Review

Goodpasture syndrome and anti-glomerular basement

membrane disease
F. Reggiani1,2, V. L’Imperio3, M. Calatroni1,2, F. Pagni3, R.A. Sinico2

1
Department of Biomedical Sciences, ABSTRACT tibodies (1). Most patients present with
Humanitas University, Anti-glomerular basement membrane alveolar haemorrhage and rapidly pro-
Pieve Emanuele, Milan; (anti-GBM) disease is a rare life-threat- gressive crescentic glomerulonephritis
2
Nephrology and Dialysis Unit,
ening small-vessel vasculitis that typi- that, if untreated, progresses quickly to
IRCCS Humanitas Research Hospital,
Rozzano, Milan; cally affects the capillaries of kidneys end-stage kidney disease (ESKD) (2).
3
Department of Medicine and Surgery, and lungs, with most of patients devel- The first description of this disease was
Pathology, University of Milano-Bicocca, oping rapidly progressive crescentic made in 1958 by Stanton and Tange (3).
IRCCS (Scientific Institute for Research, glomerulonephritis, and 40–60% con- They called it Goodpasture syndrome
Hospitalisation and Healthcare) comitant alveolar haemorrhage. It is in honour of Doctor Ernest William
Fondazione San Gerardo dei Tintori, caused by the deposition in alveolar and Goodpasture, which first described a
Monza, Italy.
glomerular basement membrane of cir- patient with haemoptysis and acute
Francesco Reggiani, MD culating autoantibodies directed against glomerulonephritis, both considered
Vincenzo L’Imperio, MD
antigens intrinsic to the basement mem- complications of an atypical infection
Marta Calatroni, MD
Fabio Pagni, MD brane. The exact mechanism that in- (4). The term Goodpasture syndrome
Renato Alberto Sinico, MD duces the formation of autoantibodies was thereafter used for several years to
Please address correspondence to: is unknown, but probably environmen- appoint pulmonary-renal involvement
Renato Alberto Sinico tal factors, infections or direct damage in the presence of anti-GBM antibod-
Division di Nefrologia e Dialisi, to kidneys and lungs may trigger the ies. However, nowadays the preferred
Istituto Clinico IRCCS, autoimmune response in genetically term is anti-GBM disease since after-
Via Manzoni 56, susceptible individuals. Initial therapy wards also atypical forms of this dis-
20089 Rozzano (MI), Italy. includes corticosteroids and cyclophos- ease have been described (5).
E-mail: [Link]@[Link]
phamide to prevent autoantibodies pro-
Received on March 15, 2023; accepted duction, and plasmapheresis to remove Epidemiology
on March 20, 2023.
the circulating autoantibodies. Good Anti-GBM disease is a rare small-
Clin Exp Rheumatol 2023; 41: 964-974. renal outcomes may be achieved by a vessel vasculitis and it is the cause of
© Copyright Clinical and prompt treatment initiation. However, 1–2% of acute glomerulonephritis and
Experimental Rheumatology 2023.
when patients present with severe renal 10–15% of rapidly progressive cres-
failure requiring dialysis or with a high centic glomerulonephritis (2). Among
Key words: Goodpasture syndrome, proportion of glomerular crescents at European and Asian populations, the
anti-GBM disease, crescentic biopsy, renal outcomes are bad. Relaps- incidence of anti-GBM disease is esti-
glomerulonephritis, alveolar es are rare and when renal involvement mated to be between 0.5 and 1.8 cases
haemorrhage, anti-GBM antibodies is present, the suspect of concomitant per million population per year (2,
diseases, such as ANCA-associated vas- 6-8). In United States, the prevalence
culitis and membranous nephropathy, of anti-GBM disease is 10 cases per
should be raised. Imlifidase is showing million hospitalised patients (9). Anti-
promising results, which if confirmed GBM disease has been described in
will cause a paradigm shift in the treat- White and Asian individuals, while it
ment of this disease. seems rarer in African individuals. Age
distribution is bimodal, with a peak in-
Introduction cidence in the third decade, when there
Anti-glomerular basement membrane is a slight male predominance, and in
(anti-GBM) disease is a rare life-threat- the six decade, when it affects mainly
ening small-vessel vasculitis that af- females (10-13). Patients younger than
fects pulmonary capillaries, glomerular 30 years more frequently present with
capillaries or both, caused by the depo- lung involvement, while patients older
sition in alveolar and glomerular base- than 50 years are more likely to present
Competing interests: none declared. ment membrane of circulating autoan- with isolated renal involvement (14).

