Negative correlation between organ heteroplasmy, particularly hepatic heteroplasmy, and age at death revealed by post-mortem studies of m.3243A > G cases.

Mitochondrial DNA m.3243A > G mutation causes mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and its associated multi-organ disorders, including diabetes. To clarify associations between m.3243A > G organ heteroplasmy and clinical phenotypes, including the age at death, we combined genetic and pathological examinations from seven unreported and 36 literature cases of autopsied subjects. Clinical characteristics of subjects were as follows: male, 13; female, 28; unknown, 2; the age at death, 36.9 ± 20.2 [4-82] years; BMI, 16.0 ± 2.9 [13.0-22.3]; diabetes, N = 21 (49%), diabetes onset age 38.6 ± 14.2 years; deafness, N = 27 (63%); stroke-like episodes (StLEp), N = 25 (58%); congestive heart failure (CHF), N = 15 (35%); CHF onset age, 51.3 ± 14.5 years. Causes of death (N = 32) were as follows: cardiac, N = 13 (41%); infection, N = 8 (25%); StLEp, N = 4 (13%); gastrointestinal, N = 4 (13%); renal, N = 2 (6%); hepatic, N = 1 (2%). High and low heteroplasmies were confirmed in non-regenerative and regenerative organs, respectively. Heteroplasmy of the liver, spleen, leukocytes, and kidney for all subjects was significantly associated with the age at death. Furthermore, the age at death was related to juvenile-onset (any m.3243A > G-related symptoms appeared before 20) and stroke-like episodes. Multiple linear regression analysis with the age at death as an objective variable showed the significant contribution of liver heteroplasty and juvenile-onset to the age at death. m.3243A > G organ heteroplasmy levels, particularly hepatic heteroplasmy, are significantly associated with the age at death in deceased cases.

Urinary abnormality in mixed connective tissue disease predicts development of other connective tissue diseases and decrease in renal function.

OBJECTIVE: To clarify the clinical significance of development of urinary abnormality in mixed connective tissue disease (MCTD). METHODS: Forty-one patients with an initial diagnosis of MCTD, followed at five hospitals between April 1, 2000 and December 31, 2013, were included. The relationship between urinary abnormality and various clinical parameters were retrospectively analyzed. Urinary abnormality was defined as proteinuria and/or hematuria detected by urinalysis. Development of other connective tissue diseases (CTDs) was defined as satisfaction of the criteria of each respective disease. RESULTS: Of 41 patients (34 females, 7 males, mean age at diagnosis 42.2 ± 15.2 years), 16 developed urinary abnormality (UrA(+) patients). The total incidences of development of other CTDs were higher in the UrA(+) patients than UrA(-) (62.5% versus 16.0%, p = .01). In the comparison between UrA(+) and UrA(-) patients, there were no significant differences in follow-up duration or last determined estimated glomerular filtration rate (eGFR), although eGFR decreased more significantly in the UrA(+) patients than UrA(-). (-20.2 ± 17.2 vs -6.1 ± 13.8 ml/min/1.73m2, p = .01; -21.0 ± 18.9 vs -6.7 ± 14.1%, p = .03). CONCLUSION: Urinary abnormality during the clinical course in MCTD is predictive of a higher incidence of developing other CTDs. Furthermore, it might also predict long-term renal prognosis in patients with an initial diagnosis of MCTD.

Factors contributing to discrepant estimated glomerular filtration values measured by creatinine and cystatin C in patients with rheumatoid arthritis.

