Yoko Wada

The clinical course of patients with IgG4-related kidney disease

Long-term follow-up for IgG4-related kidney disease, including relapse information, is sparse. To gather data on this we retrospectively examined the clinical course of 43 patients with IgG4-related kidney disease, in which most patients were treated with, and maintained on, corticosteroids. One month after the start of treatment, most of the abnormal serology and radiology parameters had improved. In 34 of the steroid-treated patients whose follow-up period was more than 12 months (median 34 months), excluding one hemodialysis patient, the estimated glomerular filtration rate (eGFR) before treatment was over 60 ml/min in 14 patients (group A) and under 60 ml/min in 20 patients (group B). In group A, there was no difference between the eGFR before therapy and at the last review. In group B, the mean eGFR before treatment (34.1 ml/min) was significantly improved after 1 month (45.0 ml/min), and renal function was maintained at a similar level through last follow-up. Among 24 evaluated patients at the last review, however, renal atrophy had developed in 2 of 9 in group A and in 9 of 15 in group B. Relapse of IgG4-related lesions occurred in 8 of 40 treated patients. Thus, the response of IgG4-related kidney disease to corticosteroids is rapid, not total, and the recovery of renal function persists for a relatively long time under low-dose maintenance. A large-scale prospective study to formulate more useful treatment strategies is necessary.

Two Susceptibility Loci to Takayasu Arteritis Reveal a Synergistic Role of the IL12B and HLA-B Regions in a Japanese Population

Takayasu arteritis (TAK) is an autoimmune systemic vasculitis of unknown etiology. Although previous studies have revealed that HLA-B*52:01 has an effect on TAK susceptibility, no other genetic determinants have been established so far. Here, we performed genome scanning of 167 TAK cases and 663 healthy controls via Illumina Infinium Human Exome BeadChip arrays, followed by a replication study consisting of 212 TAK cases and 1,322 controls. As a result, we found that the IL12B region on chromosome 5 (rs6871626, overall p = 1.7 × 10(-13), OR = 1.75, 95% CI 1.42-2.16) and the MLX region on chromosome 17 (rs665268, overall p = 5.2 × 10(-7), OR = 1.50, 95% CI 1.28-1.76) as well as the HLA-B region (rs9263739, a proxy of HLA-B*52:01, overall p = 2.8 × 10(-21), OR = 2.44, 95% CI 2.03-2.93) exhibited significant associations. A significant synergistic effect of rs6871626 and rs9263739 was found with a relative excess risk of 3.45, attributable proportion of 0.58, and synergy index of 3.24 (p ≤ 0.00028) in addition to a suggestive synergistic effect between rs665268 and rs926379 (p ≤ 0.027). We also found that rs6871626 showed a significant association with clinical manifestations of TAK, including increased risk and severity of aortic regurgitation, a representative severe complication of TAK. Detection of these susceptibility loci will provide new insights to the basic mechanisms of TAK pathogenesis. Our findings indicate that IL12B plays a fundamental role on the pathophysiology of TAK in combination with HLA-B(∗)52:01 and that common autoimmune mechanisms underlie the pathology of TAK and other autoimmune disorders such as psoriasis and inflammatory bowel diseases in which IL12B is involved as a genetic predisposing factor.

Effective Anti-TNF-α Therapy Can Induce Rapid Resolution and Sustained Decrease of Gastroduodenal Mucosal Amyloid Deposits in Reactive Amyloidosis Associated with Rheumatoid Arthritis

