Paroxysmal Atrioventricular Block in a Relatively Young Patient with COVID-19.

Cardiac involvement has been reported in patients with coronavirus disease 2019 (COVID-19). We herein report a 41-year-old man who presented with recurrent paroxysmal atrioventricular block without showing significant cardiac injuries or comorbidities. The patient was diagnosed with COVID-19 and admitted to our hospital, where he was noted to have paroxysmal atrioventricular block. Cardiac biomarkers, echocardiography, and cardiac magnetic resonance imaging findings were fairly normal. An endomyocardial biopsy performed before the implantation of a permanent pacemaker revealed mild myocardial fibrosis without inflammatory infiltrates. The unusual myocardial involvement of the novel coronavirus was suspected.

Clinical Manifestations and Myositis-Specific Autoantibodies Associated with Physical Dysfunction after Treatment in Polymyositis and Dermatomyositis: An Observational Study of Physical Dysfunction with Myositis in Japan.

OBJECTIVE: The physical function of PM/DM patients after remission induction therapy remains unknown adequately. The aim of our study was to evaluate the present status of physical dysfunction and to clarify the clinical manifestations and myositis-specific autoantibodies (MSAs) associated with physical dysfunction after treatment in PM/DM. METHODS: We obtained clinical data including the age at disease onset, gender, disease duration, laboratory data prior to initial treatment, and the specific treatment administered. We evaluated disease activity and physical dysfunction after treatment using the core set provided by the International Myositis Assessment and Clinical Studies Group. RESULTS: 57% of the 77 enrolled patients with PM/DM had troubles in daily living after treatment. At the enrolment, disease activity evaluated by physicians was only revealed in 20% of patients. In a multivariate analysis, the age at disease onset, female gender, and CK levels before treatment were significantly associated with the severity of physical dysfunction after treatment. Anti-SRP positivity was associated with more severe physical dysfunction after treatment than anti-ARS or anti-MDA5. CONCLUSIONS: Half of the PM/DM patients showed physical dysfunction after treatment. Age at disease onset, gender, CK level before treatment, and anti-SRP were significant predictors associated with physical dysfunction after treatment in PM/DM.

Cytokine profiles in polymyositis and dermatomyositis complicated by rapidly progressive or chronic interstitial lung disease.

OBJECTIVE: PM and DM are often complicated by interstitial lung disease (ILD). In this study we aimed to evaluate various serum cytokines in patients with PM/DM with ILD so as to clarify the differences in pathophysiology between anti-melanoma differentiation-associated gene 5 antibody-associated ILD (anti-MDA5-ILD) and anti-aminoacyl tRNA synthetase antibody-associated ILD (anti-ARS-ILD). METHODS: We evaluated the serum cytokine profiles of 38 patients with PM/DM and compared the cytokine profiles of the non-ILD and ILD subsets as well as the anti-MDA5-ILD and anti-ARS-ILD subsets. RESULTS: The myositis intention-to-treat activity index score, which indicates whole disease activity, significantly correlated with serum IL-6, IL-8, TNF-α and IP-10. These cytokine levels were significantly higher in the ILD subset than the non-ILD subset and were lower in the ILD subset following treatment. By multivariate analysis, TNF-α was the most significant cytokine [P = 0.0006, odds ratio (OR) 1.4, CI 1.1, 2.2] associated with PM/DM with ILD. IL-8 levels were significantly higher in anti-MDA5-ILD than in anti-ARS-ILD, although IL-6, TNF-α and IP-10 levels were high in both subsets. IL-8 was the most significant cytokine (P = 0.0006, OR 1.5, CI 1.1, 3.0) associated with anti-MDA5-ILD by multivariate analysis. Moreover, the ratio of IL-4 to IFN-γ was lower in anti-MDA5-ILD than in anti-ARS-ILD. CONCLUSION: IL-6, IL-8, TNF-α and IP-10 are associated with global disease activity in PM/DM. These cytokine levels were high, especially in the ILD subset. Serum IL-8 levels and the balance between IL-4 and IFN-γ may contribute to the differences in pathophysiology between anti-ARS-ILD and anti-MDA5-ILD.

IL-6, IL-8, and IL-10 are associated with hyperferritinemia in rapidly progressive interstitial lung disease with polymyositis/dermatomyositis.