964 Clinical and Experimental Rheumatology 2023

 Goodpasture syndrome and anti-GBM disease / F. Reggiani et al.

Fig. 1. Schematic representation of anti-GBM antibodies development.

EA and EB epitopes of α3 collagen chain are normally hidden inside the collagenous structure of the alveolar and glomerular basement membrane (GBM),
which is held together by disulfide bonds across NC1 domains (red lines). Several environmental factors, such as smoking, hydrocarbon exposure, and infec-
tions, together with kidney injury, cause the disruption of hexamer structure and exposure of the hidden antigens. In patients with genetic predisposition this
process may lead to the development of anti-GBM autoantibodies.
AAV: ANCA-associated vasculitis; alpha-3(IV) NC: noncollagenous (NC1) domain of the alpha-3 chain of type IV collagen; HLA: human leukocyte anti-
gens; MN: membranous nephropathy.

Pathogenesis peroxidase that contributes to the for- oxidase (anti-MPO Abs) compared to
Anti-GBM disease is an autoimmune mation of the sulfonimine cross-links antibodies against proteinase-3 (anti-
disorder caused by circulating autoan- in the NC1 domain (25), which may PR3 Abs) (14, 27). It has been demon-
tibodies directed against an antigen in- be disrupted by autoantibodies directed strated that ANCAs positivity precedes
trinsic to GBM (Fig. 1). In the common against peroxidasin, causing the expo- the appearance of anti-GBM antibod-
form of anti-GBM disease, the autoan- sure of cryptic epitopes (23). Laminin ies, suggesting a possible role of AN-
tibody is a polyclonal immunoglobulin is a family of αβγ heterotrimeric glyco- CAs in exposing the cryptic epitopes
G (IgG), with IgG1 and IgG3 subclass- proteins that are abundant components (28).
es predominant, that target the epitopes of all basement membranes. LM521 is Anti-GBM disease is frequently of
EA and EB of the noncollagenous (NC1) the major isoform in the mature GBM unknown aetiology. There is increas-
domain of the alpha-3 chain of type IV and is also abundant in alveolar base- ing evidence that genetic susceptibil-
collagen (alpha-3(IV) NC) (15–17). ment membrane (ABM) (24). The role ity to anti-GBM disease is present, in
There are also rare cases in which IgG4 of antibodies against LM521 is still particular in patients with HLA-DR15
subclass and IgA (18, 19), or monoclo- not completely known. The nephrito- and -DR4, while DR1 and DR7 seems
nal immunoglobulins (20, 21), have genicity of these antibodies has been to be protective (29). Immune dysregu-
been described. Anti-GBM antibodies demonstrated in animal models (26). lation appears to predispose both the
may also target other alpha chains. A In humans, a retrospective study found release of autoantibodies that unveil
study demonstrated that antibodies that that antibodies against LM521 occur in hidden cryptic epitopes and anti-GBM
strongly bind to alpha-3(IV) NC may about one third of anti-GBM disease antibodies. Moreover, several triggers
also recognise alpha-5(IV) and, to a patients and are significantly associat- causing kidney or pulmonary injury,
lesser extent, alpha-4(IV) (22). Re- ed with lung involvement (24). Finally that favors the release of increased
cently, autoantibodies directed against also anti-neutrophil cytoplasmic anti- amounts of auto-antigen, have been
peroxidasin (23) and laminin-521 bodies (ANCAs) have been described described (13). Pulmonary infections
(LM521) (24) have been identified in in up to 21-47% of patients with anti- (30), smoking (22), hydrocarbon sol-
patients with positive anti-GBM anti- GBM disease, with a predominance of vent exposure and lung cancer have
bodies. Peroxidasin is an extracellular antibodies directed against myeloper- been identified as lung injury causes

Clinical and Experimental Rheumatology 2023 965

Goodpasture syndrome and anti-GBM disease / F. Reggiani et al.

