Sjögren's Syndrome Presenting with Temporary Hemiplegia Mimicking Transient Ischemic Attack.

Sjögren's syndrome manifests with a wide variety of neurologic symptoms. This case report presents a 53-year-old woman with Sjögren's syndrome associated with temporal hemiplegia, which was suspected to be a transient ischemic attack. After induction of immunosuppressive therapies [high-dose prednisolone (1 mg/kg/day) and intravenous cyclophosphamide (total 5 g)], the hemiplegia did not reappear and the blood flow abnormalities remarkably improved as depicted on electroencephalography and single photon emission computed tomography. This case suggests that temporal hemiplegia presenting with transient ischemia-like attack symptoms may be a neurologic manifestation of Sjögren's syndrome and responsive to immunosuppressive therapy.

Refractory Takayasu arteritis successfully treated with rituximab: case-based review.

Takayasu arteritis (TAK) is a subtype of the large-vessel vasculitis, affecting the aorta and its major branches. Although T cell-mediated autoimmunity is mainly involved in vascular inflammation, in recent years, accumulating evidence suggests the important role of B cells in the pathogenesis and effectiveness of B-cell-targeted therapy with rituximab (RTX), a chimeric anti-CD20 monoclonal antibody in refractory TAK. Herein, we report for the first time a case involving a 34-year-old man with TAK who was refractory to four different biologic agents, such as one selective T-cell co-stimulation modulator (abatacept), one anti-interleukin-6 receptor monoclonal antibody (tocilizumab), and two tumor necrosis factor-α inhibitors (infliximab and etanercept), but eventually achieved remission with RTX. He received a total of six courses of RTX, and doses of prednisolone and methotrexate were tapered without relapse. The current case provided further evidence to the potential role of RTX therapy in patients with refractory TAK, and its efficacy needs to be validated in a controlled trial.

High Prevalence of Acute Exacerbation of Interstitial Lung Disease in Japanese Patients with Systemic Sclerosis.

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by extensive fibrosis and autoantibodies. Its clinical manifestations are diverse and include Raynaud's phenomenon, gastrointestinal dysmotility, interstitial lung disease (ILD), pulmonary hypertension, and renal crisis. Among these, ILD is the primary cause of SSc-related death. It has been considered that acute exacerbation of ILD (AE-ILD) is not common in patients with SSc; however, little is known about the prevalence of AE-ILD in Japanese patients with SSc. In this study, we aimed to clarify the prevalence, clinical characteristics, and prognosis of patients with SSc who developed AE-ILD and to identify predictive factors for AE-ILD in our Japanese cohorts. Clinical data of patients who visited our department from 1990 to 2014 and fulfilled the 2013 classification criteria for SSc were retrospectively reviewed. A total of 139 patients were enrolled. The mean age of onset was 49.1 years, and 113 (81.3%) patients were female; 116 (83.5%) had limited cutaneous involvement, and the overall 10-year survival rate was 92.0%. Among 66 (47.5%) patients with ILD, 13 (9.4%) developed AE-ILD. Patients with AE-ILD had a significantly higher incidence of overlap with polymyositis (PM) or dermatomyositis (DM) and lower prevalence of anticentromere antibodies with higher mortality rate compared with those without AE-ILD. Multivariate Cox regression analysis identified that an overlap with PM or DM was the most significant predictive factor for AE-ILD. Our study results suggest that Japanese patients with SSc, particularly patients overlapped with PM or DM, have a high risk of AE-ILD.

Extracorporeal Shock Wave Therapy for Digital Ulcers of Systemic Sclerosis: A Phase 2 Pilot Study.

