Overview of IgG4-related disease
IgG4-RD is a fibroinflammatory disease that can affect almost any organ, with nearly
identical histopathologic findings in all tissues: a lymphoplasmacytic infiltrate
of polyclonal lymphocytes, IgG4+ plasma cells, and eosinophils 1], 2], often most prominent in the early stages of disease, and fibrosis, more commonly
seen in the chronic phase of the disease. The pathophysiology is complex and incompletely
understood; aberrant T helper type 2 (Th2)/T regulatory cells are responsible for
profibrotic cytokine production leading to collagen deposition and fibrosis 3]–5]. The most common clinical manifestations are autoimmune pancreatitis (AIP), sialadenitis,
dacryoadenitis, and retroperitoneal fibrosis; other common clinical manifestations
are listed in Table 1. Intrinsic renal involvement is found in about 12 % of patients 6].
Table 1. Common manifestations of IgG4-RD by organ system
IgG4-RD in general affects middle-aged to elderly patients with a slight male preponderance
3], 7] and can mimic other systemic conditions such as sarcoidosis, lymphoma, and Sjögren’s
syndrome. However, the epidemiology may vary depending on the pattern of organ involvement.
For example, pulmonary IgG4-related disease affects middle-aged men and women more
than the elderly 8], 9], whereas biliary disease is more common in older males 10], 11], and Mikulicz’s disease (IgG4-RD of the lacrimal and salivary glands) tends to affect
younger females 12]. IgG4-RD affecting a single-organ system may be initially misdiagnosed as an autoimmune
disorder such as nephritis, pancreatitis, or cholangitis.
Definitive diagnosis of IgG4-RD requires an adequate tissue biopsy demonstrating storiform
fibrosis, mild to moderate tissue eosinophils, lymphoplasmacytic infiltrate, increased
IgG4 levels (generally 50–100/hpf for most tissues), and an IgG4/IgG+ plasma cell
ratio 40 % 1], 2], 13]. Measurement of serum IgG4 is important, but is neither sensitive nor specific by
itself. Extremely elevated serum IgG4 levels 10–15 g/L are rarely seen outside of
IgG4-RD, but moderately elevated serum IgG4 can be seen in a number of inflammatory,
autoimmune, and neoplastic conditions; conversely, 30–45 % of patients with histologically
confirmed IgG4-RD (usually in a single system) have normal serum IgG4 levels 6], 14]. Clinicians must therefore be sufficiently aware of the clinical, radiologic, and
laboratory features to seek tissue biopsy and alert the pathologist when IgG4-RD is
suspected. Once diagnosed, IgG4-RD can be treated favorably with steroids and/or rituximab,
and the highly variable degrees of recovery appear dependent on the extent of fibrosis
at the time of diagnosis 7]. The disease was initially thought to be monophasic when first reported, but cumulative
literature now shows that it is typically a chronic disease with frequent relapse.
Furthermore, regression of the disease in one organ may be followed by emergence of
the disease in another organ. This underscores the need for early diagnosis to limit
the extent of irreversible fibrosis and improve patient outcomes.
Despite rising awareness, the epidemiology remains poorly understood and the true
incidence and prevalence are likely underestimated 2], 7], 15]. Japanese population-based studies have reported that the prevalence of AIP seems
to have risen from 2.2 per 100,000 population in 2007 to 4.6 per 100,000 in 2011 16], 17]. Most of these patients (87.6 % in 2007 and 86.4 % in 2011) were considered to have
IgG4-related (type I) AIP 16], 17]. Whether this rise in prevalence from 2007 to 2011 reflects increased recognition
as opposed to increased incidence of new cases is not clear. To our knowledge, there
are no similar population-based studies in North American or European populations
on any subtype of IgG4-RD, including IgG4-RKD.
Many retrospective studies have revealed that IgG4-RD is responsible for many cases
of “idiopathic” or unexplained disease in diverse organs. For example, one review
of 26 patients with autoimmune hepatitis revealed that nine had characteristics suggestive
of IgG4-RD 18]. Subsequently, the hepatology community has increased efforts to identify IgG4-associated
cholangitis, given that the treatment is vastly different from non-IgG4 cholangitis—steroids
versus surgery 18]–20]. IgG4-RD involvement in many organs, including the kidneys, remains under-recognized.