microscopy, focal or diffuse crescentic

and/or necrotising glomerulonephritis
is typical (Fig. 3). 95% of patients will
have evidence of crescent formation
on kidney biopsy, and that in 80% of
patients more than half of glomeruli
will be affected (41, 42). Together with
this finding, various degrees of intra-
capillary proliferation or interstitial
inflammation may be present. Intra-
glomerular inflammation can finally
lead to Bowman capsule rupture, a po-
tentially irreversible damage that can
have prognostically unfavorable im-
pact, as already demonstrated in other
crescentic glomerulonephritis (43-45).
In advanced stages, the inflammatory
lesions may evolve to fibrous one,
generating fibrous crescents, glomeru-
Fig. 2. Schematic representation of the pathogenesis of anti-GBM glomerulonephritis. losclerosis, interstitial fibrosis, and/or
In the left panel antibodies (most frequently of the IgG1 and IgG3 subtype) are directed against the tubular atrophy (13). At immunofluo-
epitope EA and EB of the noncollagenous (NC1) domain of the alpha-3 chain of type IV collagen rescence, bright linear deposits of IgG1
(alpha-3(IV) NC) of the glomerular basement membranes (GBM). This phenomenon leads to the re-
cruitment of different inflammatory cells in the capillary loops of glomerular tuft (right panel), causing and IgG3 (rarely IgG4 or IgA) and C3
the disruption of GBM and capillary wall and extravasation of different cell types, with the formation are pathognomonic. Up to 1964, the
of crescentic glomerulonephritis. diagnosis of anti-GBM disease was
based on clinical data. After the advent
triggering anti-GBM disease develop- may be played by regulatory T cells of immunofluorescence, Scherr and
ment (22). Recently, a fivefold increase (CD4+ CD25+). These cells regulate the Grossman described this typical lin-
above the expected incidence was ob- autoimmune response countering the ear IgG deposition in GBM, changing
served in North-West London during effects of autoreactive T cells (37), in the history of this disease (46, 47). No
the severe acute respiratory syndrome particular T-helper1 (Th1) and T-helper electron-dense deposits are detected
coronavirus-2 (SARS-CoV-2) pandem- 17 (Th17), which play a role in cres- at electron microscopy, while signs of
ic, supporting the association between cent formation (38). In a murine model crescentic glomerulonephritis, such as
lung injury and anti-GBM disease de- of anti-GBM disease, regulatory T cells GBM rupture and extracapillary locali-
velopment (31). Ureteral obstruction, (CD4+ CD25+) reduced the severity of sation of fibrin and proliferating cells,
membranous nephropathy, ANCA-as- glomerular lesions (39). may be observed. Lung biopsy is not
sociated glomerulonephritis and litho- Anti-GBM antibody localisation in the routinely used in the diagnosis of anti-
tripsy have been described as potential basement membrane causes inflam- GBM disease. If performed, linear de-
triggers of kidney injury (2, 22). mation, activation of the complement posits of IgG along the ABM may be
Experimental and clinical studies sug- system and release of reactive oxy- observed, even if immunofluorescence
gested that also autoreactive T cells gen species. This inflammatory milieu on lung tissue is often not informative
may contribute to the development of causes the necrosis and the rupture of (2).
anti-GBM disease. In addition to en- the GBM. The subsequent leakage of
hancing B cell function and antibody proteins in the Bowman space deter- In search of the
production, T cells may have a direct mines the activation and proliferation anti-GBM antibody
causative role in alveolar and glomer- of parietal cells, which lose polarity. The demonstration of circulating or de-
ular injury (32). It has been demon- These events, together with lympho- posited anti-GBM antibodies is neces-
strated that T cells from patients with cyte and macrophage infiltration, cause sary for the diagnosis. In routine diag-
anti-GBM disease react against the the formation of cellular crescents (Fig. nostics, the alpha-3(IV) NC is utilised
alpha-3(IV) NC (33, 34). Moreover, 2) (13, 40). as substrate by various immunoassay
the T cell immune response may be formats, most notably enzyme-linked
triggered by specific T cells epitopes of Pathology immunoassay (ELISA) and indirect im-
alpha-3(IV) NC, which are presented The presence of crescents and the lo- munofluorescence tests, to detect anti-
by the major histocompatibility com- calisation of anti-GBM antibodies in GBM antibodies. The detection of anti-
plex (35, 36). This process was suffi- the basement membrane are the two GBM antibodies in serum using ELISA
cient to determine acute glomerulone- most important histological character- with the specificity of the antibody
phritis (35). Finally, an important role istics of anti-GBM disease. At light eventually confirmed by Western blot,

