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This study investigated the clinical features of IgG4-RKD patients with hypocomplementemia compared with those without it, so as to clarify the factors related to hypocomplementemia.In this single-center retrospective study, we analyzed the clinical features of 25 patients with IgG4-RKD according to the presence/absence of hypocomplementemia. Additionally, we validated the results of a single-center study in a separate large multicenter cohort of 328 patients with IgG4-RD, and searched for factors related to hypocomplementemia.Serum IgG levels (The present study suggests that hypocomplementemia is associated with elevation of IgG subclasses other than IgG4 including IgG1 in IgG4-RKD.

Objectives In IgG4-related dacryoadenitis and/or sialadenitis (IgG4-DS), involvement of two or more sets of lacrimal glands (LGs) and/or major salivary glands (MSGs) is regarded as a specific finding with diagnostic significance. This study aimed to clarify the influence of this factor on the overall clinical picture of IgG4-DS. Methods We retrospectively reviewed the medical records of 130 patients with IgG4-related disease, 97 of whom were diagnosed with IgG4-DS. We determined their clinical features according to the presence/absence of involvement of ≥2 sets of LGs and/or MSGs and compared the results with those obtained in 33 DS-limited patients. Results The IgG4-DS patients comprised 60 men and 37 women (median age 65 years). The median serum IgG4 level at diagnosis was 548 mg/dL. The patients with involvement of ≥2 sets (n = 44) had significantly more affected organs, lower serum C3 and C4 levels, and a tendency to have higher serum IgG levels and IgG4-RD responder index than did those without it (n = 53). In the 33 DS-limited patients, these two groups had no significant differences in clinical features. Conclusions Involvement of ≥2 sets of LGs and/or MSGs suggests greater systemic disease activity mainly reflected by involvement of more organs.

The objective of this study is to evaluate the efficacy and safety of bortezomib for treating systemic lupus erythematosus (SLE), in patients whose disease activity could not be controlled.Fourteen SLE patients with persistent disease activity were selected, who required prednisolone doses of10 mg/d despite concomitant immunosuppressive therapy. Patients were randomly administered either bortezomib or a placebo, eight times. The primary and secondary end-points were a change in anti-dsDNA antibody titer at week 24 and the SLE Responder Index (SRI), respectively.In the bortezomib group, four out of eight patients discontinued the trial; three others failed to complete the minimum protocol treatment due to adverse reactions. The changes in anti-dsDNA antibody titers at week 24 were 4.24% and -1.96%, for the bortezomib and placebo groups, respectively, disconfirming bortezomib's efficacy. In contrast, the corresponding SRI at week 12 was 75% and 40%.As bortezomib therapy for SLE is associated with many adverse reactions, treatment indications should be selected carefully, and protocols should aim to prevent these occurrences. Although the change in anti-dsDNA antibody titer did not support the efficacy of bortezomib as a treatment for SLE, high SRI in the treatment group suggests bortezomib may utilize mechanisms other than inhibition of anti-dsDNA antibody production.

The purpose of our study was to define the clinical characteristics of anti-centromere antibody and anti-SS-A/Ro antibody (ACA/SS-A) double positive Sjögren's syndrome (SS) and to clarify the clinical impact of these antibodies.We examined 108 patients (6 males, mean age 57.9 years) with SS who underwent labial salivary gland biopsy. The patients were divided into four groups by ACA and anti-SS-A/Ro antibody positivity. Symptoms, laboratory and pathological data, and scleroderma-related data were compared among the groups.The cohort consisted of 16 ACA/SS-A double positive, 20 ACA single positive, 67 SS-A single positive, and 5 ACA/SS-A double negative SS. ACA/SS-A double positive SS were significantly older than SS-A single positive SS (mean age 71.1 vs. 53.1 years). They had higher EULAR Sjögren's syndrome disease activity index (ESSDAI) at diagnosis (mean 3.81 vs. 0.50) and higher serum IgG (mean 2009 vs. 1389 mg/dL) than ACA single positive SS. No patients developed skin sclerosis during a mean follow-up period of 45.6 months (range: 1-178).These results demonstrate that ACA/SS-A double positive SS is distinct from ACA single positive and SSA single positive SS. The combination of ACA and anti-SS-A/Ro antibody in SS should deserve greater attention in clinical practice.

