Structure-based lead optimization to improve potency and selectivity of a novel tetrahydroimidazo[1,2-a]pyridine-5-carboxylic acid series of heparanase-1 inhibitor.

Heparanase-1 (HPSE1) is an endo-ß-d-glucuronidase that is the only mammalian enzyme known to cleave heparan sulfate (HS) of heparan sulfate proteoglycans (HSPG), a key component of the glycocalyx layer of the vascular endothelium matrix. Inhibition of HPSE1 has therapeutic potential for cancer and proteinuric kidney diseases. We previously reported that 2 showed a moderate potency as an HPSE1 inhibitor and an issue of selectivity against exo-ß-d-glucuronidase (GUSß) and glucocerebrosidase (GBA) remained. A structure-based lead optimization of 2 using X-ray co-crystal structure analysis and fragment molecular orbital calculation resulted in 4e, which showed a more than 7-fold increase in HPSE1 inhibitory activity. The subsequent introduction of a methyl group into the 6-hydroxy group of 4e resulted in 18 with reduced inhibitory activities against GUSß and GBA while maintaining the inhibitory activity against HPSE1. The inhibitory activities of 18 against serum HPSE1 in mice were significant and lasted for 4 h at doses of 3, 30, and 100 mg/kg. Compound 18 could be a novel lead compound for HPSE1 inhibitors with improved inhibitory activity against HPSE1 and increased HPSE1 selectivity over GUSß and GBA.

Successful treatment of a patient with Takayasu's arteritis complicated with Crohn's disease with ustekinumab: A case report.

A 17-year-old woman was referred to our department with fever, general malaise, and weight loss. She was diagnosed with Takayasu arteritis (TAK) and Crohn's disease (CD) following positron emission tomography-computed tomography (PET-CT) and colonoscopy, respectively. Serological human leukocyte antigen (HLA) typing revealed HLA-B52 positivity. Initial treatment with prednisolone (PSL) (0.5 mg/kg) was insufficient; therefore, ustekinumab and 5-aminosalicylic acid were added. This treatment achieved PSL-free remission for both diseases, as confirmed by PET-CT and colonoscopy. Although treatment guidelines for TAK and CD have been previously established, treatment of patients with TAK with coexisting CD is controversial. Our case suggests that ustekinumab has the ability to achieve TAK remission in addition to its therapeutic effect on CD.

A case of acute diffuse large B cell lymphoma in an anti-human T-cell leukaemia virus type 1-positive rheumatoid arthritis patient treated with methotrexate, who died.

A 70-year-old woman was hospitalised due to jaundice and fever. She was diagnosed with rheumatoid arthritis (RA) at 54 years of age. Treatment with methotrexate (MTX) was successful, and her RA was in remission. Five weeks before the hospitalisation, she was diagnosed with optic neuritis due to a decline in the visual acuity of the right eye. She was treated with methylprednisolone pulse therapy, followed by prednisolone (PSL), before the hospitalisation, which were not effective. Blood tests showed increased C-reactive protein (CRP) levels, liver injury, and thrombocytopenia. Abdominal echo revealed numerous enlarged lymph nodes in the hepatic portal region. Malignant lymphoma was suspected due to high serum levels of soluble interleukin-2 receptor. None of the treatments were effective, and she died on the fifth hospital day. Diffuse large B cell lymphoma was diagnosed during the autopsy, which showed infiltration of CD20-positive atypical lymphocytes in almost all organs. Since she was taking MTX, she was diagnosed with immunosuppressive drug-associated lymphoproliferative disease (LPD). Anti-human T-cell leukaemia virus type 1 (HTLV-1) antibody was detected in her serum after her death; however, adult T cell leukaemia/lymphoma was not observed. LPD develops during the treatment of RA with disease modifying anti-rheumatic drugs; however, a rapid clinical course leading to death is rarely observed. Previous reports suggest that T cell dysregulation observed in HTLV-1 may contribute towards the development of B cell lymphoma. We have discussed the possible roles of HTLV-1 in LPD development in this case.

Effectiveness of cryofiltration and mizoribine combination with oral steroid therapy in a patient with membranoproliferative glomerulonephritis due to essential cryoglobulinemia.