966 Clinical and Experimental Rheumatology 2023

 Goodpasture syndrome and anti-GBM disease / F. Reggiani et al.

lonephritis, the diagnosis of anti-GBM

disease is based on the detection of the
anti-GBM antibodies either in serum
or deposited in tissue, as described
above. Although lung involvement is
not always present, in the suspect of
alveolar haemorrhage radiological ex-
amination and broncho-alveolar lavage
are indicated. A characteristic feature
of alveolar bleeding is the presence of
haemosiderin-laden macrophages in the
broncho-alveolar lavage (53). Haemop-
tysis is not always evident, therefore
lung involvement should be suspected
even in the absence of haemophtoe if
severe anaemia is present (53).

“Atypical” anti-GBM disease

Unusual presentations of anti-GBM
disease have been described since the
discovery of this disease. Several cases
and series of less severe renal involve-
ment have been published (47, 54-57).
It’s still not clear whether these milder
cases represent a less frequent pheno-
typic expression of a disease with a wide
spectrum of severity or a distinct clinical
sub-phenotype determined by a different
Fig. 3. Histological features of anti-GBM glomerulonephritis on renal biopsy. pathogenesis (2). In a series of 20 pa-
A: Light microscopy shows the interruption of the GBM (white arrow) with deposition of fibrinoid necrosis tients with hematuria, proteinuria, mild
and consequent extravasation of different cellular elements forming circumferential cellular crescents, fi-
nally leading to the disruption of Bowman capsule (white arrowhead, Jones Methenamine silver stain, x20). kidney function impairment, and with-
B: Masson trichrome stain highlights fuchsinophilic areas corresponding to fibrinoid necrosis (white out pulmonary haemorrhage, kidney
asterisk) in a glomerulus globally involved by cellular crescent and periglomerular inflammation. biopsy showed bright, linear IgG depo-
C: Immunofluorescence demonstrates diffuse and global linear positivity of the capillary walls for IgG
sition along the GBM without features
antisera (3+, x20) in areas still spared from the GBM break and cellular crescents formation.
D: This is almost invariably associated with the deposition of C3 with the same pattern (2-3+, x20), with of crescentic glomerulonephritis. Mono-
focal extension to the Bowman capsule interrupted by the increase of intraglomerular inflammation. clonality was commonly observed and
anti-GBM antibodies were not detected
is the preferred technique, while indi- Moreover, it is a reliable and efficient with conventional assays (49). The au-
rect immunofluorescence is rarely per- fully automated process (52). thors hypothesised that differences in
formed (48). The sensitivity of ELISA antigen specificity, Ig subclass, and/or
varies depending upon the commercial Clinical presentation ability to recruit inflammatory cells may
kit used, ranging from 63 to nearly 100 and diagnosis account for the milder disease pheno-
percent (49, 50). False negative results “Typical” anti-GBM disease type (57). This hypothesis is supported
may occur, as in the case of low anti- Up to 80–90% of patients present also by the findings of a Swedish series,
body titres (51) or in the presence of with features of rapidly progressive in which four young females, who had
different immunoglobulins subclasses glomerulonephritis, characterised by severe lung disease but minimal kidney
(as IgA or IgG4) and/or antibodies tar- active urinary sediment analysis, sub- involvement, presented with IgG4 sub-
geting antigens different from alpha- nephrotic proteinuria and reduced uri- class anti-GBM antibodies, that were not
3(IV) NC (52). False-positive may re- nary output. 40–60% of patients will detectable with conventional anti-GBM
sult with commercial ELISA assays that have concurrent lung haemorrhage assays (19). The discrepancy between
do not use purified Goodpasture antigen with haemoptysis and various degrees positive linear staining for IgG in kidney
(15, 50). Recently, chemiluminescence of dyspnoea. A small minority of pa- biopsy and negative anti-GBM antibod-
immunoassay (ChLIA) has been pro- tients may present with isolated pul- ies may be explained by the fact that in
posed as a promising alternative tool monary disease. In few cases, patients “atypical” anti-GBM disease autoanti-
for accurate anti-GBM antibodies (IgG) present with severe acute kidney injury bodies may be directed against epitopes
assessment since it demonstrated sensi- requiring dialytic treatment (2). In the different from the common epitopes pre-
tivity of 100% at a specificity of 98.6%. presence of rapid progressive glomeru- sent in commercial immunoassays (51).

