IgG4- related disease: an orphan disease with many faces

In January 2012, a 61 year- old female presented to a rheumatology unit with a long- standing history of recurrent inflammatory lesions of unknown origin since 1989, which had been previously diagnosed as pseudolymphoma and Sjögren’s syndrome (SS). The leading symptom was bilateral orbital masses, which eventually led to enucleation of the left eye. Further, suspicious enlarged lymph nodes in the head and neck region as well as recurrently enlarged salivary glands were evident. Moreover, paravertebral masses as well as thickening of ocular muscles and nerves were present.

The patient underwent a series of organ biopsies over the years including resections of the orbital pseudotumor and left submandibular salivary gland, as well as biopsies of ocular muscles. All biopsies showed dense lymphoplasmacellular infiltrates of the respective organs. Due to the lack of evidence for monoclonal disease based on these biopsies and inconspicuous bone marrow investigations, the results were interpreted as “pseudolymphoma”. Nonetheless, the patient received treatments such as chlorambucil and radio-chemotherapy. All prednisone- containing treatment schemes were successful in decreasing mass sizes and organ swellings for a short period. However, the patient’s disease course was chronic relapsing during the first years. In the last 8 years before referral, however, the disease changed to a more chronic, stable course without major complications.

When we saw the patient first in 2012, her medication included azathioprine 100 mg and prednisone 5 mg per day. She reported dry eyes and mouth, which had not changed during the last years. Otherwise, she was in good condition. Upon physical examination, mild swelling of the right submandibular gland was evident. On imaging, we found massive thickening of the ocular nerves (Figure 1A). Laboratory examination revealed negative anti-nuclear antibodies (ANA), extractable nuclear antigens (ENA), anti-neutrophil cytoplasmic antibodies (ANCA), rheumatoid factor, normal complement C3 and C4, and no cryoglobulins. Erythrocyte sedimentation rate (ESR), C- reactive protein (CRP) and blood chemistry were within normal range. However, total IgG levels were slightly elevated with IgG4 being strongly elevated (519 mg/dl, normal 5 – 125 mg/dl).

We retrieved biopsies of the ocular muscles, parotid gland and the left submandibular gland and asked the pathology department for re-evaluation of the specimens and staining for plasma cells, IgG and IgG4. All specimens revealed dense infiltration of IgG4- producing plasma cells with a highly increased tissue IgG4/IgG ratio of >40% (Figure 1B). Further, tissue eosinophilia, storiform fibrosis and obliterative phlebitis were present, thus confirming the diagnosis of IgG4- RD.

The first descriptions of IgG4-RD organ manifestations were published in the late 19th century. In 1892, Johann von Mikulicz - a scholar of Theodor Billroth - first described a patient with an inflammatory disease of the salivary glands (Mikulicz’ syndrome) [[1]]. Subsequently, Küttner described in 1896 a patient suffering from a tumor-like lesion of the submandibular glands (Küttner’s tumor) [[2]]. In the same year, Riedel reported on “eisenharte Struma”, a condition characterized by a stone-hard, fibrous transformation of the thyroid gland and adjacent tissue [[3]]. However, the true nature of these disease manifestations remained unclear for another century.

Many organ manifestations of IgG4-RD including among others retroperitoneal fibrosis, sclerosing cholangitis, and sclerosing pancreatitis have since been described. Already decades ago, the systemic nature of the disease was recognized as evidenced by patients presenting with more than one organ involvement. For instance, Bartholomew et al. reported in 1963 on two patients with a combination of Riedel’s thyroiditis, retroperitoneal fibrosis and sclerosing cholangitis [[4]].

Significant progress was made in 1995, when a patient with a steroid- responsive form of pancreatitis was reported of presumed autoimmune origin (autoimmune pancreatitis, AIP) [[5]]. Later, in 2001 Hamano et al. reported elevated IgG4 levels in AIP patients and, finally, in 2002 infiltration of IgG4-bearing plasma cells in tissue samples from patients with “sclerosing pancreatitis” (as well as in concomitant retroperitoneal fibrosis) were documented by the same group [[6],[7]].

These findings have been replicated in different cohorts of patients with the above- described syndromes [[8],[9]]. Thus, a distinct disease entity comprising patients presenting with inflammatory and/or fibrosing single or multiple organ lesions in conjunction with elevated serum IgG4 levels and tissue IgG4 production became clear. While different names for this syndrome were used in the past 10 years, the term “IgG4- related disease” has recently evolved as most appropriate [[10]]. Consequently, the organ manifestations of IgG4-RD were renamed and eponyms were abandoned (Table 1).

IgG4-RD can affect any organ or tissue. Thus, the clinical picture is highly heterogeneous. While some patients may present with a single site involved, others may have a few or many organs affected by IgG4-RD. These may arise synchronously or metachronously. The disease may manifest as a tumefactive lesion or a rather diffuse infiltrative process, further contributing to a diverse clinical picture. In addition, some organs show a distinct involvement, as for instance lymphadenopathy, periaortitis, or a secondary form of membranous glomerulonephritis (GN) [[11]–[13]].

