Giant cell arteritis successfully treated with subcutaneous tocilizumab monotherapy.

Glucocorticoid remains the mainstay for treatment of large vessel vasculitis (LVV) including giant cell arteritis (GCA); however, the disease affects the elderly for whom the adverse effects of glucocorticoid are problematic. Recently, some reports have suggested that intravenous tocilizumab (TCZ) monotherapy is effective for this disease. To date, it remains unknown whether subcutaneous TCZ monotherapy is also effective. Here, we present a first case of GCA successfully treated with subcutaneous TCZ monotherapy. A 75-year-old woman presented with shoulder and hip pain. She was diagnosed with polymyalgia rheumatica (PMR) and treated with low-dose prednisolone (15 mg daily); however, she discontinued glucocorticoid therapy at her discretion due to the psychiatric adverse effect (cognitive dysfunction). Seven months later, her shoulder and hip pain relapsed. Furthermore, 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) revealed uptake in the descending thoracic aorta, indicating a complication of LVV. She refused to take glucocorticoid for fear of psychiatric adverse effects and chose subcutaneous TCZ monotherapy (162 mg weekly) for treating this life-threatening urgent condition. Nine months later, her shoulder and hip pain resolved and FDG-PET/CT demonstrated no uptake in the descending thoracic aorta, indicating a successful treatment with subcutaneous TCZ monotherapy for the disease. No adverse events and disease relapse were found during observation period. Our case and the literature review suggest that not only intravenous injection but also subcutaneous injection of TCZ monotherapy can serve as an alternative treatment for patients with GCA who have comorbidities or refuse to take glucocorticoid.

Dropped head in systemic sclerosis: a case based review.

Dropped head syndrome is a rare disease entity characterized by severe weakness of the cervical para-spinal muscles, resulting in a chin-on-chest deformity. Systemic sclerosis is one of the causes of dropped head syndrome, but its characteristics and prognosis remain unclear due to the extreme rarity of this condition. We present a case of dropped head which occurred in systemic sclerosis. He presented with severe dropped head and relatively mild weakness of the proximal limb muscles. Serum level of creatine kinase was elevated, myopathic change was observed in electromyography, and gadolinium enhancement was found in magnetic resonance imaging of his posterior neck muscles. Anti-topoisomerase I antibody was positive, while other autoantibodies such as anti-PM/Scl and anti-Ku antibodies were negative. Since his dropped head acutely progressed, high dose of glucocorticoid therapy was initiated, which successfully improved dropped head, serum level of creatine kinase, and gadolinium enhancement in magnetic resonance imaging. Our present case and literature review suggest that dropped head occurring in systemic sclerosis can be treatable with immunosuppressive therapy. It is important to recognize this rare but treatable involvement of systemic sclerosis because early diagnosis and treatment initiation are crucial to prevent the irreversible organ damage and the significant decrease of daily activities.

[ALLERGIC DISEASES IN ADULT-ONSET STILL'S DISEASE AND RHEUMATOID ARTHRITIS].

BACKGROUND: A high prevalence of allergic diseases was found in patients with adult-onset Still's disease (AOSD). However, the relative prevalence is unknown compared with other diseases. OBJECTIVES: We sought to compare the prevalence of allergic diseases in the control group of patients with rheumatoid arthritis (RA). METHODS: We retrospectively examined consecutive patients diagnosed with AOSD or RA in our hospital from 2010 to 2020. The patients with AOSD met the preliminary criteria for classification of AOSD. The patients with RA met the EULAR/ACR 2010 criteria. We included patients with RA without other rheumatic diseases. The analysis was performed on six types of allergic reactions: food allergy, drug allergy, allergic contact dermatitis, allergic rhinitis and/or allergic conjunctivitis, and asthma. RESULTS: Twenty-four patients with AOSD and 409 patients with RA were enrolled. The median ages (AOSD, RA) were 46.6, 68.2 years old. Females were 83.3%, 78.0%. Fifty% of AOSD patients and 34.5% of RA patients presented at least one type of allergic diseases (p = 0.12). These included food allergy (4.2%, 6.4%: p = 1.0), drug allergy (37.5%, 16.6%: p = 0.02), allergic rhinitis/allergic conjunctivitis (25.0%, 8.6%: p = 0.02), contact dermatitis (4.2%, 4.4%: p = 1.0), and asthma (4.2%, 5.9%: p = 1.0). CONCLUSION: Patients with AOSD had a higher prevalence of drug allergy, and allergic rhinitis/allergic conjunctivitis than patients with RA.

