Tomoyuki Mukai

Pharmacological inhibition of tankyrase induces bone loss in mice by increasing osteoclastogenesis

Tankyrase is a poly (ADP-ribose) polymerase that leads to ubiquitination and degradation of target proteins. Since tankyrase inhibitors suppress the degradation of AXIN protein, a negative regulator of the canonical Wnt pathway, they effectively act as Wnt inhibitors. Small molecule tankyrase inhibitors are being investigated as drug candidates for cancer and fibrotic diseases, in which the Wnt pathways are aberrantly activated. Tankyrase is also reported to degrade the adaptor protein SH3BP2 (SH3 domain-binding protein 2). We have previously shown that SH3BP2 gain-of-function mutation enhances receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis in murine bone marrow-derived macrophages (BMMs). Although the interaction between tankyrase and SH3BP2 has been reported, it is not clear whether and how the inhibition of tankyrase affects bone cells and bone mass. Here, we have demonstrated that tankyrase inhibitors (IWR-1, XAV939, and G007-LK) enhanced RANKL-induced osteoclast formation and function in murine BMMs and human peripheral blood mononuclear cells through the accumulation of SH3BP2, subsequent phosphorylation of SYK, and nuclear translocation of NFATc1. Tankyrase inhibitors also enhanced osteoblast differentiation and maturation, represented by increased expression of osteoblast-associated genes accompanied by the accumulation of SH3BP2 protein and enhanced nuclear translocation of ABL, TAZ, and Runx2 in primary osteoblasts. Most importantly, pharmacological inhibition of tankyrase in mice significantly decreased tibia and lumbar vertebrae bone volumes in association with increased numbers of osteoclasts. Our findings uncover the role of tankyrase inhibition in bone cells and highlight the potential adverse effects of the inhibitor on bone.

Bacteremia Possibly Caused by Helicobacter cinaedi and Associated with Painful Erythema in Rheumatoid Arthritis with Malignant Lymphoma

We herein report the case of a 69-year-old woman with rheumatoid arthritis (RA) and malignant lymphoma who developed Helicobacter cinaedi bacteremia after starting rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. She had a recurrent fever and painful erythema for 13 months before the diagnosis was made. This delayed diagnosis was attributable to the underlying RA, which typically presents with various cutaneous manifestations and elevated C-reactive protein levels. The erythema on the thighs, abdomen, and left forearm improved following treatment with intravenous aminobenzyl penicillin; she received antibiotics for six weeks. This case emphasizes the importance of recognizing this opportunistic infection in immunocompromised patients.

Bladder carcinoma in situ in a patient with Lupus cystitis

Abstract Lupus cystitis is a well-known but rare complication of systemic lupus erythematosus. This manifestation is frequently associated with lupus enteritis. We report here a case of a 34-year-old man with lupus cystitis and enteritis who presented with diarrhea and bladder storage symptoms such as urinary frequency and nocturia. Serological tests showed positivity for anti-dsDNA, anti-SS-A and anti-SS-B antibodies. Enhanced computed tomography showed diffuse thickening and abnormal enhancement of bowel wall as well as right hydronephrosis. Cystoscopy revealed bladder trabeculation, a characteristic ribbed appearance, suggesting the presence of lupus cystitis. However, unexpectedly, a biopsy of randomly selected bladder tissue revealed bladder carcinoma in situ. Treatment with prednisolone (50u2009mg/day) improved abdominal symptoms, while the bladder irritation symptoms remained unchanged. After tapering the prednisolone dose to 20u2009mg/day, treatment of the bladder carcinoma in situ was started with intravesical Bacillus Calmette-Guèrin. To our knowledge, no reports of bladder cancer in association with lupus cystitis have been published to date. It is necessary to be aware of this serious complication when caring for patients with lupus cystitis.

Scrub typhus (Tsutsugamushi disease) in a patient presenting with hemophagocytic syndrome

Abstract Scrub typhus is a mite-borne infectious disease caused by Orientia tsutsugamushi, which is found mainly in East and Southeast Asia and in Australia. The disease presents with a variety of non-specific symptoms, including fever, headache, cough, myalgia, and rash. Delay in starting appropriate antimicrobial therapy may lead to serious complications and even death. We report the case of an 84-year-old Japanese patient with scrub typhus who developed hemophagocytic syndrome (HPS) and was successfully treated with minocycline in addition to corticosteroids. A pathognomonic skin ulcer on her right buttock, which was initially covered with black eschar, prompted us to consider the possibility of scrub typhus. Blood polymerase chain reaction and antibody assays confirmed the diagnosis. Scrub typhus must be considered as one of the underlying diseases that may cause HPS in patients living in the Asia-Pacific region and in those who have recently returned from endemic areas.