We aimed to evaluate the association between the change in serum IL-6 during the clinical course of tocilizumab (TCZ) therapy and rheumatoid arthritis (RA) disease activity or occurrence of adverse events.General laboratory data including serum IL-6 levels and physical findings were obtained every 4 weeks, and, in addition, at the time when any adverse events occurred.The proportion achieving Clinical Disease Activity Index (CDAI) remission at 52 weeks was significantly lower in 20 patients with serum IL-6 ≥ 30 pg/ml at 12 weeks than 24 patients with serum IL-6 30 pg/ml. In 17 patients with serum IL-6 ≥ 30 pg/ml at 24 weeks, the proportion achieving CDAI remission was also significantly lower than 27 patients with serum IL-6 30 pg/ml then. In these 17 patients, Disease Activity Score (DAS) 28-ESR and CDAI at 52 weeks were significantly higher than those with serum IL-6 30 pg/ml. Age- and sex-adjusted logistic regression analysis showed logIL-6 at 12 weeks to be a predictive factor for DAS28-ESR remission at 52 weeks.Serum IL-6 levels from 12 to 24 weeks after TCZ initiation better reflect the efficacy of TCZ at 52 weeks.

We describe an 81-year-old man with immunoglobulin G4-related disease (IgG4-RD) presenting with submandibular gland, lymph node, lung, kidney, aortic wall, and prostate lesions with concomitant gastric cancer. After curative surgical treatment of the gastric cancer, corticosteroid therapy for progressively decreasing renal function was started. Before starting steroid therapy, fluorodeoxyglucose positron emission tomography-computed tomography revealed multiple lesions of IgG4-RD but no metastasis of the cancer. However, the patient died 3 months after initiation of corticosteroid therapy because of recurrence of the gastric cancer. In this case, the imaging features of IgG4-tubulointerstitial nephritis dramatically changed during the clinical course of co-existing gastric cancer. The imaging features of the present case may provide clues to the pattern of spread of IgG4 lesions in the kidney.

To evaluate the clinical and structural efficacy of tocilizumab (TCZ) during its long-term administration in patients with rheumatoid arthritis (RA).In total, 693 patients with RA who started TCZ therapy were followed for 3 years. Clinical efficacy was evaluated by DAS28-ESR and Boolean remission rates in 544 patients. Joint damage was assessed by calculating the modified total Sharp score (mTSS) in 50 patients.When the reason for discontinuation was limited to inadequate response or adverse events, the 1-, 2-, and 3-year continuation rates were 84.0%, 76.8%, and 72.2%, respectively. The mean DAS28-ESR was initially 5.1 and decreased to 2.5 at 6 months and to 2.2 at 36 months. The Boolean remission rate was initially 0.9% and increased to 21.7% at 6 months and to 32.2% at 36 months. The structural remission rates (ΔmTSS/year ≤ 0.5) were 68.8%, 78.6%, and 88.9% within the first, second, and third years, respectively. The structural remission rate at 3 years (ΔmTSS ≤ 1.5) was 66.0%, and earlier achievement of swollen joint count (SJC) of 1 or less resulted in better outcomes.TCZ was highly efficacious, and bone destruction was strongly prevented. SJC was an easy-to-use indicator of joint destruction.

To the Editor,Occasionally, we encounter patients who develop overlapping features of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), which is termed as ‘rhupus syndrome’ [1]. Thi...