Overview of IgG4-related kidney disease
IgG4-RD can affect structures adjacent to the kidney, leading to acute or chronic
kidney disease. The most common of such manifestation is retroperitoneal fibrosis
leading to obstructive uropathy. Involvement of the renal pelvis in the form of IgG4
pyelitis has been reported but is rare. Intrinsic renal disease is encompassed by
the term IgG4-related kidney disease (IgG4-RKD) 21], 22]. In a large case series of 125 patients with IgG4-RD, 23 (18.4 %) had RPF and 15
(12 %) had intrinsic IgG4-RKD 6]. The kidney is unique among organ systems in that there are two histologic subtypes
of IgG4-RD involvement: most commonly, tubulointerstitial nephritis (IgG4-TIN) and
rarely, membranous glomerulonephropathy (IgG4-MGN). IgG4-MGN is reported in about
10 % of cases of IgG-RKD and may occur with or without TIN. Unlike idiopathic membranous
glomerulonephropathy, IgG4-MGN is not associated with anti-PLA2R antibodies 23].
Patients with IgG4-RKD are demographically similar to those with IgG4-RD in general,
most commonly middle aged to elderly with a male preponderance 7], 24]. Some patients present with isolated renal disease, but involvement of other organs,
most commonly sialadenitis and lymphadenopathy, is common. In a large American series,
28 of 34 patients (83 %) with IgG4-TIN had another organ affected by IgG4-RD at the
time of diagnosis by Kawano and Saeki and Raissian et al. 24], 25], and in a Japanese series, extra-renal lesions were present in 42 of 43 patients
(98 %) 26].
IgG4-TIN: clinical presentation and radiologic and histologic findings
The clinical presentation of tubulointerstitial IgG4-RKD is variable, and renal function
may range from normal to severely compromised 21], 26]. Out of 35 patients with IgG4-TIN from the Mayo Clinic study, 27 (77 %) had acute
or progressive chronic renal failure at the time of their renal biopsies 25]. Unlike medication-related TIN, IgG4-TIN may not be associated with an increase in
urinary WBCs or WBC casts 24]. IgG4-TIN causes local tissue inflammation, but systemic acute phase reactants tend
to be normal or minimally elevated; thus, unlike other forms of TIN, markedly elevated
CRP is rarely observed 24]. Most patients (70–88 %) with TIN related to IgG4-RKD have elevated serum IgG and/or
IgG4 levels 24], 25]. At the Mayo Clinic, 56 % of patients with IgG4-TIN presented with hypocomplementemia
25] compared to 20 % of patients with IgG4-RD without renal involvement. On contrast
CT scan, typical lesions are small, bilateral, nodular, or wedge-shaped, in the renal
parenchyma diffusely or in the peripheral cortex 27], 28]. The lesions are low-enhancing on both contrast CT and T2-weighted MRI 27]. Notably, they are isointense on T1-weighted MRI and are not visible on non-contrast
CT scan 27]. Less commonly, they may be extra-parenchymal (in the renal sinus, pelvis, or surrounding
the renal cortex), or take on the appearance of masses or cysts 27], 29]. MRI with diffusion-weighted imaging (DWI) will enhance the ability to diagnose IgG4-RKD,
as the hyperintense DWI lesions appear to be detected with 100 % sensitivity as compared
to the lower sensitivity (77.4 %) of T2-weighted MRI 28]. Mass lesions or enlarged kidneys may be seen initially and atrophic kidneys may
be seen later in the disease course.