OBJECTIVE: Hyperferritinemia is frequently accompanied by rapidly progressive (RP) interstitial lung disease (ILD) with polymyositis (PM)/dermatomyositis (DM). To clarify the mechanism of RP-ILD with hyperferritinemia, we investigated the associations between serum ferritin levels and various cytokines in patients with PM/DM. METHODS: This retrospective study included 38 patients admitted to our hospital with PM/DM. Levels of serum ferritin and cytokines (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, IL-18, TNF-α, IFN-α, IFN-γ, and IP-10) were measured. Disease activity was evaluated using the tool proposed by the International Myositis Assessment and Clinical Studies Group. We analyzed the associations between disease activity and levels of serum ferritin and cytokines. RESULTS: The levels of serum ferritin, IL-8, IL-10, IL-18, and TNF-α, were significantly correlated with disease activity. In a multivariate analysis, IL-6 (t = 3.6, P = 0.0010), IL-8 (t = 4.8, P < 0.0001), and IL-10 (t = 5.7, P < 0.0001) significantly contributed to serum ferritin levels. The levels of serum ferritin, IL-6, IL-8, and IL-10, were higher in the RP-ILD subset than in the non-ILD subset or the chronic ILD subset. CONCLUSION: IL-6, IL-8, and IL-10 are significant contributors to hyperferritinemia in PM/DM. The regulation of these cytokines might offer a possible treatment strategy for RP-ILD with PM/DM.

Clinical manifestations of Adult-onset Still's disease presenting with erosive arthritis: Association with low levels of ferritin and Interleukin-18.

Objective: Adult-onset Still's disease (AOSD) is a clinical entity with heterogeneous etiology. We have encountered patients with AOSD who had severe polyarthritis and who fulfilled the classification criteria for rheumatoid arthritis (RA); however, most patients with AOSD typically exhibit mild arthritis. In this study, we proposed two clinical subsets of AOSD and investigated the clinically significant characteristics of the two subtypes. Methods: We retrospectively analyzed 71 consecutive patients with AOSD. We reviewed the medical records of all patients who were followed up for more than 2 years. We classified all the patients with AOSD into the following 2 subsets: an RA subtype for patients who met the criteria for RA according to the American College of Rheumatology and a non-RA subtype for patients who did not meet the criteria for RA. Results: Our results indicated that the non-RA subtype was accompanied by severe inflammatory complications, including pleuritis and hemophagocytic syndrome. In addition, the serum ferritin and serum IL-18 levels were significantly higher in patients with the non-RA subtype than in those with the RA subtype. Interestingly, only 1 patient with the RA subtype had anti-CCP antibodies, and 1 non-RA subtype patient had rheumatoid factor. These findings distinguish these patients from patients with true RA. Conclusions: There were two subsets of patients with AOSD in the examined population. Patients with high levels of IL-18 or ferritin presented with severe systemic inflammatory disorders (the non-RA subtype), and patients with low levels of IL-18 or ferritin developed severe arthritis (RA subtype).

Anti-NR2A antibody as a predictor for neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: The aim of this study is to establish a detection method for anti-N-methyl-d-aspartate receptor subunit 2A (NR2A) antibody and to evaluate the relationship between anti-NR2A antibody and various organ involvement in SLE. METHODS: Serum anti-NR2A antibody was measured by ELISA using a peptide with a core of either DWEYS or DWDYS as autoantigen. Additionally, clinical characteristics were compared between 27 anti-NR2A antibody-positive (P group) and 80 antibody-negative (N group) SLE patients using DWDYS peptide. RESULTS: The optical density (OD) values of anti-NR2A antibody using DWDYS and DWEYS peptides correlated significantly (r = 0.94, P < 0.0001). The median OD value was significantly higher (P < 0.0001) with DWDYS. Additionally, the SLEDAI was significantly higher (P = 0.023) in the P group. The frequency of neuropsychiatric SLE (NPSLE) was significantly higher (P = 0.0002) in the P group, although the frequencies of serositis and nephritis were not statistically significant. Significant correlations were found between anti-NR2A antibody and leucocyte count (r(s) = -0.31, P = 0.001) and haemoglobin (r(s) = -0.42, P < 0.0001), although no correlation was found between anti-NR2A antibody and the titre of anti-dsDNA antibody. NPSLE was the most significant independent variable (P = 0.0008) associated with anti-NR2A antibody positivity, as estimated by multiple linear regression analysis. CONCLUSION: Serum anti-NR2A antibody can be associated with the complication of NPSLE and may indicate the involvement of non-nervous tissue. The use of peptides that include DWDYS is preferable to detect anti-NR2A antibody in ELISA.

Effects of KP-496, a novel dual antagonist for cysteinyl leukotriene receptor 1 and thromboxane A2 receptor, on Sephadex-induced airway inflammation in rats.

