MPO‐ANCA‐positive granulomatosis with polyangiitis and concurrent IgG4‐related disease with periaortitis and tubulointerstitial nephritis: A case report of a new overlap syndrome?

Immunoglobulin G4‐related disease (IgG4‐RD) is a fibroinflammatory condition that was first recognized as a unique disease entity in the early 2000s. Its diagnosis is based on specific pathologic, serologic, and clinical features, and the exclusion of several differential diagnoses, such antineutrophil cytoplasmic antibody (ANCA)‐associated vasculitis (AAV). However, emerging evidence suggests that these 2 conditions may overlap in some cases. Here, we report a new case of overlapping IgG4‐RD and AAV. The patient was diagnosed with IgG4‐RD owing to the presence of periaortitis and IgG4 positive tubulointerstitial nephritis. Myeloperoxidase (MPO)‐ANCA positivity, chronic paranasal sinusitis, and glomerulonephritis with granuloma led to a concurrent diagnosis of MPO‐ANCA‐positive granulomatosis with polyangiitis. Our case supports the hypothesis that diagnoses of IgG4‐RD and AAV are not mutually exclusive but can overlap. It can be assumed that an overlap with IgG4‐RD typically affects the granulomatous form of AAV, suggesting a common pathophysiological pathway for these 2 conditions.

In 2019, the classification criteria for IgG4-RD were published by the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR). To discriminate IgG4-RD from disease mimickers, preliminary inclusion and exclusion criteria were defined. One of the exclusion criteria was ANCA positivity. 4 However, emerging evidence suggests that IgG4-RD and AAV can simultaneously occur. 5 We report a new case that simultaneously fulfilled the criteria for IgG4-RD and AAV.

| REP ORT OF A C A S E
A 59-year-old woman was referred to the Department of Rheumatology with complains of malaise, weight loss, fever, and night sweats for a few months. The patient's medical history revealed chronic paranasal sinusitis. Except for hypothyroidism, she had no pre-existing conditions. Physical examination did not reveal any pathological findings. Laboratory tests revealed an increased CRP level of 30 mg/L (reference <5 mg/L), normal C3c level of 1.3 g/L (reference 0.9 to 1.8 g/L), normal C4 level of 0.33 g/L (reference 0.1 to 0.4 g/L) and a creatinine level of 70 μmol/L with an estimated glomerular filtration rate (eGFR) of 82 mL/min. Urine sediment showed mild hematuria (1+ hemoglobin), and no proteinuria. The serum IgG4 level was elevated to 1.85 g/L (reference 0.08-1.4 g/L).
Indirect immunofluorescence test showed a positive ANCA pattern.
Hence, an enzyme-linked immunosorbent assay (ELISA) against the antigens myeloperoxidase (MPO) and proteinase 3 (PR3) were performed, which revealed a positive MPO-ANCA level of 9 U/L (reference <2.5 U/mL). Kidney biopsy showed an interstitium with diffuse, dense infiltrates of plasma cells, granulocytes, and lymphocytes. Notably, there was significant partially cartwheel-type fibrosis in the interstitium. The biopsy showed also multiple small areas of necrosis with cellular debris and focal giant cell infiltration ( Figure 2). One out of 10 glomeruli presented with crescent formation and segmental fibrinoid necrosis ( Figure 3). Furthermore, a few vascular branches with dense transmural inflammatory infiltrates and fibrinoid necrosis of the walls were observed. Immunostaining revealed significant positivity of interstitial plasma cells for IgG4 (max. 23/high-power field) with an IgG4+:IgG+ ratio of 50% in the hotspot areas ( Figure S2).
No evidence of immune complex glomerulonephritis or complement deposition were found as IgA, IgG, IgM as well as C1q and C3c were negative in all glomeruli.
In conclusion, the histopathological analysis revealed 2 major pathologies: a focal pauci-immune crescentic necrotizing glomerulonephritis with additional vasculitis of arteries/arterioles, which is consistent with a renal manifestation of AAV, and a severe, diffuse aggressive tubulointerstitial nephritis, which is consistent with The patient was diagnosed with IgG4-RD due to elevated serum Due to kidney involvement with incipient decline in kidney function, methylprednisolone pulse therapy at 500 mg/d for 3 consecutive days and oral prednisone at 1 mg/kg/d with gradual tapering was administered. We decided to commence immunosuppressive induction therapy with rituximab with 2 pulses of 1 g at intervals of 2 weeks, followed by remission maintenance therapy with 500 mg rituximab at 6 months intervals.
The patient subjectively felt much better after the first days of prednisone therapy, and the fever and night sweats resolved. Two weeks after therapy initiation, CRP levels normalized, there was no further hematuria in the urine analysis, and kidney function remained stable with a creatinine level of 94 μmol/L and an eGFR of 58 mL/min.