This study aimed to clarify the factors underlying the discrepancy that has been noted between estimated glomerular filtration ratio (eGFR) measured using serum creatinine (Cr) and eGFR using serum cystatin C (CysC) in patients with rheumatoid arthritis (RA) and to identify those patients whose renal function should be evaluated using CysC. We retrospectively evaluated clinical features, disease activity, Steinbrocker radiological staging, and co-morbidities (diabetes mellitus, hypertension, dyslipidemia) in 238 RA patients. eGFR using serum creatinine (eGFR-Cr) and eGFR using serum cystatin C (eGFR-CysC) were calculated using the new Japanese coefficient-modified Modification of Diet in Renal Disease study equation. To clarify the cause(s) of differences of 20% or more between the two eGFRs, we divided our RA patients into Group A (eGFR-Cr/eGFR-CysC ≥ 1.2) and Group B (eGFR-Cr/eGFR-CysC < 1.2), and searched for factors independently related to Group A. Forty-five patients (18.9%) were assigned to Group A, and 193 (81.1%) to Group B. BMI (Odds Ratio [OR] 0.820, 95% confidence interval [CI] 0.675-0.996), Hb (OR 0.633, 95% CI 0.433-0.926), CK (OR 0.773 per 10 units, 95% CI 0.644-0.933), NSAID use (OR 0.099, 95% CI 0.020-0.494), diabetes mellitus (OR 6.024, 95% CI 1.508-24.390) and stage 4 Steinbrocker radiological stage (OR 10.309, 95% CI 2.994-35.714) were identified as independent relevant factors for Group A by a multifactorial analysis. Renal function in RA patients with low BMI, diabetes, anemia and low CK may be overestimated using eGFR-Cr alone, and such patients need to be evaluated using eGFR-CysC.

Antiphospholipid antibody syndrome-associated renal thrombotic microangiopathy improved not with rivaroxaban but with warfarin in a systemic lupus erythematosus patient without lupus nephritis.

A 34-year-old Japanese woman with systemic lupus erythematosus (SLE) was admitted to our hospital for exacerbation of renal dysfunction, hemolytic anemia and thrombocytopenia. Twenty-two years before admission, she was diagnosed with SLE. Eight years before, lupus anticoagulant (LAC) positivity was detected without any thrombotic findings. Fourteen months before, renal function started to worsen. Three months before, unprovoked left leg swelling appeared. She was diagnosed with deep vein thrombosis (DVT) by ultrasonography. Blood examination revealed mild anemia, thrombocytopenia, and renal dysfunction. Rivaroxaban was started after which the left leg swelling subsided. When she was referred to our hospital, LAC was positive, but hypocomplementemia nor elevation of serum anti-double-stranded DNA antibodies was detected. Renal biopsy showed acute and chronic thrombotic microangiopathy (TMA) without concurrent lupus nephritis. Brain magnetic resonance imaging showed new small multiple cerebral infarcts. Antiphospholipid antibody syndrome (APS), causing renal TMA, new cerebral infarction, and DVT was diagnosed. Rivaroxaban was changed to warfarin. Two months after admission, renal impairment improved, and the complete disappearance of DVT and brain infarcts was confirmed. This case suggests that warfarin may be more effective than direct oral anticoagulants in the treatment of APS-associated renal TMA.

Contribution of HLA-DRB1 * 09: 01 allele to development of minocycline induced antineutrophil cytoplasmic antibody (ANCA)-associated cutaneous vasculitis: report of two cases.

We report two cases of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) that developed after long-term oral administration of minocycline and consider the contribution of human leukocyte antigen (HLA)-DRB 1 * 09: 01 allele to its development. Case 1; A 47-year-old man receiving minocycline for palmoplantar pustulosis for 24 months developed fever, arthralgia, and irregular livedo on the bilateral lower legs. Skin biopsy demonstrated vasculitis, while a blood test showed positivity of myeloperoxidase (MPO)-ANCA. Discontinuation of minocycline and oral administration of prednisolone relieved the symptoms promptly. Case 2; A 53-year-old woman developed reddish-brown livedo reticularis with tenderness on the bilateral lower legs after administration of minocycline to treat palmoplantar pustulosis for 24 months. Although skin biopsy did not demonstrate vasculitis, a blood test showed MPO-ANCA positivity. Cessation of minocycline resulted in rapid improvement of the cutaneous lesions and constitutional symptoms. We diagnosed both cases as having Drug-associated ANCA-associated Vasculitis (DAV) caused by minocycline according to the diagnostic criteria proposed by Cluver et al. Further examination revealed the presence of HLA-DRB1 * 09:01 allele in both cases. This allele has been implicated in the genetic background of idiopathic microscopic polyangiitis (MPA) in the Japanese population. Our finding suggests a relationship between the development of MPO-ANCA or DAV caused by minocycline and HLA-DRB1 * 09:01 allele, but will have to confirmed by further studies with larger numbers of patients.

