Kiyoaki Ito

Henoch-Schönlein purpura nephritis in a patient with IgG4-related disease: A possible association.

We report a case of Henoch- Schönlein purpura nephritis (HSPN) associated with tubulointerstitial nephritis (TIN) and chronic sclerosing sialoadenitis. The patient is a 75-year-old Japanese woman who had bilateral submandibular gland swelling, palpable purpura on the lower legs, and decreased renal function with hematoproteinuria and marked hypocomplementemia, but no skin lesion suggestive of systemic lupus erythematosus (SLE), and did not fulfill the classification criteria for SLE. Her serum IgG4 level was high and immunostaining of renal biopsies revealed marked infiltration by IgG4-positive plasma cells in the interstitium, confirming the diagnosis of IgG4- related disease. On the other hand, glomeruli showed endocapillary proliferative glomerulonephritis with mesangial IgA and C3 deposition demonstrated by immunofluorescence staining, which were typical glomerular lesions for HSPN. The glomerular and tubulointerstitial lesions responded to steroid therapy dramatically, and her renal function recovered to within the normal range within a month. This case suggests a possible new association between HSPN and IgG4-related disease.

Hints to the diagnosis of uromodulin kidney disease

Abstract Background Uromodulin kidney disease (UKD) is an inherited kidney disease caused by a uromodulin (UMOD) gene mutation. The UMOD gene encodes the Tamm–Horsfall protein (THP), which is the most abundant protein in healthy human urine. Because of its rarity, the incidence of UKD has not been fully elucidated. The purpose of the present study is to clarify the frequency of UKD among patients who underwent renal biopsy. Methods Immunostaining for THP was performed for patients <50 years of age with renal insufficiency and hyperuricemia without overt urinalysis abnormality from renal biopsy databases. Serum and urinary THP concentrations were evaluated in available individuals. Results Fifteen patients were selected for immunostaining from a total of 3787 patients. In three independent patients, abnormal THP accumulation in renal tubular cells was observed. A novel missense A247P UMOD mutation was detected in two of the three patients, including one having a typical family history of familial juvenile hyperuricemic nephropathy. Serum and urinary THP concentrations of all available patients with UMOD A247P mutation were significantly lower than those of controls. Conclusions In the present study, UKD was detected in <1 in 1000 subjects who underwent renal biopsies. However, in subjects meeting all of the above criteria, abnormal THP accumulation was detected in 20% (3/15), suggesting that renal biopsy with immunostaining for THP is a good tool for diagnosing UKD. Also, low serum THP concentration detected in the present subjects might be a good diagnostic marker or important in understanding the pathogenesis of UKD.

A case developing minimal change disease during the course of IgG4-related disease

We describe a 66-year-old male with immunoglobulin G4-related disease (IgG4-RD) presenting with minimal change disease (MCD). Three years prior to this admission, the patient had been diagnosed with IgG4-RD. The development of sudden massive proteinuria (4+; 16.7 g/gCr) with a weight gain of 8 kg within a two-week period was noted, and nephrotic syndrome was suspected. The patients serum IgG4 level did not increase and hypocomplementemia was not found. A renal biopsy showed no cellular infiltration in the renal interstitium, and no spiking or bubbling was found on periodic acid methenamine silver staining. On electron microscopy, foot process effacement was seen, but no subepithelial electron-dense deposits were found. The patient was diagnosed with MCD. Ten days after starting prednisolone (60 mg/day), proteinuria was negative. Since IgG4-RD and MCD share a T-helper 2-dominant immunoreaction, the development of MCD in IgG4-RD patients may reflect more than a mere coincidence.

Analysis of IgG4-positive clones in affected organs of IgG4-related disease

Abstract Objective: We investigated class switch reaction (CSR) in affected organs and evaluated whether the same or genetically related clones exist in IgG4-RD. Methods: We studied three patients with IgG4-RD. Total cellular RNA was extracted from salivary glands and peripheral blood and lung tissue. Activation-induced cytidine deaminase (AID) and immunoglobulin heavy chain third complementarity determining region (IgVH-CDR3) of IgM and IgG4 were detected by reverse transcription polymerase chain reaction (RT-PCR). We analyzed the clonal relationship of infiltrating IgG4-positive cells, as compared with IgM. We determined the existence of common clones among organs and patients. Result: AID was expressed in salivary glands of all patients and lung tissue in one. Closely related IgVH-CDR3 sequences in infiltrating IgG4-positive cells were detected in salivary glands and lung tissue. Identical IgVH-CDR3 sequence between IgM and IgG4 in salivary glands was detected in one patient, indicating CSR in salivary glands. Identical IgVH-CDR3 sequences of IgG4-positive cells were detected between salivary glands and peripheral blood in two patients. Four identical sequences of IgVH-CDR3 existed between patients. Interestingly, one of the four sequences was detected in all patients. Conclusion: Our results demonstrate the existence of common antigen(s) shared by patients with IgG4-RD.