Bronchial asthma is characterized by chronic airway inflammation. Eosinophils are involved in airway inflammation and play crucial roles in asthma. There is accumulating evidence to suggest contributions of cysteinyl leukotrienes (cysLTs) and thromboxane (TX) A(2) to the recruitment of eosinophils into lung in asthmatics. KP-496 is a novel dual antagonist for CysLT receptor type 1 and TXA(2) receptors. The aim of this study was to evaluate the anti-inflammatory effects of KP-496 on Sephadex-induced airway inflammation. Sephadex suspension was intratracheally injected into rats. Amounts of regulated on activation, normal T cell expressed and secreted (RANTES) and eotaxin, and numbers of infiltrating cells in bronchoalveolar lavage fluid were measured 24 and 48 h after Sephadex injection, respectively. KP-496 (30, 100 microg/head) was intratracheally administered to rats 1 h before and 7 h after Sephadex injection. KP-496 and prednisolone (10 mg/kg, per os) exhibited significant inhibitory effects on infiltration of total cells and eosinophils into lung. Production of RANTES was significantly inhibited by KP-496 and prednisolone. Production of eotaxin was significantly inhibited by prednisolone. KP-496 also inhibited the production of eotaxin, though this effect was not significant. These results demonstrate that KP-496 exhibited the anti-inflammatory effects by inhibiting infiltration of inflammatory cells and productions of RANTES and eotaxin.

Effects of KP-496, a novel dual antagonist for leukotriene D4 and thromboxane A2 receptors, on contractions induced by various agonists in the guinea pig trachea.

BACKGROUND: A dry powder inhaler of KP-496 is currently in clinical development in Japan as an anti-asthmatic agent. The aim of this study was to evaluate the in vitro pharmacological profile of KP-496. METHODS: The antagonistic activities of KP-496 for leukotriene (LT) D(4) and thromboxane (TX) A(2) receptors were examined using the LTD(4)- and U46619-induced contractions of the isolated guinea pig trachea. The selectivity of KP-496 was examined using various agonist-induced contractions in the isolated guinea pig trachea. RESULTS: KP-496 produced parallel rightward shifts of the LTD(4) and U46619 concentration-response curves in a concentration-dependent manner. Schild plot analyses of the antagonistic activities of KP-496 demonstrated that it is a competitive antagonist for LTD(4) and TXA(2) receptors with pA(2) values of 8.64 and 8.23, respectively. The LTD(4) antagonistic activity of KP-496 was comparable to that of pranlukast and zafirlukast but was more potent than that of montelukast. The TXA(2) antagonistic activity of KP-496 was comparable to that of seratrodast. KP-496 and seratrodast also inhibited the prostaglandin (PG) D(2)- and PGF(2alpha)-induced contractions of the isolated guinea pig trachea. KP-496 had no effect on the histamine-, acetylcholine-, serotonin- and substance P-induced contractions of the isolated guinea pig trachea. CONCLUSIONS: These results indicate that KP-496 is a selective dual antagonist for LTD(4) and TXA(2) receptors. LTD(4) and TXA(2) play important roles in asthma, and antagonists for these mediators are being used for the treatment of asthma. Thus, KP-496 is expected to become a novel potent therapeutic agent for asthma.

Effect of insulin-mimetic vanadyl sulfate on cytochrome P450 2E1-dependent p-nitrophenol hydroxylation in the liver microsomes of streptozotocin-induced type 1 diabetic rats.

CYP2E1 is known to be induced in streptozotocin (STZ)-treated diabetic rats (STZ rats), and its induction is improved by insulin. We have examined the age-dependent changes of CYP2E1 in the liver microsomes of type 1 diabetic STZ rats, the effects of VOSO4 on the contents of total P450 and CYP2E1, and the activities of CYP2E1 in terms of p-nitrophenol hydroxylation. The contents of P450 and CYP2E1 and CYP2E1 activity were enhanced with the development of diabetes. When the hyperglycemia of STZ rats was improved by daily intraperitoneal injections of VOSO4 for 10 days at the doses of 7 mg/kg body weight for 5 days, 5 mg/kg for the following 3 days, and then 2.5 mg/kg for 2 days, the P450 and CYP2E1 levels and CYP2E1 activity were lowered than those in the untreated STZ rats. To understand the mechanism underlying CYP2E1-dependent hydroxylation activity, the production of reactive oxygen species was examined in the NADPH-liver microsomal systems by ESR spin-trapping. Singlet oxygen (1O2) was detected in all microsomal systems, while superoxide anion radical(*O2-) and hydroxyl radical (*OH) were not. On the basis of these results, we conclude that (1) CYP2E1 level and activity are enhanced in the diabetic state, however, they are improved by VOSO4 treatment, and (2) 1O2 is generated during CYP2E1-dependent substrate oxygenation.