| DISCUSS ION
Some studies have investigated the prevalence of ANCA positivity in patients with IgG4-RD. Its prevalence varies widely between 10% and 30%. 6  The exact prevalence of overlapping AAV and IgG4-RD differs widely across study cohorts but seems to be very low. 9   The other way around, additional diagnosis of AAV in a case of IgG4-RD significantly affects the therapy, as discussed below.
Therefore, in our opinion, the discussion whether these cases of overlapping AAV and IgG4-RD can be also interpreted as massbuilding AAV only, has no immediate relevance for clinical practice. However, the observation that AAV and IgG4-RD can overlap or at least share some clinical features may help in understanding their pathophysiology, suggesting there might be a common inflammatory pathway in these 2 conditions. T follicular helper cells appear to play a crucial role in the pathogenesis of IgG4-RD by secreting interleukin (IL)-4 and IL-10, which leads to the expansion of B cells and IgG4-class switching. 13 Studies have shown that the number of T follicular helper cells is increased in the peripheral blood and tissues of patients with IgG4-RD. 14 Several in vitro and in vivo studies have shown that PR3-and MPO-ANCA play pathogenic roles in AAV. 15 Although the mechanisms of ANCA-induced inflammation are well understood, it is still unclear how ANCA is induced. 16 Some studies have shown a predominance of T helper cell cytokine profiles in granulomatous inflammation in GPA. 17,18 Thus it has been discussed that an aberrant T helper cell response might lead to the initiation of GPA. 16 Danlos et al suggested that follicular T helper cells may be the pathogenic link between AAV and IgG4-RD. 5 As elaborated above, in their study, most patients with AAV IgG4-RD overlap were PR3 positive and were diagnosed with GPA.
Interestingly, in our case, granulomatous inflammation with giant cells was seen in the kidney biopsy, which is a possible but rare manifestation of MPO-AAV. The latter typically presents without granulomas and is described as microscopic polyangiitis in the older classification of AAV. 19 Owing to the detected granulomatous inflammation, our case can be classified as MPO-ANCA-positive granulomatosis with polyangiitis. This is consistent with the abovementioned findings of Danlos et al that the overlap of IgG4-RD and AAV predominantly affects patients with granulomatosis and polyangiitis. Furthermore, this finding supports the hypothesis that T follicular helper cells might be a pathophysiological link between these 2 conditions.
It is well known that ANCA positivity can precede the clinical manifestation of AAV. 20 There are some case reports of patients with ANCA-positive IgG4-RD without any clinical features of AAV at the time of diagnosis who developed vasculitis during the follow-up. 21 It is conceivable that the AAV in our patient was in the initial stage, while the IgG4-associated inflammatory processes were highly active. Consistent with this, MPO-ANCA was only moderately high, and glomerulonephritis was rather incipient, while tubulointerstitial nephritis was severe and aggressive.
The additional diagnosis of AAV significantly influences therapy.
Due to the renal vasculitis, the patient was treated with glucocorticoid pulse therapy and rituximab. 3 If there were a sole diagnosis of IgG4-RD, the patient would have been treated with oral glucocorticoids at a significantly lower dosage as monotherapy for remission induction; steroid-sparing maintenance therapy is not necessarily required in IgG4-RD. 22 In summary, our case represents a new example of IgG4-RD with concomitant AAV. Whether these 2 diagnoses represent the 2 phases of a common immunological process remains unclear.
However, they were not mutually exclusive. Even if the diagnosis of IgG4-RD is clear, in case of ANCA positivity in ELISA, an underlying AAV should be considered and accordingly treated.

AUTH O R CO NTR I B UTI O N S
AK and JHB provided informations and figures regarding the pathological findings, AW provided informations and figures regarding the radiological findings. LK wrote the manuscript supported by TW.

ACK N O WLE D G E M ENTS
We thank the patient for agreeing to have an anonymous case report published.. Open Access funding enabled and organized by Projekt DEAL.

CO N FLI C T O F I NTE R E S T S TATE M E NT
There are no relevant conflicts of interest for this paper.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.