Clinical and Experimental Rheumatology 2023 967

Goodpasture syndrome and anti-GBM disease / F. Reggiani et al.

Other variants ANCA-associated vasculitis (27, 59, L4A5 gene mutation is the most com-
Double-positive anti-GBM 62). The risk of ESKD is increased by mon, giving rise to typical X-linked Al-
and ANCA-associated disease the tendency to relapse, therefore pro- port syndrome (70). In these patients,
ANCA-associated vasculitis, in par- longed maintenance immunosuppres- the immune system is accustomed to a
ticular granulomatosis with polyangii- sion and careful long-term follow-up defective form of α3, α4, or α5 chains.
tis (GPA) and microscopic polyangiitis is mandatory, unlike patients with just Therefore, the normal antigens con-
(MPA), and anti-GBM disease have anti-GBM antibodies (63). tained in α3, α4, or α5 chains of the
similar clinical manifestations, charac- kidney allograft cause an alloimmune
terised by acute glomerulonephritis with Anti-GBM disease associated response with the development of anti-
or without pulmonary haemorrhage. In with membranous nephropathy GBM antibodies (22). Also in the pres-
the approach to this clinical presenta- There are several cases of anti-GBM ence of anti-GBM antibodies, the de-
tion, ANCA and anti-GBM antibodies disease associated with membranous velopment of overt glomerulonephritis
are tested together and, in much higher nephropathy (MN) (64-68). As for the is infrequent probably due to the effect
frequency than expected by chance association with ANCA vasculitis, it of immunosuppression (71). However,
alone, they may both test positive. As has been postulated that the unveiling of when glomerulonephritis develops, an
described above, up to 10–50% of pa- hidden epitopes caused by one disease higher risk of graft loss is present (72)
tients with anti-GBM disease also test may be the trigger for the other disease and repeated transplantation leads to
positively for ANCA (usually anti-MPO occurrence. Consistently with this hy- more aggressive disease recurrence and
Abs), and up to 10% of patients with pothesis, the onset of anti-GBM disease rapid graft loss (73).
ANCA positivity also have circulat- may precede, coincide with, or follow
ing anti-GBM antibodies (58, 59). The the diagnosis of MN. In one series of IgA-mediated anti-GBM disease
pathogenic mechanism of this associa- 8 patients with combined anti-GBM Few cases of anti-GBM disease medi-
tion is still debated, but since low levels disease and MN, the antibody levels ated by circulating IgA anti-GBM anti-
of ANCA may be detected years before against the EB conformational epitope of bodies have been described (18, 20, 74-
the appearance of anti-GBM antibodies alpha-3(IV) NC were lower and serum 83). In these cases, the antibody may
and clinical symptoms, it has been hy- antibodies against the phospholipase A2 not be recognised by standard ELISA
pothesised that ANCA antibodies may receptor (PLA2R) were absent (66). In and Western blotting techniques. In
induce glomerular inflammation that the same series patients had a lower se- most of these cases rapidly progres-
modify or expose usually sequestered rum creatinine level at diagnosis, lower sive glomerulonephritis was present,
disease epitopes in GBM, triggering proportion with oliguria/anuria, and while pulmonary involvement was
anti-GBM antibodies formation (28). A better kidney survival at one year, com- found in 40% of cases. At kidney bi-
recent study by Nishibata demonstrated pared to the typical anti-GBM disease opsy, the immunofluorescence showed
that proteases released from neutrophils (66). A rapid decline in kidney func- linear staining for IgA. The prognosis
activated by ANCA can digest type IV tion in a patient with known MN should of IgA-mediated anti-GBM disease
collagen with subsequent unveiling of raise suspicion of the development of was poor compared with typical anti-
alpha-3(IV) NC (60). Another study superimposed anti-GBM disease. These GBM disease, with high mortality re-
demonstrated that up to 60% anti-GBM patients should be treated aggressively lated to pulmonary involvement and
patients also have autoantibodies that as for anti-GBM disease, while long- poor renal survival (50% of patients
target linear epitopes of MPO, versus term treatment is uncertain (2). progressed to ESKD) (18, 20, 74–83).
24% with autoantibodies that target in- The pathophysiology of this disorder is
tact MPO. The authors hypothesised that Anti-GBM disease after still unknown, but the heterogeneity of
anti-MPO Abs targeting linear and con- kidney transplantation the autoantigen and the peculiar clini-
formational epitopes may arise sequen- A peculiar form of anti-GBM disease cal presentation and prognosis suggest
tially, through a process of inter- and occurs in up to 5–10% of kidney trans- that this IgA-related condition should
intra-molecular epitope spreading (61). plants in patients with underlying Al- be considered a different disease.
Patients with double positivity for anti- port syndrome (69). Alport Syndrome
GBM and ANCA antibodies frequently is a hereditary disorder characterised Anti-GBM disease and thrombotic
experience the typical severe clini- by progressive kidney disease, hearing thrombocytopenic purpura
cal presentation of anti-GBM disease, loss, and ocular abnormalities. This dis- Very few cases of anti-GBM disease
with acute glomerulonephritis and lung order is determined by mutations in any with concomitant thrombotic throm-
haemorrhage requiring aggressive im- of the genes that encode the α3, α4, or bocytopenic purpura (TTP) have been
munosuppressive therapy and plasma α5 chains, causing an alteration of the described (84-87). TTP is a thrombotic
exchange (27). Mortality and renal normal type IV collagen network pre- microangiopathy caused by severely
survival is similar to that of anti-GBM sent in GBM (70). The mutated genes reduced activity of ADAMTS13, a von
disease, while the multiorgan dam- are COL4A3 and COL4A4 genes, lo- Willebrand factor-cleaving protease,
age and the tendency to relapse during cated in chromosome 2, and COL4A5 that leads to small-vessel platelet-rich
long-term follow-up are comparable to gene, located in chromosome X. CO- thrombi, thrombocytopenia, and mi-