Elderly-onset Still's Disease Complicated by Macrophage Activation Syndrome: A Case Report and Review of the Literature.

Adult-onset Still's disease (AOSD) usually affects young adults. Some cases of elderly-onset Still's disease (EOSD) have been reported, but its clinical features are unclear. We herein report a 74-year-old woman who developed AOSD with macrophage activation syndrome (MAS). We also reviewed 24 previous EOSD cases in patients over 70 years old and compared the findings with overall AOSD. While the clinical features were similar between the two, including the presence of MAS, disseminated intravascular coagulation was more frequent in EOSD than in AOSD. Furthermore, despite a similar frequency of glucocorticoid use, immunosuppressants and biologics were less frequently administered in EOSD than in AOSD. This report highlights the fact that typical AOSD can develop in elderly patients with some characteristic features.

Epidemiological analysis of multicentric and unicentric Castleman disease and TAFRO syndrome in Japan.

Castleman disease is a polyclonal lymphoproliferative disease which is clinically classified into unicentric (UCD) and multicentric (MCD). TAFRO syndrome is a relatively new concept that partly overlaps with MCD. Due to their rarity, their incidence remains unknown. This study investigated the incidence and prevalence of UCD, MCD, and TAFRO syndrome in Japan using a fixed-point observation method based on their incidence in Ishikawa prefecture. The annual incidences of MCD, UCD, and TAFRO syndrome in Japan were 309-731, 71-542, and 110-502, respectively, yielding annual incidence rates per million individuals of 2.4-5.8, 0.6-4.3, and 0.9-4.9, respectively, and nationwide prevalence of 4,180-14,900, 1,350-10,300, and 860-7,240, respectively. In conclusion, MCD, UCD and TAFRO syndrome may not be as rare as previously estimated in Japan.

Changes in serum interleukin-6 levels as possible predictor of efficacy of tocilizumab treatment in rheumatoid arthritis.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Serum IL-6 levels from 12 to 24 weeks after TCZ initiation better reflect the efficacy of TCZ at 52 weeks.

Apparent diffusion coefficient map based on diffusion-weighted magnetic resonance imaging is useful in diagnosing the brainstem variant of reversible posterior leukoencephalopathy syndrome with uremia.

A 54-year-old Japanese man entered our hospital for investigation of appetite loss. His blood pressure was 201/113 mmHg, and laboratory findings revealed renal failure and hyponatremia. On physical examination, disorientation and dysarthria were observed. Hemodialysis was performed the same day. Magnetic resonance imaging (MRI) after hemodialysis revealed swelling of the brainstem and a high signal intensity on fluid-attenuated inversion recovery (FLAIR) imaging, similar to findings of central pontine myelinolysis (CPM), which is generally irreversible. However, on an apparent diffusion coefficient (ADC) map based on diffusion-weighted MRI, higher signal intensity was observed in the area of the high signal intensity on FLAIR imaging, which is not seen in CPM. The abnormal neurological symptoms improved within a few days, and MRI findings also normalized. We diagnosed the lesion as the brainstem variant of reversible posterior leukoencephalopathy syndrome (RPLS) with uremia. ADC map was very useful in diagnosing RPLS with uremia.

Late onset of cholesterol crystal embolism after thrombolysis for cerebral infarction.

A 73-year-old man was admitted to our hospital because of bilateral foot pain. He was treated with thrombolysis for cerebral infarction about 5 months ago. Anticoagulants had not been used because of hemorrhagic infarction. The pulses of bilateral pedal arteries were palpable, but cyanosis was present in the bilateral toes. Laboratory data indicated azotemia and eosinophilia. Magnetic resonance imaging revealed multiple plaques of the thoracic and abdominal aorta, one of which was ulcerated. Skin biopsy proved the diagnosis of cholesterol crystal embolism (CCE). Because no invasive vascular procedure was performed, we assumed that CCE in this patient was related to thrombolysis. We should be cautious for late onset of CCE after thrombolysis.

Fatal cytomegalovirus infection with CD4+ T-lymphocytopenia during corticosteroid therapy for bronchial asthma.

