. Plasmapheresis In published case series and one randomized trial, plasmapheresis has been shown to be beneficial in the treatment of GS by removal of anti-GBM antibodies [57,68,72–74]. Plasmapheresis is generally instituted after the diagnosis of GS is established either by renal biopsy or by detection of anti-GBM antibodies. When a patient presents in a life-threatening situation secondary to pulmonary hemorrhage, however, plasmapheresis may be initiated if the diagnosis appears very likely, even though confirmation is not available immediately. The extent and duration of plasmapheresis is not known, but 4-liter plasma exchanges daily or every other day is usually performed. The plasmapheresis is continued for 2–3 weeks or until the patient's clinical course has improved and serum anti-GBM antibodies are not detected. 8.3. Renal transplantation Renal transplantation has been used for end-stage renal disease secondary to GS [75]. It is optimal to delay renal transplantation until antiGBM antibodies are undetectable in the serum for 12 months and the disease has been in remission for at least 6 months without the use of cytotoxic agents. Many patients develop linear deposits of IgG along glomeruli of the renal allograft. However, this development does not cause histologic or functional damage to the transplanted kidney. Interestingly anti-GBM disease can occur in approximately 3–5% of male patients who have hereditary nephritis (Alport syndrome) undergoing renal transplantation, known as de novo anti-GBM disease. Patients receiving renal transplants must be informed that anti-GBM disease can recur in the transplanted kidney, although graft loss due to this is very rare. 9. Conclusions GS is a rare autoimmune disorder characterized by the association of pulmonary hemorrhage, glomerulonephritis and extracapillary antibodies against the glomerular basement membrane. The disease is caused by autoantibodies against the NC1 domain of the alpha 3 chain of type IV collagen. The limited presence of this molecule in the body explains the interest confined to specific target organs, such as the lung and kidney.
It occurs when the immune system attacks the walls of the lungs and the tiny filtering units in the kidneys. Without prompt diagnosis and treatment, 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 antibodies using immunosuppression with medications; and (c) to remove offending agents that may have initiated the antibody production. The therapy with corticosteroids, cyclophosphamide and plasmapheresis allows obtaining a survival of the 75% in one year. Severe renal impairment and pulmonary hemorrhage may require urgent dialysis and/or assisted ventilation. It is very important to avoid fluid overload and to treat infections quickly. The renal survival at one year is greater than 90% for patients treated early, while it is less than 10% for those undergoing dialysis since the beginning of the treatment. 10 .Search strategy PubMed, Google Scholar, and Scopus were databases. Keywords were “Goodpasture syndrome”; “Goodpasture disease”; “anti-GBM disease”; “crescentic glomerulonephritis”; and “pulmonary-renal syndrome”. Inclusion criteria were: original article, case report, and review, with particular focus on the last five years (range: 2009–2014). Take-home messages • Goodpasture's syndrome is a rare disease characterized by crescentic glomerulonephritis accompanied by pulmonary hemorrhage that may be life-threatening. • It is an organ-specific autoimmune disease, mediated by anti-GBM antibodies. It is a possible genetic predisposition HLA-associated. The disease is caused by autoantibodies against the NC1 domain of the alpha 3 chain of type IV collagen. • Constitutional symptoms like malaise, chills and fever, and/or arthralgias may precede or be concurrent with pulmonary or renal manifestations. Initial symptoms may include fatigue, weakness, or lethargy nausea 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 antiGBM antibodies are valuable for confirming the diagnosis and monitoring the adequacy of therapy. • The 3 principles of therapy are the following: (a) to rapidly remove circulating antibody, primarily by plasmapheresis; (b) to stop further production of antibodies using immunosuppression with medications; and (c) to remove offending agents that may have initiated the antibody production. The therapy with corticosteroids, cyclophosphamide and plasmapheresis allows obtaining a survival of the 75% in one year.
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New insights into Chlamydia and arthritis. Promise of a cure? Chlamydia trachomatis and Chlamydia pneumoniae together comprise the most frequent causative pathogens that elicit reactive arthritis (ReA). Advances in their understanding of the molecular biology/molecular genetics of these organisms have improved significantly the ability to detect chlamydiae in the joint for diagnostic purposes, as well as extending their current understanding of the pathogenic processes they elicit in the joint and elsewhere. An important aspect of the latter is that synovial chlamydiae infect the joint in an unusual but metabolically active state. While some standard treatments can provide a palliative effect on the ReA disease phenotype, many reports have indicated that standard antibiotic treatment does not provide a cure. Of critical importance, however, two recent reports of controlled clinical trials demonstrated that Chlamydia-ReA can be treated successfully using combination antibiotic therapy. These observations offer the opportunity of a cure for this disease, thereby increasing the practical importance of awareness and diagnosis of the spondyloarthritis caused by Chlamydia. In this viewpoint, Zeidler H. and Hudson AP. (Ann Rheum Dis. 2014; 73(4): 637-44) provide an overview of recent key findings in the epidemiology, pathophysiology, clinical manifestations, diagnosis and treatment of Chlamydia-induced arthritis. Their intention is for these insights to be translated rapidly into clinical practice to overcome misdiagnosis and under diagnosis of the disease, and for them to stimulate the continued development of a cure.