968 Clinical and Experimental Rheumatology 2023

 Goodpasture syndrome and anti-GBM disease / F. Reggiani et al.

croangiopathic haemolytic anaemia is debated. Some reports on young cyclophosphamide toxicity is low since
(88). This disease is frequently caused Asian patients described the presence the treatment is usually continued for
by the presence of anti-ADAMTS13 of anti-GBM antibodies in patients with no longer than 2-3 months (109, 110).
antibodies (88). Patients with anti- SLE and rapidly progressive renal fail- The use of plasmapheresis is supported
GBM and associated TTP presented ure (100-104). In these patients, alveo- by the fact that allows a rapid reduction
with acute glomerulonephritis and lung lar haemorrhage was significantly more of antibodies titre (up to 60–65% every
haemorrhage, together with the symp- frequent than in SLE patients without session) and is able to improve renal
toms of TTP (84-87). It is not known if anti-GBM antibodies, and prognosis and patient survival compared to im-
this association is casual, or a common was worse (103). However, these find- munosuppression alone (14, 112, 113).
pathogenic mechanism is present. It ings were not confirmed on Caucasian Moreover, a small (n=17) randomised
has been hypothesised that the immu- patients (105). If this discrepancy is due trial that compared the addition of plas-
nological mechanism associated with to ethnic differences (106) or to the dif- ma exchange to cyclophosphamide and
the presence of anti-GBM antibodies is ferent specificity of the commercial anti steroids in anti-GBM disease confirmed
also responsible for the production of GBM assays (49) is still not known. the benefit of plasma exchange. In fact,
anti-ADAMTS13 antibodies (87), but in the plasma exchange group the fall
stronger evidences are required. Treatment of anti-GBM antibodies was rapid and
Standard treatment renal outcomes were better (114).
Anti-GBM disease after Since the most frequent clinical pres- Immunoadsorption is an alternative to
alemtuzumab treatment entation of anti-GBM disease is severe, plasmapheresis, although it may still be
Alemtuzumab is a humanised mono- a prompt and aggressive initial therapy considered an investigational therapy. It
clonal antibody directed against the is recommended (107). The therapy is is more efficient than plasma exchange
cell surface antigen CD52. It is used based on plasmapheresis, which rapidly for the removal of pathogenic autoanti-
for the treatment of relapsing multiple remove the pathogenic autoantibody, body (up to 71–86% every session) and
sclerosis (89). Few cases of anti-GBM together with corticosteroids and cyclo- has the advantage to minimise allergic
disease during the lymphocytes’ repop- phosphamide, which inhibit autoanti- reactions (112, 115). The clinical out-
ulation phase have been described (90- body production and ameliorate inflam- comes of immunoadsorption are com-
92). The marked autoreactivity of the mation (Table I) (2). This treatment was parable to plasma exchange (115, 116).
lymphocytes’ repopulation phase may firstly described in 1976 by Lockwood
be responsible for the anti-GBM anti- et al. (108), and is still recommended Therapeutic alternatives