The aims of this study were to clarify the long-term outcome of patients with polymyositis and dermatomyositis (PM/DM) and to elucidate prognostic factors using statistical analysis.We enrolled patients with PM/DM who visited our department between 1990 and 2014. Diagnoses of PM/DM and clinically amyopathic DM were based on the definitions of Bohan and Peter, and Sontheimer, respectively. We also obtained clinical data, such as age of onset, sex, medications, and presence of interstitial lung disease and malignancies, as well as laboratory tests, including the values of creatine kinase, KL-6, and ferritin. The follow-up was conducted until June 2014.A total of 124 patients (PM: 46, DM: 78) were enrolled. The mean age of onset was 53.5 years, and females were predominant (64.5%). Overall survival rates were 93%, 86%, and 78% for 1, 5, and 10 years, respectively. The survival rates were significantly lower in patients with higher age of onset, with malignancies, and with hyperferritinemia in univariate analysis; however, multivariate analysis identified age of onset and serum ferritin as the most significant prognostic factors.Our study indicates that when age of onset and serum ferritin are used in combination, we can predict prognosis of patients with PM/DM.

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 patient's 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.

This study aimed to investigate the diagnostic sensitivity of the cutoff values of IgG4-positive plasma cell (PC) number and IgG4-positive/CD138-positive cell ratio proposed by the International consensus statement (ICS) on the pathology of IgG4-related disease (IgG4-RD) in typical multiple lesions of patients with IgG4-RD.We evaluated IgG4-positive PC number and IgG4-positive/CD138-positive cell ratio in 39 samples from 18 IgG4-RD patients having more than two typical lesions of IgG4-RD.We evaluated 12 submandibular, 12 ophthalmic, six skin, five kidney, two pancreatic, and one bronchus and prostate lesion each in 18 patients with typical clinical, serological, and radiographic features. Concerning IgG4 + PC number per high-power field, most ophthalmic (11/12), kidney (5/5), pancreatic (2/2), and bronchial lesions (1/1) fulfilled the cutoff value of ICS, whereas many of the submandibular (6/12) and skin lesions (0/6) did not. In contrast to the absolute number, all lesions fulfilled the cutoff value of IgG4+/CD138 + cell ratio. In eight cases, only one or two lesions in the same patient fulfilled the cutoff value of ICS, while the others did not.These results suggest that ICS criteria have different sensitivities among the affected organs for the diagnosis of IgG4-RD.

We describe a patient with refractory cutaneous polyarteritis nodosa (CPAN) with hepatitis B virus (HBV) carrier status who was successfully treated with tumor necrosis factor alpha (TNF-α) blockade, using etanercept, and we review 5 similar cases. We administered etanercept because of the occurrence of repeated flares despite aggressive therapy. C-reactive protein normalization; prednisolone dose-sparing; and absence of any adverse events, including HBV reactivation with nucleotide analogue administration, or renal dysfunction, have been achieved for 8 months. TNF-α blockade should be considered for intractable CPAN. © 2012 Japan College of Rheumatology., This is the pre-peer reviewed version of the following article: http://informahealthcare.com/doi/abs/10.3109/s10165-012-0732-8, which has been published in final form at http://dspace.lib.kanazawa-u.ac.jp/dspace/handle/2297/36280 .

We investigated class switch reaction (CSR) in affected organs and evaluated whether the same or genetically related clones exist in IgG4-RD.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.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.Our results demonstrate the existence of common antigen(s) shared by patients with IgG4-RD.

We describe a 64-year-old woman with chronic sclerosing sialadenitis and dacryoadenitis, which developed during treatment for cervical lymph node tuberculosis. Anti-tuberculosis treatment did not improve the swelling in the lacrimal and submandibular glands, and a biopsy specimen of the lacrimal gland showed inflammation, with abundant lymphoid follicles with fibrosis and granuloma without caseous necrosis. Immunohistological examination of a repeat biopsy specimen showed abundant immunoglobulin (Ig) G4-positive plasma cell infiltration. Corticosteroid therapy improved the salivary gland swelling without reactivation of the tuberculosis. This case suggests that an abnormal immunological reaction to tuberculosis may be one of the etiological candidates for IgG4-related disease.