Post‐infectious acute glomerulonephritis with podocytopathy induced by parvovirus B19 infection

Human parvovirus B19 infection causes a variety of glomerular diseases such as post‐infectious acute glomerulonephritis and collapsing glomerulopathy. Although each of these appears independently, it has not been fully determined why parvovirus B19 provokes such a variety of different glomerular phenotypes. Here, we report a 68‐year‐old Japanese man who showed endocapillary proliferative glomerulonephritis admixed with podocytopathy in association with parvovirus B19 infection. The patient showed acute onset of heavy proteinuria, microscopic hematuria and kidney dysfunction with arthralgia and oliguria after close contact with a person suffering from erythema infectiosum. In the kidney biopsy specimen, glomeruli revealed diffuse and global endocapillary infiltration of inflammatory cells, with some also showing tuft collapse with aberrant vacuolation, swelling, and hyperplasia of glomerular epithelial cells. Immunofluorescence revealed dense granular C3 deposition that resembled the “starry sky pattern”. Intravenous glucocorticoid pulse therapy followed by oral prednisolone and cyclosporine combination therapy resulted in considerable amelioration of the kidney dysfunction and urinary abnormalities. The present case reveals that parvovirus B19 infection can induce different glomerular phenotypes even in the same kidney structure. This finding may provide hints useful for the further elucidation of the pathogenesis of parvovirus B19‐induced glomerular lesions.

Abundant a proliferation-inducing ligand (APRIL)-producing macrophages contribute to plasma cell accumulation in immunoglobulin G4–related disease

Abstract Background This study aimed to investigate the contribution of a proliferation-inducing ligand (APRIL), a member of the tumor necrosis factor (TNF) superfamily implicated in plasma cell survival, to the development of plasma cell–rich lesions in immunoglobulin G4–related disease (IgG4-RD). Methods We performed immunohistochemical staining for APRIL with Stalk-1 and Aprily-8 antibodies specifically recognizing APRIL-producing cells and secreted APRIL, respectively, in renal and submandibular lesions of IgG4-RD in comparison with those of Sjögren’s syndrome and sialolithiasis. Results Numerous Stalk-1-positive APRIL-producing cells were detectable in lesions of IgG4-RD. These cells, identified as CD163-positive M2 macrophages, secreted APRIL that distributed close to and even on infiltrating plasma cells. In contrast, APRIL-producing cells and the secreted form of APRIL were rarely detectable in lesions of Sjögren’s syndrome or sialolithiasis. Notably, APRIL expression decreased concomitantly with the level of plasma cell infiltration after successful glucocorticoid treatment. Conclusions Abundant infiltration into tissue lesions of APRIL-producing M2 macrophages and retention of secreted APRIL in plasma–cell–rich areas support a role for APRIL in the pathogenesis of plasma cell–rich lesions in IgG4-RD.

THU0432 Pericardial effusion is an independent factor predictive of scleroderma renal crisis

Background Scleroderma renal crisis (SRC) adversely affects renal and patient survival in systemic scleroderma (SSc)[.1, 2 The survival rate of SRC has been improved dramatically by angiotensin-converting enzyme inhibitor therapy, but SRC still has a poor prognosis.3 Factors predictive of SRC include early diffuse skin involvement, rapid skin thickening, anti-RNA polymerase (RNAP) III antibodies, arthralgia/synovitis, and high glucocorticoid dosage.4 Although classical data have implicated pericardial effusion as another predictive factor of SRC,5 its role in SRC has not been well established. Objectives To clarify the clinical impact of pericardial effusion as a predictor of SRC. Methods Ninety-five patients diagnosed with SSc at our hospital between January 2003 and December 2017 were enrolled in the study. They were divided into a pericardial effusion group (n=21) and non-pericardial effusion group (n=74), and their clinical features retrospectively compared. Cox-regression analysis was performed to identify factors predictive of SRC. Results The patients comprised 14 men and 81 women with an average age of 57.4 years (range, 14 to 82) and the mean observation period was 65 months (range, 1 to 125). Pericardial effusion was detected in 21 of 95 (22.1%) cases. In the pericardial effusion group, SRC, modified Rodnan’s total skin thickness score (mRSS), C-reactive protein, maximum glucocorticoid dose, proteinuria, finger apex ulcers, and interstitial pneumonia were significantly more prevalent compared to the non-pericardial effusion group. Cox regression analysis indicated that pericardial effusion (hazard ratio; HR 11.8 [95% CI 1.6–84.6], p=0.014) and anti-RNAP III antibodies (HR 11.1 [95% Cl 2.0–59.6], p=0.005) were independent risk factors for SRC, while mRSS (HR 1.0 [95% CI 0.9–1.1], p=0.12), finger apex ulcers (HR 0.57 [95% CI 0.073–4.2], p=0.57), max glucocorticoid dose (HR 1.0 [95% CI 0.9–1.0, p=0.89]), and interstitial pneumonia (HR 0.9 [95%CI 0.2–3.7], p=0.96) were not. In the Kaplan-Meier method, SRC was significantly increased in the pericardial effusion group compared to non-pericardial effusion group (p<0.0001 by log rank test). Conclusions Pericardial effusion is another independent factor predictive of SRC in addition to anti-RNAP III antibodies. References [1] Steen VD, et al. Scleroderma renal crisis. Rheum Dis Clin North Am2003;29:315–33. [2] Hamaguchi Y, et al. Clinical and immunologic predictors of scleroderma renal crisis in Japanese systemic sclerosis patients with anti-RNA polymerase III antibodies. Arthritis Rheumatol2015;67:1045–52. [3] Penn H, et al. Scleroderma renal crisis: patient characteristics and long-term outcomes. QJM2007;100:485–94. [4] Woodworth TG, et al. Scleroderma renal crisis and renal involvement in systemic sclerosis. Nat Rev Rheumatol2016;12:678–91. [5] Steen VD, et al. Factors predicting development of renal involvement in progressive systemic sclerosis. Am J Med1984;76:779–86. Disclosure of Interest None declared