bodies development. This hypothesis is by the KDIGO guidelines (109). These To date, there is insufficient evidence to
supported by the fact that no cases of guidelines recommend initiating immu- support other immunosuppressive ther-
anti-GBM disease have been reported nosuppression with cyclophosphamide apies. Few reports on successful treat-
when alemtuzumab was used together and corticosteroids plus plasmapheresis ment with mycophenolate mofetil and
with strong immunosuppression, as in in all patients with anti-GBM glomeru- cyclosporine have been reported in lit-
the case of kidney transplant. lonephritis, except in those who are erature (117-119). Interesting evidence
treated with dialysis at presentation, is emerging with rituximab (RTX) and
Anti-GBM disease and pregnancy have 100% crescents or more than 50% imliflidase. RTX is a chimeric mouse/
De novo anti-GBM disease in preg- global glomerulosclerosis in an ad- human monoclonal antibody (mAb)
nancy is rare and just few cases have equate biopsy sample, and do not have with binding specificity to CD20 (120).
been described (93–99). Most patients pulmonary haemorrhage (109). The are several case reports on anti-
presented after the first trimester with The recommended treatment schedule GBM disease in which RTX has been
acute kidney injury, haematuria, pro- includes prednisolone at the dosage of 1 used as either “add-on” to standard
teinuria and anaemia (98). When hae- mg/kg per day (maximum 60 mg) giv- therapy or as a substitute for cyclophos-
modialysis was required antepartum, en orally. The dosage must be reduced phamide (121, 122). The usual dosage
renal recovery with haemodialysis dis- weekly to 20 mg by 6 weeks, then grad- was 375 mg/m2 (2 to 6 weekly doses)
continuation was unlikely. Most of the ually tapered until complete discontinu- or 1000 mg (1 to 2 doses). RTX demon-
cases described in the literature ended ation at 6 months (110). Some authors strated a rapid reduction of anti-GBM
in live births. However, anti-GBM an- suggest starting with 1 gram of meth- antibodies, but without benefits on re-
tibodies may cross the placenta causing ylprednisolone given daily for three nal outcomes (122). Therefore, wait-
pulmonary renal syndrome in the fetus days, but this indication is debated (2, ing for randomised trials, RTX should
with subsequent spontaneous abortion 13, 14). Cyclophosphamide should be be reasonably used in patients that are
or stillbirth (98). given orally since the equivalence of refractory to standard treatment or with
daily oral and pulsed intravenous cy- contraindications to cyclophospha-
Anti-GBM antibodies in clophosphamide has been demonstrated mide. Imlifidase is an immunoglobulin
systemic lupus erythematosus (111). The starting dosage is 2–3 mg/kg G (IgG)-specific protease that cleaves
The presence of anti-GBM antibodies per day, to be adjusted in case of renal human IgG into F(ab’)2 and Fc frag-
in systemic lupus erythematosus (SLE) failure and older patients. The risk of ments, causing a rapid decrease in anti-

Clinical and Experimental Rheumatology 2023 969

Goodpasture syndrome and anti-GBM disease / F. Reggiani et al.

Table I. Initial treatment of anti-GBM disease.