Patients with systemic sclerosis (SSc) often display Raynaud's phenomenon and digital skin ulcers. As these ulcers are not associated with autoimmune factors or abnormal coagulation, conventional immunosuppressive therapies, vasodilators, and anticoagulants are often ineffective. Here, we used extracorporeal shock wave therapy (ESWT) to treat these ulcers. Nine SSc patients with new digital ulcers, previously treated with at least one currently available vasodilator or anticoagulant were enrolled. One ESWT session consisted of 100 pulses at 0.08-0.25 mJ/mm(2) in 20 areas on both hands and 15 areas on both feet, totaling 7,000 pulses. Treatment was performed once per week for 9 weeks with observations over 20 weeks. Outcomes were evaluated according to the number and diameter of ulcers, Rodnan skin score, Health Assessment Questionnaire (HAQ), EuroQol 5 dimensions (EQ-5D), visual analog scale for pain, and the PainVision system. The surface skin temperature of all the fingers was measured using thermography. Ulcers showed signs of healing after one session, and their mean number decreased from 5.4 to 1.1 at 9 weeks. In particular, of the 18 large ulcers (> 5 mm) observed in 7 patients before the treatment, 10 disappeared and the rest became smaller; namely, the mean size decreased from 10.9 mm to 2.5 mm at 20 weeks. The average scores on the HAQ, EQ-5D, and PainVision system also improved. Treatment was minimally invasive and could be repeated without any adverse effects. ESWT may be added to standard treatments for indolent digital ulcers of SSc, as an effective and safe method.

Chronic lupus peritonitis is characterized by the ascites with a large content of interleukin-6.

Systemic lupus erythematosus (SLE) is an autoimmune disease and can cause multi-organ damage. Peritoneal involvement, also called lupus peritonitis, is a rare but sometimes fatal manifestation. Deposition of immune complexes consisting of immunoglobulin G and complement is considered to be involved in the pathogenesis of lupus peritonitis; however, it remains unknown whether inflammatory cytokines contribute to the pathology of this manifestation. Here we present two patients with treatment-resistant lupus peritonitis: a 37-year-old woman with a 26-year history of SLE who had been treated with prednisolone and cyclophosphamide followed by azathioprine and a 65-year-old woman with a 33-year history of SLE who had been treated with prednisolone alone. Both patients were admitted to our department because of abdominal distention. Computed tomography scans showed massive ascites. Ascitic fluid examinations of both patients showed leukocytosis with no evidence of malignancy or infection. After eliminating other causes for ascites, they were diagnosed with lupus peritonitis. Despite the intensified immunosuppressive therapy, they died of uncontrolled peritonitis several months after admission. Examinations of the ascites at admission also revealed a large content of interleukin (IL)-6, compared with other inflammatory cytokines, IL-1ß and tumor necrosis factor-α. In fact, the ascitic IL-6 levels of these two patients were 12,389 pg/mL and 5,486 pg/mL, much higher than their serum IL-6 levels of 36 pg/mL and 140 pg/mL, respectively. We therefore suggest that IL-6 may contribute to the pathogenesis of lupus peritonitis and that the inhibition of IL-6 signaling may provide a novel therapeutic strategy for lupus peritonitis.

Bortezomib treatment induces a higher mortality rate in lupus model mice with a higher disease activity.

BACKGROUND: Bortezomib (Bz) is a proteasome inhibitor that directly targets antibody-producing plasma cells. We recently reported the first randomized control trial that evaluated the effects of Bz in patients with systemic lupus erythematosus (SLE). In that study, we demonstrated that Bz treatment is associated with many adverse reactions in patients with refractory disease. In the present study, we examine the therapeutic and toxic effects of Bz on MRL/MpJ-lpr/lpr (MRL/lpr) mice with severe disease activity. METHODS: Female MRL/lpr mice at 10 and 14 weeks of age were treated with phosphate buffered saline (PBS) (n = 19), Bz (750 µg/kg twice weekly) (n = 27), or cyclophosphamide (Cyc) (1 mg/body, once in 2 weeks) (n = 20). Cellular subsets, serum immunoglobulin, anti-double-stranded DNA (anti-dsDNA) antibody titer, and a pathological index of glomerulonephritis were then analyzed at 22 weeks of age. Survival curves of the 10-week-old and 14-week-old Bz-treated groups were compared. Blood counts, creatinine, liver enzymes, and serum cytokine levels were measured 1 week after Bz treatment. Gene expression profiling of spleens from Bz and Cyc treatment mice were compared with those from control mice. RESULTS: The anti-dsDNA antibody levels were significantly higher in 14-week-old than in 10-week-old mice, indicating a higher disease activity at 14 weeks. A significant decrease in the number of splenic cells and glomerulonephritis index was observed in Bz-treated and Cyc-treated mice. Bz, but not Cyc, significantly decreased serum immunoglobulin and anti-dsDNA antibody titer levels. Survival curve analysis revealed a significantly higher mortality rate in 14-week-old than in 10-week-old Bz-treated and control groups. Following two injections of Bz, serum IL-6 and TNF-α levels were significantly more elevated in 14-week-old than in 10-week-old mice. Potentially immunogenic molecules, such as heat shock proteins, were characteristically upregulated in spleens of Bz-treated but not Cyc-treated mice. CONCLUSIONS: In spite of its therapeutic effect, Bz treatment had more toxic effects associated with increased proinflammatory cytokine levels in mice with a higher disease activity. Understanding the mechanism of the toxicity and developing preventive strategies against it is important for the safe clinical application of Bz in human SLE.