Histology is of primary importance to diagnosing IgG4-RKD. Of the many organs affected
by IgG4-RD, the kidney is unique in having two distinct patterns of histologic involvement:
TIN (Fig. 1) and, less commonly, membranous glomerulonephropathy (Fig. 2). The following diagnostic features have been described in both American and Japanese
populations: diffuse or multifocal TIN, with variability in the ratio of fibrosis
to inflammation; moderate to marked interstitial increase in IgG4+ plasma cells; and
increased mononuclear cells with eosinophils in most, but not all, cases 13], 21], 25], 30], 31]. Mononuclear cell tubulitis, if present, is focal and mild, and plasma cell tubulitis
is rarely seen. Glomeruli are normal or have mild mesangial matrix expansion, and
there may be tubular basement membrane immune complex deposits, made up of polyclonal
IgG and complement C3. Simply looking for plasma cell infiltration would lead to over-diagnosis,
and only looking at biopsies with moderate to severe interstitial inflammation may
lead to under-diagnosis 25]. Ruling out lupus, vasculitis, lymphoma, and other causes of kidney conditions is
crucial, as increased IgG4+ plasma cells have been reported in the renal parenchyma
in various diseases 32]. A Mayo Clinic study reviewed 414 biopsies taken over a 1-year period which had moderate
to severe inflammation 25]. Of those, 20 % were found to have increased plasma cells (defined as 5 plasma cells/×400
magnification hpf in ?3 fields). Of those cases, the authors found that 2 % were subsequently
confirmed to represent IgG4-TIN, 76 % were ascribed to other etiologies, and 22 %
remained unable to classify. Their data suggest that while IgG4-TIN is a rare cause
of moderate to severe interstitial inflammation with accompanying plasma cells, the
prevalence in patients with mild interstitial inflammation and plasma cell infiltrates
is unknown. The Mayo Clinic has proposed a diagnostic framework for IgG4-TIN, outlined
in Table 225]. These criteria should be considered complementary to the International Consensus
Criteria for IgG4-RD 13], which are the standard diagnostic criteria for IgG4-RD in general.
Fig. 1. IgG4-related tubulointerstitial nephritis (IgG4-TIN). a Periodic acid-Schiff (PAS) stain of a case of clinically confirmed IgG4-related kidney
disease (IgG4-RKD) showing tubulointerstitial nephritis with a significant number
of plasma cells and a plasma cell tubulitis. b IgG4 immunohistochemistry confirming a large number of IgG4 expressing plasma cells
in the infiltrate. c For comparison, periodic acid-Schiff (PAS) stain of a case of obstructive uropathy
due to benign prostatic hypertrophy (BPH), showing a similarly cellular interstitial
infiltrate but with fewer plasma cells
Fig. 2. IgG4-related membranous glomerulonephropathy. a Periodic acid-Schiff (PAS) stain of a case of clinically confirmed IgG4-related kidney
disease (IgG4-RKD, same patient as in Fig. 1), showing a membranous pattern of glomerulonephropathy with occasional plasma cells
in the mesangium. b IgG4 immunohistochemistry confirming several IgG4 expressing plasma cells in the
glomerulus. c Electron microscopy demonstrating subepithelial electron dense deposits, consistent
with membranous glomerulonephropathy
Table 2. Mayo Clinic proposed diagnostic criteria of IgG4-TIN
IgG4-TIN should be considered in patients with AIN who do not have an obvious pharmacologic
or infectious etiology, and it should be considered in patients with systemic symptoms
potentially consistent with extra-renal IgG4-RD, and when there are findings of other
organ involvement characteristic of IgG4-RD. Renal imaging showing low-attenuating
lesions in the kidneys should also prompt suspicion of IgG4-TIN. When IgG4-TIN is
suspected, the renal biopsy should be examined for a lymphoplasmacytic infiltrate,
and if increased plasma cells are present, these should be stained for IgG and IgG4.
These stains can also be performed on archived tissue samples from kidney and other
organs, as many of these patients have chronic disease with previous “non-diagnostic”
biopsies. Given the non-specific nature of the histologic appearance of IgG4-TIN,
the pathologist should be specifically informed of a high degree of clinical suspicion
for IgG4-RD in order to trigger appropriate immunohistochemical evaluation. Serum
IgG, IgG subclasses, serum protein electrophoresis, complement levels, and imaging
for multiple and bilateral low-attenuating renal lesions should also be considered.
When a renal biopsy demonstrates TIN and increased IgG4+ plasma cells, other diagnoses
to consider include pauci-immune glomerulonephritis, medication-induced interstitial
nephritis, autoimmune TIN, lupus, Sjögren’s syndrome, and chronic pyelonephritis.
Once pauci-immune GN is ruled out, the IgG4 stain has a sensitivity of 100 % and specificity
of 92 % for IgG4-RKD 25]. Other features detailed in Table 2 can assist in ruling in or out IgG4-TIN. Early steroid responsiveness is characteristic
of IgG4-TIN, but this feature is of limited diagnostic value given that several other
diseases on the differential diagnosis are also steroid responsive.