Laboratory findings in IgG4-RD are often inconspicuous. Inflammatory markers such as ESR and CRP may be highly elevated, but can be normal despite active disease in a substantial proportion of patients. Anti-nuclear antibodies, anti- SS-A as well as anti- SS-B antibodies are negative in the majority of patients, while low complement levels (C3 and C4) are not uncommon [[14],[15]]. Polyclonal hypergammaglobulinemia is often found in IgG4-RD. Increased serum IgE levels and allergic diseases are present in about one third of patients [[16]]. IgG subclass analyses reveal highly elevated serum IgG4 levels in many but not all patients. It should be underlined that IgG4 levels can be substantially misleading when they are used as a sole criterion for diagnosis (or exclusion) of IgG4-RD. On the one hand, a number of other diseases, such as cancer, infections and autoimmune diseases, including vasculitis, are associated with increased IgG4 levels [[17]]. On the other hand, a number of IgG4-RD patients may have normal IgG4 levels. Thus, the sensitivity of IgG4 in IgG4-RD was found to be 90% and the specificity 60% in one study [[18]]. In another study the positive predictive value of an elevated serum IgG4 for IgG4-RD was found to be as poor as 10% [[19]].

In some patients with active IgG4-RD IgG4 levels were found to be inappropriately low due to the prozone effect, a situation where too many antibodies prevent agglutination of antigenic particles in the test system. If disease activity is high, but IgG4 levels are low, sample dilution may lead to correction of the prozone effect and reveal – appropriately – much higher IgG4 levels in particular patients [[20]].

While the location of disease manifestation may vary, the histological pattern is – with some exceptions – more or less uniform and shares particular features: (i) storiform fibrosis (resembling the spokes of a cartwheel), (ii) a dense lymphoplasmatic infiltrate with an increased number of IgG4+ plasma cells (at least > 10/high power field (HPF) – depending on the particular organ) and/or an increased IgG4/IgG ratio (usually >40%) and (iii) an obliterative phlebitis. Tissue eosinophilia is also very characteristic. The presence of neutrophils, granulomas, neutrophilic microabscesses, and necrotizing vasculitis strongly argues against IgG4-RD [[21]]. In some organs, IgG4-RD can manifest with distinct histopathological features, e.g. in kidney and lymph nodes (see section on clinical manifestations). Recently, a Japanese study group proposed diagnostic criteria for IgG4-RD in general (Figure 2) [[22]]. In addition, there have been proposals for diagnostic criteria of organ- specific IgG4-RD manifestations such as in kidney or pancreatic disease [[23],[24]].

There are few studies reporting on the epidemiology of IgG4-RD, mainly derived from Asian studies. A cross-sectional study in 2009 estimated that approximately 8000 individuals in Japan were suffering from IgG4-RD, thus accounting for a prevalence of approx. 60 affected individuals per million inhabitants [[25]]. Slightly more males were affected and mean age was 58 years well in line with previous reports. There are no data on the prevalence of IgG4-RD in Europe or elsewhere, but IgG4-RD is thought to be rarer in these areas. IgG4-RD usually affects middle-aged individuals and at least for some organ manifestations such as type 1 AIP a male predominance is evident.

Little is known about the initiation process of IgG4-RD or how and why these specific organ infiltrations occur. There is some evidence from Asian populations, that certain HLA alleles – particularly DRB1*0405 and DQB*0401 – increase the susceptibility to type 1 AIP [[26]]. Further, few single- nucleotide polymorphisms (SNP) in genes related to immune system such as CTLA-4 and Fc- receptor-like 3 have been linked to IgG4-RD [[27],[28]]. In AIP, autoantibodies against the plasminogen- binding protein of H. pylori were found in the majority of patients in one study [[29]]. Plasminogen- binding protein of H. pylori shares homology to a protein expressed in pancreatic acinar cells. The authors hypothesized, that through molecular mimicry this immune response could lead to IgG4-RD.

It is suspected but unclear, whether IgG4-RD truly belongs to the group of autoimmune disorders. There is evidence of autoantibodies such as ANA, rheumatoid factor, and others in some patients [[30]]. However, these autoantibodies are far beyond from being specific for IgG4-RD. The same is true for organ- specific autoantibodies to proteins expressed for instance in the pancreas or bile ducts [[31]].

In contrast to many autoimmune disorders, IgG4-RD seems to have a skewed T- cell response towards a TH2 phenotype. Increased tissue levels of TH2-cytokines such as Interleukin-4 (IL-4), −5 (IL-5) and −13 (IL-13) were found in IgG4-RD [[32]]. Further, 40% of IgG4-RD patients have increased serum IgE levels and allergic diseases are common [[16]]. Moreover, tissue eosinophilia is typical for IgG4-RD [[33]]. Some studies also suggested an increased activation of regulatory T cells (Treg), which might be due to the over-expression of transforming growth factor β (TGF-β), an important regulator of Treg development [[34],[35]]. Previously it could be demonstrated that the expression of IgG4 class switch-related molecules is different in labial salivary glands and peripheral blood mononuclear cells. In glands of IgG4-RD patients upregulated Treg cytokines such as IL-10 and TGF-β appear to play pathogenic roles in IgG4-specific class-switch recombination and fibrosis. Activation-induced cytidine deaminase (AID), as a marker of nonspecific immunoglobulin class-switch recombination, was also found to be increased in labial salivary glands of IgG4-RD patients and could contribute to upregulation of IgG4-specific class-switch recombination. IgG4 class-switch recombination seemed to be mainly upregulated in affected organs [[36]].