Agent Details Considerations and warnings

Standard therapy Plasma exchange • Daily 4 L exchange for 5% human • Add fresh human plasma (0.3-2.0 L)
albumin solution within 3 days of invasive procedure
• Continue until antibody levels are (e.g. kidney biopsy) or if alveolar
fully suppressed or for 14 d haemorrhage is present.
• Monitor platelet count, fibrinogen,
haemoglobin and calcium

Cyclophosphamide • 2–3 mg/kg per day given orally for 2–3 • Monitor leukocyte count
months • Stop if leukocyte count falls to <4 × 109/L
• 2 mg/kg if patients > 55 yr and restart at reduced dose (75%) when
• Adjust for renal function: recovered
• -25% if GFR 45-59 mL/min • No sufficient data to support IV
• -40% if GFR 30-44 mL/min cyclophosphamide
• -50% if GFR 15-29 mL/min • Other potential side effects (bladder and
• -60% if GFR <15 mL/min gonadal toxicity, tumor risk) are rare since
the low cumulative dosage

Corticosteroids • Prednisolone 1 mg/kg per day • Prednisolone is minimally removed by

(maximum 60 mg) given orally plasmapheresis, so should be administered
• Oral therapy may be preceded by pulse after plasma exchange
IV methylprednisolone (15-30 mg/kg
[max 1000 mg] per day for 3 consecutive
days)
• Reduce gradually to 20 mg per day by
6 weeks
• Gradually taper until complete
discontinuation at 6–9 months

Alternatives to cyclophosphamide Rituximab • 1 g for two doses • Rituximab is removed by plasma exchange
• Start rituximab after 7 days of corticosteroids
and plasma exchange, and wait 48 hours after
the infusion to restart plasma exchange

Mycophenolate mofetil • Start with 500 mg twice daily and titrate • Monitor for leukopenia and GI side effects
up as tolerated to a dose of 1000 mg
twice daily

Investigational therapies Immunoadsorption • Performed as part of the plasmapheresis • Useful for patients allergic to blood products
procedure or with body weight >90 kg

Imlifidase • Add on therapy in severe and/or • Clinical utility of this approach remains to
forms of anti-GBM disease be determined

GBM: glomerular basement membrane; GFR: glomerular filtration rate; GI: gastro-intestinal; IV: intravenous.

body level and inhibiting antibody- and ance of antibodies was demonstrated. cyclophosphamide, and corticosteroids,
complement-dependent cytotoxicity Unfortunately, no benefits on renal out- the survival at 1 year is 80-90% and the
(123). Imlifidase has been proposed as comes were observed and after 6 to 13 efficacy of lung haemorrhage treatment
an alternative to plasmapheresis in re- days a rebound of antibodies occurred is greater than 90% (12, 14). Renal sur-
fractory forms of anti-GBM disease. In (125). In an open-label phase 2a study vival is strictly related to the degree of
an experimental model, imlifidase was on 15 patients with anti-GBM antibod- kidney involvement at presentation. In
able to reduce both circulating and de- ies, the same rapid and complete clear- patients with initial creatinine values
posited antibodies. In particular, it was ance of anti-GBM antibodies after imli- less than 5.65 mg/dL, renal survival
able to remove the Fc portion of the fidase infusion (in addition to standard was 95% and 94% at 1 and 5 years,
antibodies attached to the GBM, pre- therapy including plasma-echange) was respectively. In those with creatinine
venting complement activation (124). observed. However, in this study also greater than 5.65 mg/dL, but not requir-
Data on the use of imlifidase in clini- an improvement of renal outcomes was ing immediate dialysis, renal survival
cal practice is limited. In a Swedish achieved, with 67% of patients being was 82% and 50 at 1 and 5 years, re-
study, 3 patients affected by anti-GBM dialysis-independent at 6 months (126). spectively. In patients requiring imme-
disease with acute glomerulonephritis diately dialysis, renal recovery occurred
requiring dialysis and without pulmo- Outcome and prognosis in only 8% at 1 year (121). Together
nary involvement were treated with If the patients are promptly treated with with kidney function, also the propor-
imlifidase. A rapid and complete clear- the combination of plasma exchange, tion of glomeruli affected by crescents

970 Clinical and Experimental Rheumatology 2023

 Goodpasture syndrome and anti-GBM disease / F. Reggiani et al.

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