An 80-year-old woman was admitted with dyspnea. She had been treated with oral prednisolone for bronchial asthma. She was intravenously treated with dexamethasone. On the 9th day, she presented oliguria and thrombocytopenia. She was diagnosed as dehydration and disseminated intravascular coagulation, and was treated with hydration and heparin infusion. On the 12th day, she presented macroscopic hematuria and melena. Cystoscopy revealed hemorrhagic cystitis. Bone marrow aspiration showed hemophagocytosis. Serum antigen of cytomegalovirus (CMV) was positive. CD4+ T cell count was very low (40/microL). She was diagnosed as disseminated CMV infection, and was treated with gancyclovir and immunoglobulin infusion. On the 14th day, she died of pneumonia. This is the first report of fatal CMV infection during corticosteroid therapy for bronchial asthma.

Impact of inflow reduction of arteriovenous fistula on systemic hemodynamics in a patient with high-output heart failure during hemodialysis: A case report.

A 68-year-old woman was admitted with dyspnea. The patient had been treated with hemodialysis for renal failure for 11 years. On admission, chest X-ray showed pulmonary edema. Right-heart catheterization revealed high cardiac output (11.8 l/min) and elevated pulmonary capillary wedge pressure (PCWP). Doppler ultrasonography showed high-flow of an arteriovenous fistula (AVF) for hemodialysis. The patient was diagnosed as having high-output heart failure due to a high-flow AVF. Inflow reduction of the AVF was performed by proximal radial artery ligation. Right-heart catheterization performed 2 weeks after the operation revealed that cardiac output had decreased from 11.8 to 9.5 l/min and PCWP was also reduced from 21 to 9 mmHg. Furthermore, flow of the AVF measured by Doppler ultrasonography was also decreased. To our knowledge, this is the first report that assessed hemodynamics of high-output heart failure before and after inflow reduction of the AVF by repeated right-heart catheterization.

A case of immunoglobulin G4-related chronic sclerosing sialadenitis and dacryoadenitis associated with tuberculosis.

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.

Aortoesophageal fistula following nasogastric tube placement.

A 78-year-old woman was admitted to our hospital because of fresh cerebral infarction. She had been diagnosed as having rheumatoid arthritis, but had not been treated for 50 years. She could not take in sufficient food. Upper gastrointestinal endoscopy revealed no esophageal or gastric lesions, but the procedure was difficult because of her stiff neck from severe rheumatoid degenerative changes of the cervical spine. A nasogastric (NG) tube was placed, and enteral nutrition was initiated. On the 15th day from initiation of enteral nutrition, she presented hematemesis, and suddenly went into a state of shock and died. An autopsy revealed two esophageal ulcers, one of which penetrated into the descending thoracic aorta. The patient was diagnosed with hemorrhagic shock due to aortoesophageal fistula. We suspect that the NG tube compressed the esophageal wall, and ischemia caused the ulcers.

Bilateral total knee arthroplasty after spontaneous osseous ankylosis in rheumatoid arthritis.

Total knee arthroplasty (TKA) was carried out on both knee joints for spontaneous bony ankylosis due to rheumatoid arthritis (RA). Preoperative fixation angles were 40 degrees . First, the peroneal nerve was released prior to TKA. Quadriceps snip was performed to evert the patella laterally. Bilateral TKAs were carried out using a stabilized prosthesis. The results showed full extension to 70 degrees flexion at 3 years after the surgery. Absence of pain, maintenance of stability, and walking ability were achieved, without any significant complication. Total knee arthroplasty following takedown of a spontaneous ankylosed knee is an effective procedure under appropriate knee conditions.

Crow-Fukase syndrome associated with high-output heart failure.

A 64-year-old woman was admitted with systemic edema and exertional dyspnea. High-output heart failure was diagnosed by right heart catheterization and she was treated with diuretics. After 3 weeks, her symptoms disappeared but a high cardiac output state persisted. A diagnosis of Crow-Fukase syndrome was made based on the presence of polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes. Her serum vascular endothelial growth factor (VEGF) level was markedly elevated after recovery from heart failure. We suspect that an elevated VEGF level and a high cardiac output state may play a role in the pathogenesis of heart failure in Crow-Fukase syndrome.