THU0623 Serum igg4 levels at diagnosis can predict the outcomes of untreated patients with igg4-related disease: a retrospective study

Background IgG4-related disease (IgG4-RD) is a recently recognised systemic fibro-inflammatory disorder that can affect many organs.1 In IgG4-RD, spontaneous, or at least temporary, remissions without treatment have been reported, and watchful waiting may be appropriate in certain patients with asymptomatic and inactive disease.2 However, the outcomes of patients with IgG4-RD who do not undergo treatment are still unclear. Objectives This study aimed to clarify the outcomes of untreated patients with IgG4-RD and the factors related to the outcomes. Methods We retrospectively reviewed the medical records of 107 patients with IgG4-RD, who were followed up for more than 6 months, at a single centre in Japan. Among them, 27 patients were followed up without treatment after the initial diagnosis. We compared the clinical features of these 27 patients with those of the 80 patients who underwent treatment. The outcomes of untreated patients were investigated, and logistic regression analysis was performed to assess factors related to the outcomes. Deterioration of IgG4-RD was defined as symptomatic, radiological, or functional exacerbation of the organ involved or new organ involvement. Results The patients comprised 73 men and 34 women (mean age 65.7 years). The follow-up periods were 7–252 (mean, 64.1) months, and the serum IgG4 levels at diagnosis were 10.7–3610 (mean, 706) mg/dL. The 27 untreated patients had significantly fewer affected organs (1.9±1.2 vs 3.0±1.6, p=0.001), lower IgG4-RD responder index (10.8±5.1 vs 13.8±6.8, p=0.048), and lower frequency of ophthalmic and renal parenchymal lesions (25.9% vs 53.8%, p=0.015, and 3.7% vs 26.3%, p=0.012, respectively) than did the 80 patients who underwent treatment. Of these 27 patients, 8 experienced deterioration of IgG4-RD 3–232 months (mean, 62.8) after the diagnosis. New organ involvement was observed in all 8 patients, 2 of whom concurrently suffered exacerbation of the organs involved. In age- and sex-adjusted logistic regression analysis, serum IgG4 elevation (per 100 mg/dL, odds ratio 1.194, 95% confidence interval 1.017–1.402, p=0.030) was the only significant factor related to deterioration of disease in untreated patients with IgG4-RD. Conclusions The present study suggests that serum IgG4 levels may be useful to predict the outcomes of untreated patients with IgG4-RD, who tend to have fewer affected organs and lower IgG4-RD responder index. References [1] Stone JH, et al. IgG4-related disease. N Engl J Med2012Feb 9;366(6):539–51. [2] Khosroshahi A, et al. International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease.Arthritis Rheumatol2015Jul;67(7):1688–99. Disclosure of Interest None declared

FRI0617 Diagnostic sensitivity of cutoff values of IGG4-positive plasma cell number and IGG4-positive/CD138-positive cell ratio in typical multiple lesions of patients with IGG4-related disease