A 65-year-old male patient with nephrotic syndrome was admitted to our hospital due to worsening systemic edema and purpura on the limbs. He had an impaired renal function, low serum complement level, and elevated rheumatoid factor level. He was positive for cryoglobulin (monoclonal IgM-κ and polyclonal mixed-type IgG), and the results of his kidney biopsy showed a tissue profile of membranoproliferative glomerulonephritis (MPGN). Due to the fact that the secondary cause was unclear, he was diagnosed with MPGN due to essential mixed cryoglobulinemia. On hospital day 20, he was initiated on 50 mg/day prednisolone (PSL). On hospital day 43, oral mizoribine (MZR) at a dose of 150 mg/day was prescribed. On hospital day 49, cryofiltration was performed because the disease was steroid resistant. The treatment promptly decreased urine protein levels. Serum albumin and serum complement levels increased, and complete remission was achieved approximately three months after the initiation of treatment. The PSL and MZR doses were gradually reduced to 2 mg/day and 100 mg/day, respectively, without any reemergence of the symptoms of cryoglobulinemia or relapse of the nephrotic syndrome for three years. Here, we report this case with essential mixed cryoglobulinemia in whom we could achieve complete remission of the disease by adding cryofiltration to the oral corticosteroid and immunosuppressant therapy with mizoribine and could maintain for a long time.

The Successful Treatment of Myeloperoxidase Antineutrophil Cytoplasmic Antibody-positive Hypertrophic Pachymeningitis in Patients with the Limited Form of Granulomatosis with Polyangiitis Using Methotrexate: Two Case Reports.

Recent findings have indicated a close relationship between myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-positive hypertrophic pachymeningitis and the limited form of granulomatosis with polyangiitis (GPA). In Japan, MPO-ANCA-positive hypertrophic pachymeningitis predominantly occurs in elderly individuals. We herein describe the cases of two patients with MPO-ANCA-positive hypertrophic pachymeningitis associated with the limited form of GPA who were successfully treated with a combination of corticosteroids and methotrexate. Although methotrexate has been shown to be less effective than cyclophosphamide for inducing the remission of GPA in patients with organ-threatening diseases, its safety and efficacy may make it a useful alternative treatment modality for patients with the limited form of GPA who show meningeal involvement.

Association of anti-aminoacyl-transfer RNA synthetase antibody and anti-melanoma differentiation-associated gene 5 antibody with the therapeutic response of polymyositis/dermatomyositis-associated interstitial lung disease.

BACKGROUND: We attempted to clarify whether the presence of anti-aminoacyl-transfer RNA synthetase antibody (anti-ARS Ab) or anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) is associated with the therapeutic response of polymyositis/dermatomyositis-associated interstitial lung disease (PM/DM-ILD). METHODS: We retrospectively investigated 22 patients with PM/DM-ILD (10 positive for anti-ARS Ab and nine positive for anti-MDA5 Ab) for whom antibody analysis of conserved serum was possible. We assessed mortality in the first three months as the therapeutic response in the acute phase and compared changes in clinical data for up to one year considered as the chronic phase. We classified the clinical changes over the year into three groups: Improvement (increased % vital capacity [%VC] or diffusing capacity of the lung for carbon monoxide [%DLCO]≥10 or 15%), deterioration (decreased %VC or %DLCO≥10 or 15%), and no change (remainder of the changes). The extent of abnormality demonstrated by high-resolution computed tomography (HRCT) was scored. RESULTS: Positivity for anti-MDA5 Ab, but not for anti-ARS Ab, was associated with mortality in the first 3 months. Evaluation of the therapeutic response in the first year showed that positivity for the anti-ARS Ab, but not for the anti-MDA5 Ab, was associated with an improvement in %DLCO and a decline in the serum KL-6 levels. Positivity for the anti-ARS Ab or negativity for anti-MDA5 Ab was associated with a greater decrease in bronchial dilatation as seen by HRCT. CONCLUSIONS: Anti-ARS and anti-MDA5 Abs are associated with the therapeutic response of PM/DM-ILD.

An Autopsy Case of Anti-melanoma Differentiation-associated Gene-5 Antibody-positive Clinical Amyopathic Dermatomyositis Complicated by Rapidly Progressive Interstitial Lung Disease.