IgG4-TIN: treatment and natural history
The treatment of IgG4-TIN mirrors the treatment of IgG4-RD in general. The 2015 International
Consensus Statement for treatment of IgG4-RD advocates treating active disease urgently
and that many patients with asymptomatic disease also require treatment to prevent
or minimize future organ damage 33]. Glucocorticoids for IgG4-RD are first line, and a typical regimen is prednisone
0.6–1 mg/day × 4 weeks with a slow taper thereafter and maintenance prednisone in
many cases 33]. A prospective single-arm Japanese study of 57 patients reported an overall response
rate of 82 % with a relapse rate of 12 % with such a regimen 34]. The main toxicity was new or worsening diabetes in 30 % of patients. The general
strategy of first-line steroid treatment has been retrospectively examined in Japanese
patients with IgG4-TIN, and most patients have a clinically significant degree of
sustained renal recovery 26], 35], 36]. While steroids are the standard first-line therapy in Japan, B cell depletion with
rituximab is also very potent. A prospective, single-arm clinical trial examining
the effect of two doses of rituximab (1 g IV rituximab 2 weeks apart) demonstrated
a clinical response in 29 of 30 patients 37]. Of these, 22 patients had a sustained disease response at 12 months while 7 relapsed
during that period, requiring re-treatment with rituximab. Steroid-sparing agents
such as azathioprine, mycophenolate mofetil, 6-mercaptopurine, methotrexate, tacrolimus,
or cyclophosphamide have been used, mainly in the setting of AIP, with limited success
38]. Rituximab is effective in most cases refractory to steroids and other immunomodulators,
although rare cases requiring more intensive therapy such as purine analogues have
been reported 39]. A recent case report confirmed the effectiveness of rituximab in a steroid-refractory
patient with IgG4-TIN, with sustained improvement in renal function 40]. Two other case reports suggest that treatment of steroid-refractory renal disease
may be successful when low-dose prednisolone is combined with either and azathioprine
or mizoribine 41].
With respect to prognosis, most patients’ renal function improves once treatment is
initiated, and this tends to plateau after weeks to months or may slightly decline
from its peak recovery 35], 42]. As in other organs affected by IgG4-related fibrosis, fibrosis is generally not
reversible. Some patients may still have fibrotic lesions in the tubulointerstitium
after treatment despite improvements in renal function, imaging, and other histologic
findings 26], 27], 36], 40]. Serum IgG4, hypocomplementemia, and proteinuria are helpful disease markers to follow
for relapse, especially if present initially 26]. Quantitative flow cytometry of peripheral blood plasmablasts has shown promise as
a more sensitive disease marker than serum IgG4, but this test is not routinely available
in most centers 43]. Radiographic improvement is variable: in a Japanese review, 18 of 40 patients had
radiographic recovery 26], whereas in a Mayo study, 10 of 13 patients experienced radiographic resolution of
their renal lesions 27]. In general, patients with a lower estimated glomerular filtration rate (eGFR) at
time of diagnosis (60 mL/min) tend to progress more frequently than those whose eGFR
is 60 mL/min, despite treatment 26], 44], but even in those with significant renal dysfunction (eGFR 60 mL/min), a 1-month
course of steroids resulted in significant improvement 36]. While some patients go on to develop dialysis dependence 36], the number of patients with end-stage renal disease as a result of IgG4-TIN is unknown.
There is a paucity of data on renal transplant, but anecdotally, one patient in our
center was transplanted for end-stage renal disease due to IgG4-MGN in November 2014
and remains in remission on prednisone 2.5 mg daily as well as mycophenolate mofetil
and tacrolimus with monthly monitoring of kidney function, serum IgG, and IgG4 (unpublished
data).
In summary, many patients will respond to steroids, with new or worsening diabetes
as the most significant toxicity, and rituximab is a potent and well-tolerated treatment
option both for steroid naïve and steroid-refractory patients. Other traditional steroid-sparing
immunosuppressives have been used with variable success, and their role is not clearly
defined. Many patients will require maintenance prednisone or re-treatment with rituximab,
and our own practice is either to maintain steroid-responsive patients on a low dose
of prednisone or for those patients who achieve a steroid-free complete response with
rituximab, to monitor serum IgG, IgG4, and kidney function closely and plan for re-treatment
at the earliest sign of relapse.