Objective. To examine the effect of anti-tumor necrosis factor-α (anti-TNF) therapy in patients with reactive AA amyloidosis associated with rheumatoid arthritis (RA). Methods. Fourteen patients with reactive AA amyloidosis associated with RA were prospectively evaluated. Four patients were treated with infliximab and 10 with etanercept. The mean period of anti-TNF therapy was 20.1 ± 13.8 months. Laboratory findings and renal function were examined before and after initiation of anti-TNF therapy. In 9 patients the area of amyloid deposits in serial gastroduodenal mucosal biopsy specimens was examined and image analysis was performed. Results. C-reactive protein and serum amyloid A protein levels were significantly reduced after initiation of anti-TNF therapy. Twenty-four hour creatinine clearance improved in 4 patients, did not change in 5, and deteriorated in 3. Twenty-four hour urinary protein excretion was significantly decreased in 3 patients, not exacerbated in 6, and increased in 3 after initiation of anti-TNF therapy. The biopsy specimens from the 9 patients who underwent serial gastroduodenal biopsies showed significant decreases in the area of amyloid deposits, from 8.8% ± 6.4% to 1.6% ± 0.6% (p = 0.003) after initiation of anti-TNF therapy. Four patients showed a sustained decrease in the areas of amyloid deposits in their third biopsy specimens, and amyloid deposits were not detectable in 2. Conclusion. Our results indicate a striking effect of anti-TNF therapy for rapid removal and sustained disappearance of amyloid deposits in gastric mucosal tissue with amelioration of renal functions in patients with reactive amyloidosis due to RA.

A Smad Signaling Network Regulates Islet Cell Proliferation

Pancreatic β-cell loss and dysfunction are critical components of all types of diabetes. Human and rodent β-cells are able to proliferate, and this proliferation is an important defense against the evolution and progression of diabetes. Transforming growth factor-β (TGF-β) signaling has been shown to affect β-cell development, proliferation, and function, but β-cell proliferation is thought to be the only source of new β-cells in the adult. Recently, β-cell dedifferentiation has been shown to be an important contributory mechanism to β-cell failure. In this study, we tie together these two pathways by showing that a network of intracellular TGF-β regulators, smads 7, 2, and 3, control β-cell proliferation after β-cell loss, and specifically, smad7 is necessary for that β-cell proliferation. Importantly, this smad7-mediated proliferation appears to entail passing through a transient, nonpathologic dedifferentiation of β-cells to a pancreatic polypeptide–fold hormone-positive state. TGF-β receptor II appears to be a receptor important for controlling the status of the smad network in β-cells. These studies should help our understanding of properly regulated β-cell replication.

Intense correlation between protein-conjugated acrolein and primary Sjögren's syndrome

BACKGROUND We recently found that an increased plasma concentration of protein-conjugated acrolein is a good biomarker for stroke. Therefore we determine whether the concentration of protein-conjugated acrolein is increased in saliva from patients with primary Sjögrens syndrome. METHODS Stimulated whole-mixed saliva was collected from 10 patients and 13 control subjects. The concentration of protein-conjugated acrolein in saliva and plasma was measured by either Western blotting or enzyme-linked immunosorbent assay. RESULTS The concentration of protein-conjugated acrolein, especially albumin-conjugated acrolein, was greatly increased in saliva from patients with primary Sjögrens syndrome (p<0.001). The concentration of protein-conjugated acrolein was inversely correlated with the flow rate of saliva. CONCLUSION The results indicate that the concentration of protein-conjugated acrolein, a marker of cell or tissue damage, in saliva is well correlated with seriousness of primary Sjögrens syndrome.

Brief report: Takayasu arteritis and ulcerative colitis: High rate of co-occurrence and genetic overlap

Takayasu arteritis (TAK) is a systemic vasculitis affecting large arteries and large branches of the aorta. Ulcerative colitis (UC) is a prevalent autoimmune colitis. Since TAK and UC share HLA–B*52:01 and IL12B as genetic determinants, and since there are case reports of the co‐occurrence of these diseases, we hypothesized that UC is a common complication of TAK. We undertook this study to perform a large‐scale analysis of TAK, both to evaluate the prevalence of concurrent cases of TAK and UC and to identify and estimate susceptibility genes shared between the 2 diseases.