A 62-year-old man presented with heliotrope rash, Gottron's sign, and mild muscle weakness. Both of his lung fields showed interstitial changes that worsened rapidly. He was diagnosed with clinical amyopathic dermatomyositis with rapidly progressive interstitial lung disease. The patient died of respiratory failure, despite the administration of immunosuppressive therapy. Autopsy revealed diffuse alveolar damage. An antibody analysis, which was performed postmortem, detected the presence of anti-melanoma differentiation-associated gene (MDA)-5 antibodies. Clinicians should note the clinical, radiologic, and serologic findings to predict anti-MDA-5 antibody-associated rapidly progressive interstitial lung disease.

Frequency of class III and IV nephritis in systemic lupus erythematosus without clinical renal involvement: an analysis of predictive measures.

OBJECTIVE: To determine the frequency of International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III or IV lupus nephritis in patients with systemic lupus erythematosus (SLE) without clinical renal involvement. METHODS: We investigated the renal pathology of 195 patients with SLE, including 86 patients without clinical renal involvement. RESULTS: Lupus nephritis other than class I was found in 58% of the patients without clinical renal involvement, and class III and IV nephritis was found in 15% of these patients. To reveal the predictive measures involved in class III or IV lupus nephritis, we explored the clinical measures in patients with SLE who did not have clinical renal involvement. Anti-dsDNA antibody titers were significantly higher (p = 0.0266) and C3 values were significantly lower (p = 0.0073) in patients with class III or IV lupus nephritis than in patients without class III or IV lupus nephritis. The sensitivity and specificity values were 77% and 73%, respectively, for cutoff levels of both 40 IU/ml for anti-dsDNA antibodies and 55 mg/dl for C3 (OR 8.8, p = 0.0011). CONCLUSION: The frequency of nephritis, including ISN/RPS class III and IV, was unexpectedly high in SLE patients without clinical renal involvement. ISN/RPS class III or IV lupus nephritis could be hidden in patients with SLE who present both a high titer of anti-dsDNA antibody and a low concentration of C3, even when they have clinically normal urinary findings and renal function.

Successful treatment for sympathetic storms in a patient with neuro-Behçet's disease.

Sympathetic storms (SyS) are characterized by hyperactivity of autonomic functions, resulting in episodes of hyperthermia, hypertension, tachycardia, and hyperhidrosis. We show here a patient with neuro-Behçet's disease (NBD) complicated by SyS. Although SyS is well known to occur with brain tumors, trauma, and hydrocephalus, this is the first report to show that SyS is a manifestation of central nervous system involvement in a patient with NBD. High concentrations of norepinephrine (NE) and IL-8 in cerebrospinal fluid reflected the activity of SyS. The patient's symptoms showed almost complete improvement after treatment with corticosteroids and intravenous cyclophosphamide. Also, the concentrations of NE and IL-8 were decreased to normal levels. An awareness of the potential for SyS and adequate immunosuppressant therapy are of importance when dealing with patients with NBD.

[Steroid pulse therapy combined with tonsillectomy in a patient with IgA nephropathy complicated with tuberculous pleurisy].

We report a case of IgA nephropathy with tuberculous pleurisy that was treated with steroid pulse therapy combined with tonsillectomy. A 27-year-old female was referred to our hospital because of hematuria and proteinuria. Her urinalysis showed mild proteinuria (0.7 to 0.9 g/day) with dysmorphic red blood cells and cellular casts. Her serum creatinine level was within the normal range. Renal biopsy specimens revealed mild mesangial proliferation with cellular crescent and adhesion of glomeruli to the Bowman's capsule. Tubulointerstitial changes including mononuclear cell infiltration and tubular atrophy were also observed. Immunohistochemical staining of IgA and C3 was detected in the mesangial area, leading to the diagnosis of IgA nephropathy. She had a past history of tuberculous pleurisy at 13 years of age and had taken antituberculosis drug for one and a half year. Although treatment with angiotensin receptor antagonist was started, the amount of proteinuria was not changed. Steroid pulse therapy with tonsillectomy followed by oral prednisolone 20 mg/day was conducted. Proteinuria and hematuria gradually decreased. Her respiratory status and chest X-ray had been closely followed up by her respiratory physician. After one and a half years of treatment with low-dose prednisolone, her urinalysis became almost normal. Recurrence of tuberculosis was not observed during the follow-up period. The successful outcome of this case encouraged us to treat IgA nephropathy with a past history of tuberculosis using interventions including steroid pulse therapy.