Clinically amyopathic dermatomyositis (CADM) is a subtype of dermatomyositis with a typical cutaneous manifestation and little or no muscle involvement [1]. CADM is frequently associated with rapid...

A 43-year-old woman with systemic lupus erythematosus (SLE) had an episode of mononeuritis multiplex prior to developing protein-losing gastroenteropathy. Four years later, she had another episode of mononeuritis multiplex, followed by choroidopathy. These manifestations are uncommon in SLE, but may be attributed to vasculitis. The laboratory findings indicated that the elevation of D-dimer and thrombin-antithrombin complex levels seen in this case might be useful in evaluating vascular lesions in SLE.

To clarify the prevalence and time course of hepatitis B virus (HBV) infection in patients with systemic lupus erythematosus under immunosuppressive therapy.We performed serological examination of 248 lupus patients to determine the presence of HBV, including hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc). Serum HBV DNA levels were measured in HBsAg-positive patients or resolved HBV carriers (HBsAg-negative, anti-HBs-positive, and/or anti-HBc-positive). If possible, we repeatedly performed examination of markers of HBV infection in resolved carriers.Two (0.8%) patients were positive for HBsAg. Among 41 (16.5%) patients who were considered as resolved HBV carriers, 1 (2.4%) showed serum HBV DNA, which indicated occult HBV infection. The mean age and positive rate of anti-double stranded DNA antibody were significantly higher in resolved carriers than in anti-HBs- and anti-HBc-negative patients. Repeated examination showed that the anti-HBs and anti-HBc titer decreased below the threshold in 4 resolved carriers.The prevalence of resolved HBV carriers in Japanese lupus patients was 16.5%. Among them, occult HBV infection and decrease in anti-HBs and anti-HBc titer were observed. These findings indicated that all lupus patients should undergo serological examination for HBV before treatment. If patients have already been treated, we must carefully monitor their liver function, even when all HBV markers are negative.

To the Editor,A 66-year-old woman was admitted to our department for the evaluation and treatment of palpable purpura and skin ulcers of the bilateral lower extremities (Figure 1A) and thrombocytop...

To the Editor,I read with interest the case report by Horai et al. [1] describing a 22-year-old patient who developed Takayasu arteritis (TAK) while undergoing infliximab therapy for ulcerative col...

Objectives This study aimed to investigate the clinicopathological changes induced by corticosteroid therapy in immunoglobulin (Ig)G4-related tubulointerstitial nephritis (TIN). Methods We studied six IgG4-related TIN patients receiving renal biopsies before and after corticosteroid therapy. Their clinical data and histological findings were evaluated before and after therapy. Results Elevated serum creatinine levels rapidly improved after corticosteroid therapy except for two patients, in whom it persisted. Abnormal radiological findings improved in all patients, although focal cortical atrophy persisted in three. Histologically, TIN-like dense lymphoplasmacytic infiltration, interstitial fibrosis, IgG4-positive plasma cell, CD4+CD25+ T cell, and Foxp3+ cell infiltration were characteristic before therapy. After therapy, the area with cell infiltration decreased and regional fibrosis became evident in the renal interstitium. The number of IgG4-positive plasma cells and Foxp3+ cells significantly diminished even in the early stage of therapy, whereas low to moderate numbers of CD4+ and CD8+ T cells still infiltrated where inflammation persisted in the later stage. Conclusions Our study shows that persistent renal insufficiency associated with macroscopic atrophy and microscopic fibrosis is not so rare in IgG4-related TIN. Pathologically, the behavior of regulatory T cells during the clinical course is quite similar to that of IgG4-positive plasma cells, and the behavior pattern of those cells is distinctive.