Background Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized systemic inflammatory disease with multi-organ involvement [1]. Diagnostically, two of the most important hallmarks of IgG4-RD are high IgG4-positive plasma cell (PC) counts and high IgG4/IgG ratios in affected organs. Although the International consensus statement (ICS) on the pathology of IgG4-RD adopted different IgG4-positive PC counts among affected organs for the diagnosis to differentiate IgG4-RD mimickers from IgG4-RD [2], histological and immunohistochemical findings of the specimens from not only one but multiple organs in the same patient has not been evaluated. Objectives This study aimed to investigate the diagnostic sensitivity of the cutoff values of IgG4-positive PC number and IgG4-positive/CD138-positive cell ratio proposed by the International consensus statement (ICS) on the pathology of IgG4-RD in typical multiple lesions of patients with IgG4-RD. Methods We evaluated IgG4-positive PC number and IgG4-positive/CD138-positive cell ratio in 35 samples from 16 IgG4-RD patients having more than two typical lesions of IgG4-RD. Results We evaluated twelve submandibular, eleven ophthalmic, four skin, four kidney, two pancreatic, and one bronchus and prostate lesion each in 16 patients with typical clinical, serological, and radiographic features. Concerning IgG4+ PC number per high power field, most ophthalmic (8/11), kidney (4/4), pancreatic (2/2), and bronchial lesions (1/1) fulfilled the cutoff value of ICS, whereas many of the submandibular (5/12) and skin lesions (0/4) did not. In contrast to the absolute number, almost all lesions fulfilled the cutoff value of IgG4+/CD138+ cell ratio. In five cases, only one or two lesions in the same patient fulfilled the cutoff value of ICS, while the others did not. Conclusions These results suggest that ICS criteria have different sensitivities among the affected organs in diagnosing IgG4-RD. References Stone JH, et al. IgG4-related disease. N Engl J Med. 2012;366:539–51. Deshpande V, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25:1181–92. Disclosure of Interest None declared

AB1171 Clinical Significance of Anti-Nuclear Antibodies in IGG4-Related Disease

Background Anti-nuclear antibodies (ANAs) are autoantibodies binding to various components of the cell nucleus. ANAs are often detected in various systemic autoimmune diseases. IgG4-related disease (IgG4-RD) is a newly recognized systemic fibroinflammatory condition of unknown etiology1) involving various organs. ANAs are detected in 15% of IgG4-RD patients1) and this fact is the basis of the suggestion that IgG4-RD may be autoimmune in nature. However, disease-specific ANAs such as anti-SS-A antibody and anti-dsDNA antibody remain to be clarified in IgG4-RD. Objectives The present study was conducted to clarify the positive rate, titer, and clinical significance of ANAs in IgG4-RD. Methods We enrolled 70 IgG4-RD patients (45 males, 25 females; mean age 64.1±1.2 years) diagnosed according to comprehensive diagnostic criteria for IgG4-RD2). The positive rate, titer and staining pattern of ANA in IgG4-RD patients using immunofluorescence method were retrospectively compared to those in 65 patients with systemic lupus erythematosus (SLE), 22 with anti-SS-A antibody positive Sjögrens syndrome (SjS), and 341 healthy controls (HC) who received medical examination. In addition, we analyzed the relationship between the titer of ANAs and serum IgG level in the IgG4-RD patients. Results The ANA titers were as follows (Figure); 21 (30.0%) patients showed ≥1:40 and 7 (10.0%) patients ≥1:160 in IgG4-RD; 65 (100%) patients showed ≥1:40 and 55 (86.4%) ≥1:160 in SLE; 21 (95.5%) patients showed ≥1:40 and 19 (86.4%) ≥1:160 in SjS; 96 (30.9%) HC showed ≥1:40 and 5 (1.5%) ≥1:160. The dominant staining pattern of ANAs was homogenous (79.0%) in IgG4-RD, but speckled with/without homogenous in SLE (speckled 31.7%, speckled + homogenous 31.7%) and SjS (speckled 47.8%, speckled + homogenous 26.1%). Serum IgG level was not different between IgG4-RD patients showing ≤1:80 and ≥1:160 of ANAs (≤1:80, mean 2,084 mg/dL, range 1,078-5,358 mg/dL; ≥1:160, mean 3,068 mg/dL, range 1,765-4,661 mg/dL; p =0.078), although serum IgG levels tended to be high in cases in which ANAs revealed high titers. Conclusions The positive rate, titer and staining pattern of ANAs in IgG4-RD were similar to those in HC, and are quite different from those in SLE and SjS. These results indicate that ANA detection is nonspecific in IgG4-RD, appearing according to serum IgG elevation. ANAs are not useful in the diagnosis and do not contribute to the pathogenesis in IgG4-RD. References Yamamoto M, Takahashi H, Shinomura Y. Mechanisms and assessment of IgG4-related disease: lessons for the rheumatologist. Nat Rev Rheumatol 2014; 10, 148-159. Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol 2012; 22, 21-30. Disclosure of Interest None declared