Well-fitting to a TH2 immune response, IgG4-RD is characterized by both systemic and localized IgG4 production. It is currently unclear, whether these antibodies are acting as pathogenic antibodies or are just a bystander phenomenon. In healthy individuals, IgG4 is the least abundant IgG subclass molecule accounting for less than 5% of total IgG [[37]]. In addition, IgG4 itself seems to be unable to activate the classic complement pathway. Another characteristic feature of IgG4 antibodies is the possible occurrence of Fab arm exchange of these antibodies [[38]]. This is due to weak bonds between the heavy chain of the IgG4 antibodies thus allowing the Fab arm exchange and formation asymmetric bispecific antibodies. This further hampers antigen cross-linking and immune complex formation of IgG4 antibodies. Nonetheless, there is evidence of importance and pathogenicity of IgG4 antibodies in human diseases. Certain autoantibody immune mediated diseases such as membranous GN and thrombotic thrombocytopenic purpura seem to be mediated by antibodies of the IgG4 type [[39],[40]].

Interestingly, low C3 and C4 complement levels can be observed in one third of IgG4-RD patients with renal involvement indicating immune complex formation [[15]]. In type 1 AIP, tissue deposition of C3c, IgG4 and IgG can be observed at the basement membrane of pancreatic and bile ducts and of acini [[41]]. C3 and IgG deposition can also be observed at the tubular basement membrane in IgG4- related tubulointerstitial nephritis (TIN) [[15]]. Thus, immune complex mediated tissue damage may occur at least in some organ manifestations of IgG4-RD.

Recent insights into the pathophysiology of IgG4-RD suggest that one of the major drivers of the disease appear to be plasmablasts. Oligoclonal expanded plasmablasts with extensive somatic hypermutation were found to be increased in IgG4-RD patients with active disease. Of interest, depletion of B cells with rituximab leads to a reduction of these plasmablasts and correlates with disease remission [[42]]. Compared to other inflammatory diseases before treatment and healthy controls, circulating plasmablasts are elevated in patients with active IgG4-RD, even in those patients with normal serum IgG4 concentrations. This observation poses plasmablasts as potential biomarkers for diagnosis and assessment of treatment response [[43]].

Overall, there is no evidence for treatment options from randomized controlled trials. Clinical experience is that most IgG4-RD patients respond favorably to glucocorticoid (GC) treatment. The effect of GCs has been reported for several sites of IgG4-RD manifestations in different cohort studies. While it appears that spontaneous remissions do occur [[114]], the use of GCs induces remission in most patients and earlier than without treatment. However, relapse is frequently seen after GCs are tapered or stopped [[52]]. Relapses may be confined to the originally affected organs but also occur in other organs. They may be preceded or accompanied by an increase in IgG4 levels [[115],[116]].

Whether treatment in patients with IgG4-RD needs to be established depends on the localization and extent of disease manifestation. In some patients with minor involvement (e.g. asymptomatic and incidentally found IgG4-related lymphadenopathy or small, indolent nodular lesions in IgG4-related lung disease), immediate treatment may not be indicated and follow-up may be more appropriate. In other cases with organ dysfunction or pseudotumors (e.g., renal involvement, AIP with bile duct obstruction and jaundice, lacrimal gland swelling, pachymenigitis, etc.) rapid introduction of therapy is necessary to avoid loss of organ function. Thus, treatment decision has to be individualized [[117]]. Most cohort studies report on IgG4-RD patients with a particular organ involvement, which may not translate to other organ manifestations. Moreover, a substantial proportion of publications are from Asian IgG4-RD patients, questioning whether these data also apply to non-Asian patients.

In general, most experts would start with a dosage of 40 mg prednisolone or 0.6 mg/kg of body weight per day and taper the dose over several months, starting with a first dose reduction after 2–4 weeks [[117]–[119]]. Treatment response is usually seen within two to four weeks. Major drawbacks of GCs are side effects as well as the need for maintenance therapy. Thus, a number of drugs such as azathioprine, mycophenolate mofetil or methotrexate have been used as GC sparing agent [[119]–[123]]. In addition, more intensive therapies such as cyclophosphamide, fludarabine and bortezomib have been reported to be of benefit in IgG4-RD patients [[123]–[125]].

A promising treatment strategy in GC- dependent or refractory patients is rituximab (RTX) [[84],[120],[126]]. RTX has been used in a case series of 10 refractory IgG4-RD patients. The duration of treatment effect is not established. Not surprisingly, relapse of IgG4-RD after rituximab treatment has been reported [[127]]. One major interesting finding was that RTX specifically reduced IgG4 levels, while the other IgG subclasses remained stable. This has led to the hypothesis that short lived plasma cells producing IgG4 are involved in the disease [[84],[120]].