Synovitis in a Patient with IgG4-related Disease.

A 71-year-old man was admitted to our department due to arthralgia and renal dysfunction. A physical examination disclosed swelling of the right shoulder and left wrist joints. Laboratory tests showed elevated serum IgG4 and creatinine levels, and magnetic resonance imaging of the wrist revealed bone erosion and synovitis. In addition, fluorodeoxyglucose positron emission tomography showed uptake in the submandibular glands, pancreas, kidneys, and affected joints and a renal biopsy revealed tubulointerstitial nephritis with the infiltration of IgG4+ plasma cells. The patient was subsequently diagnosed with IgG4-related disease (IgG4-RD) and successfully treated with corticosteroid therapy. This case suggests that erosive arthritis may occur in patients with IgG4-RD.

Aromatase in colon carcinoma.

Aromatase is one of the key estrogen-producing enzymes and is regarded as one of the therapeutic targets in estrogen receptor-positive breast cancer patients. Human colon carcinoma has also been recently proposed as being an estrogen-responsive malignancy, but the detailed status of aromatase has not yet been reported. Therefore, in this study, we evaluated the aromatase expression in colon carcinoma using immunohistochemistry and real-time polymerase chain reaction. Aromatase mRNA was significantly higher (p=0.03) in colon carcinoma than in the corresponding non-neoplastic mucosa (n=31). Aromatase immunoreactivity tended to be positively associated with the intratumoral concentration of estrogens (n=53), and in particular, the concentration of estradiol was significantly higher (p=0.02) in aromatase-positive cases in men. Aromatase immunoreactivity was detected in the cytoplasm of the carcinoma cells in 217/328 (65%) examined colon carcinoma cases. Aromatase immunoreactivity was significantly positively correlated with tubular differentiation, and inversely correlated with Ki-67 labeling index, although not necessarily correlated with the clinical outcome of the patients. All these results demonstrate that colon carcinoma expresses functional aromatase, and that estrogens are locally synthesized in the tumor tissues. The findings reported here could contribute to a better understanding of the actions of estrogen in colon carcinoma.

Steroid sulfatase and estrogen sulfotransferase in colon carcinoma: regulators of intratumoral estrogen concentrations and potent prognostic factors.

Previous epidemiologic and in vitro studies have indicated a potential involvement of estrogens in the pathogenesis of human colon carcinoma, but the precise roles of estrogens have remained largely unknown. Therefore, in this study, we first measured intratumoral concentrations of estrogens in 53 colon carcinomas using liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS). Tissue concentrations of total estrogen [estrone (E(1)) + estradiol] and E(1) were significantly (2.0- and 2.4-fold, respectively) higher in colon carcinoma tissues than in nonneoplastic colonic mucosa (n = 31), and higher intratumoral concentrations of total estrogen and E(1) were significantly associated with adverse clinical outcome. Intratumoral concentration of total estrogen was significantly associated with the combined status of steroid sulfatase (STS) and estrogen sulfotransferase (EST), but not with that of aromatase. Thus, we subsequently examined the STS/EST status in 328 colon carcinomas using immunohistochemistry. Immunoreactivities for STS and EST were detected in 61% and 44% of the cases, respectively. The -/+ group of the STS/EST status was inversely associated with Dukes' stage, depth of invasion, lymph node metastasis, and distant metastasis and positively correlated with Ki-67 labeling index of the carcinomas. In addition, this -/+ group had significantly longer survival, and a multivariate analysis revealed the STS/EST status as an independent prognostic factor. Results from our present study showed that the STS/EST status of carcinoma tissue determined intratumoral estrogen levels and could be a significant prognostic factor in colon carcinoma, suggesting that estrogens are locally produced mainly through the sulfatase pathway and play important roles in the progression of the disease.