Treatment of refractory rheumatoid pleural effusion with abatacept

Rheumatoid pleural effusion is generally responsive to corticosteroids, but refractory cases require consideration of second-line therapy. Here we report the case of a 61-year-old man with rheumatoid arthritis (RA) who developed a large right-sided pleural effusion and was successfully treated with abatacept. Thoracocentesis showed a sterile exudate and an elevated adenosine deaminase level. The methotrexate and etanercept used to treat the RA were withheld initially while he underwent a trial of prednisolone 40u2009mg/day for the pleural effusion. However, the effusion did not respond to this therapy. Thoracoscopic biopsy of the right pleura revealed fibrotic changes with lymphocyte infiltration mainly composed of CD4+ T cells and B cells but no evidence of malignancy or infection. The patient was started on abatacept and resumed methotrexate. The treatment was effective in our case. Abatacept should be considered as a treatment option in patients with refractory rheumatoid pleural effusion.

Mycophenolate mofetil treatment in a patient with recurrent lymphocytic hypophysitis

Lymphocytic hypophysitis (LHP) is a relatively rare disease characterised by lymphocytic infiltration of the pituitary gland, resulting in pituitary dysfunction. LHP is generally responsive to corticosteroid therapy, but cases with recurrence require clinicians to select second-line therapy. We report here the case of a 58-year-old patient with LHP who developed panhypopituitarism and bitemporal hemianopia. He responded to prednisolone 40u2009mg/day but relapsed during tapering. The prednisolone dose was increased again and mycophenolate mofetil (MMF) was added. Thereafter, over the course of 1u2009year, prednisolone was tapered to 8u2009mg/day without relapse. Because of the rarity of LHP, there are no standard treatment protocols that support the choice of a specific immunosuppressive drug. MMF was effective for recurrent LHP in our case. Further accumulation of cases is needed to establish the standard treatment for this disease.

IgG4-related autoimmune pancreatitis complicated by splenic artery pseudoaneurysm

A 65-year-old man presented with a 1-year history of swelling of the submandibular salivary glands bilaterally. Blood tests revealed C-reactive protein (CRP) level of 0.28u2009mg/L, leucocyte count of 5.22×109/L (neutrophil count 3.07×109/L), haemoglobin level of 13.1u2009g/dL and platelet count of 234×109/L. Serum IgG and IgG4 levels were 2054u2009mg/dL (normal 861–1747) and 540u2009mg/dL (4.8–105), respectively. Biopsy of the right submandibular gland revealed a dense lymphoplasmacytic infiltrate and storiform fibrosis with increased IgG4-positive plasma cells (IgG4:IgG ratio 67%). Contrast-enhanced CT (CE-CT), which was performed to evaluate other sites of involvement, showed diffuse enlargement of the pancreas with a capsule-like …

Necrosis of the gastrocnemius muscle in microscopic polyangiitis

A 59-year-old man presented with a 1-month history of bilateral lower leg pain. The pain was more severe in the left leg, with associated swelling of the lower leg. He did not have any eye, nose, paranasal sinus or respiratory symptoms. Physical examination of the chest and abdomen was unremarkable. Neurological examination was normal. He had a body temperature of 36.5°C, a blood pressure of 97/71u2009mmxa0Hg, and a pulse of 77 beats/min. Blood tests revealed a C-reactive protein level of 155u2009mg/L, leucocyte count of 10.3×109/L (neutrophil count 8.4×109/L), haemoglobin level of 14.2u2009g/dL and platelet count of 328×109/L. Serum creatine kinase and lactate dehydrogenase levels were slightly elevated at 237u2009U/L (normal 41–153) and 231u2009U/L (124–222), respectively. …

Chronic reactive arthritis associated with prostatitis caused by Neisseria meningitidis

A 29-year-old man presented with a 10-year history of pain in his right ankle. The ankle was tender and swollen, and there was Achilles tendinitis. He had no complaints of buttock pain, abdominal pain, dysuria or a feeling of incomplete voiding. Skin examination was normal. Laboratory investigations revealed a leucocyte count of 6.0×109/L and a serum Cxa0reactive protein level of 5.21u2009mg/dL. Liver and renal function tests were normal. Rheumatoid factor, anticyclic citrullinated peptide antibody and antinuclear antibody were negative. Urinalysis was positive for occult blood, but there was no leucocyturia. Locus B human leukocyte antigen (HLA) typing was positive for B27. Plain radiography of the right ankle joint showed narrowing of the subtalar joint space and heel spurs on the plantar aspect of the calcaneus …

POEMS syndrome in a patient with rheumatoid arthritis

Multiple myeloma has been reported to be associated with rheumatoid arthritis (RA). POEMS syndrome is a rare variant of multiple myeloma and is characterised by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes. We report the case of a 67-year-old patient with RA who developed numbness and tingling in both legs due to polyneuropathy. CT showed a massive right pleural effusion and a sclerotic lesion in the right ninth rib. Histopathological examination of the rib revealed IgA lambda-type plasmacytoma. Serum vascular endothelial growth factor was extremely high at 5530u2009pg/mL. We made a diagnosis of POEMS syndrome. A literature search of the PubMed database identified only two documented cases of POEMS syndrome in patients with RA. Neuropathies are reportedly more frequent in patients with RA than in the general population. Rheumatologists should consider POEMS syndrome in patients with RA and neurological symptoms.