Renal Outcome and Predictors of Clinical Renal Involvement in Patients with Silent Lupus Nephritis

Objectives: We investigated the development of clinically overt nephritis in patients with silent lupus nephritis in an effort to determine predictors of onset. Methods: We selected 31 patients with systemic lupus erythematosus (SLE) who were diagnosed as having silent lupus nephritis between 1985 and 1995. Urinalysis, blood cell count, serum creatinine, complement levels, and anti-double-stranded DNA antibody (anti-dsDNA antibody) levels were followed retrospectively for at least 60 months in each patient. Results: During the follow-up period, 8 patients developed clinical renal disease and 23 had no renal impairment. The mean time of overt nephritis onset was 58 months and renal function deteriorated mildly in 3 patients. Although clinical and laboratory findings were not significantly different at SLE onset, patients with overt nephritis showed both persistent elevation of anti-dsDNA antibodies and persistently low levels of serum C3 and CH50 for at least 24 months before the onset of overt nephritis. Conclusions: Although the renal prognosis was relatively favorable, 25.8% of patients developed overt nephritis during the follow-up period. Elevation of anti-dsDNA antibodies with hypocomplementemia was persisted in these patients, suggesting the utility of these factors as predictors of clinical renal involvement in silent lupus nephritis.

Smad signaling pathways regulate pancreatic endocrine development.

Expansion of the pancreatic endocrine cell population occurs during both embryonic development and during post-natal pancreatic growth and regeneration. Mechanisms of the expansion of endocrine cells during embryonic development are not completely understood, and no clear mechanistic link has been established between growth of the embryonic endocrine pancreas and the islet cell replication that occurs in an adult animal. We found that transforming growth factor-beta (TGF-β) superfamily signaling, which has been implicated in many developmental processes, plays a key role in regulating pancreatic endocrine maturation and development. Specifically, the intracellular mediators of TGF-β signaling, smad2 and smad3, along with their inhibitor smad7, appear to mediate this process. Smad2, smad3 and smad7 were all broadly expressed throughout the early embryonic pancreatic epithelium. However, during later stages of development, smad2 and smad3 became strongly localized to the nuclei of the endocrine positive cells, whereas the inhibitory smad7 became absent in the endocrine component. Genetic inactivation of smad2 and smad3 led to a significant expansion of the embryonic endocrine compartment, whereas genetic inactivation of smad7 led to a significant decrease in the endocrine compartment. In vitro antisense studies further corroborated these results and supported the possibility that interplay between the inhibitory smad7 and the intracellular mediators smad2/3 is a control point for pancreatic endocrine development. These results should provide a better understanding of the key control mechanisms for β-cell development.

Takayasu arteritis and ulcerative colitis: high rate of co-occurrence and genetic overlap.

Takayasu arteritis (TAK) is a systemic vasculitis affecting large arteries and large branches of the aorta. Ulcerative colitis (UC) is a prevalent autoimmune colitis. Since TAK and UC share HLA–B*52:01 and IL12B as genetic determinants, and since there are case reports of the co‐occurrence of these diseases, we hypothesized that UC is a common complication of TAK. We undertook this study to perform a large‐scale analysis of TAK, both to evaluate the prevalence of concurrent cases of TAK and UC and to identify and estimate susceptibility genes shared between the 2 diseases.

A case of MPO- and PR3-ANCA-positive hypertrophic cranial pachymeningitis with elevated serum IgG4

We report a case of orbital tumor and hypertrophic cranial pachymeningitis in a 64-year-old woman, who was initially suspected to have IgG4-related disease because of an elevated level of serum IgG4 at onset. However, her condition was resistant to glucocorticoid therapy, and additional cyclophosphamide was necessary to control the disease activity. Additional features included elevated levels of serum myeloperoxidase (MPO) and proteinase-3-anti-neutrophil cytoplasmic antibody (PR3-ANCA), and biopsy specimens from the orbital mass revealed very few infiltrating IgG4-positive cells. Instead, rupture of the elastic layer of the arterial walls with neovascularization and a small number of giant cells were observed. Considering these findings and the clinical course, the disease was considered more likely to be ANCA-associated pachymeningitis with elevation of the serum IgG4 level.