Development and exacerbation of pulmonary nontuberculous mycobacterial infection in patients with systemic autoimmune rheumatic diseases.

Objectives: To examine the development and exacerbation of pulmonary nontuberculous mycobacterial (NTM) infection in patients with systemic autoimmune rheumatic diseases (SARD).Methods: We conducted a case-control study. Seventeen of 7013 patients with SARD fulfilling the criteria for pulmonary NTM infection were enrolled in the NTM group. The control group was matched for age, sex, and SARD at a ratio of 2:1.Results: Eight patients with rheumatoid arthritis, four with systemic vasculitis, three with Sjögren's syndrome, and one each with dermatomyositis and systemic lupus erythematosus were included in the NTM group. Mycobacterium avium was detected in 12 (71%) patients, M. chelonae in 2, and M. intracellulare, M. abscessus, and M. kansasii in 1 patient each. Preexisting lung disease was more common in the NTM group than in the control group (88% versus 38%, p = .0009), particularly bronchiectasis (65% versus 29%, p = .033). The body mass index and serum albumin level were significantly lower in the NTM group than in the control group. Six patients (35%) experienced NTM exacerbation during observation. Clinical immune status at the time of NTM diagnosis, as indicated by the peripheral blood leukocyte/lymphocyte count and serum immunoglobulin G level, was unremarkable and comparable between patients with and without exacerbation, as were the treatments for SARD.Conclusions: In patients with SARD, pulmonary NTM infection may develop and exacerbate without clinically apparent immunosuppression.

Tocilizumab-induced psoriasis-like eruption resolved by shortening the dose interval in a patient with rheumatoid arthritis: a case-based review.

Tocilizumab (TCZ) is a humanized antihuman interleukin-6 (IL-6) receptor antibody used for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). While TCZ could act as a therapeutic agent, it has a potential for inducing adverse drug events including psoriasis-like eruption. Seven cases with specific reference to TCZ-induced psoriasis eruption have been reported worldwide so far. In these cases, treatments with the same dosage of TCZ were either maintained or discontinued. Herein, we report a case involving a 74-year-old man diagnosed with rheumatoid factor-positive and anti-citrullinated protein antibody-positive RA with comorbidity of atopic dermatitis. TCZ was administered intravenously with oral methotrexate. After the third infusion, the patient developed TCZ-induced psoriasis-like eruptions, which were resolved by shortening the dose interval. Eruption recurrence was not observed after frequent TCZ subcutaneous injection. Our case may help physicians manage TCZ-induced psoriasis-like eruption.

Paradoxical development of polymyositis-like autoimmunity through augmented expression of autoimmune regulator (AIRE).

Autoimmunity is prevented by the function of the autoimmune regulator [AIRE (Aire in mice)], which promotes the expression of a wide variety of tissue-restricted antigens (TRAs) from medullary thymic epithelial cells (mTECs) and from a subset of peripheral antigen-presenting cells (APCs). We examined the effect of additive expression of human AIRE (huAIRE) in a model of autoimmune diabetes in NOD mice. Unexpectedly, we observed that mice expressing augmented AIRE/Aire developed muscle-specific autoimmunity associated with incomplete maturation of mTECs together with impaired expression of Aire-dependent TRAs. This led to failure of deletion of autoreactive T cells together with dramatically reduced production of regulatory T cells in the thymus. In peripheral APCs, expression of costimulatory molecules was augmented. We suggest that levels of Aire expression need to be tightly controlled for maintenance of immunological tolerance. Our results also highlight the importance of coordinated action between central tolerance and peripheral tolerance under the common control of Aire.

Infliximab and etanercept have distinct actions but similar effects on cytokine profiles in rheumatoid arthritis.

OBJECTIVE: Pro-inflammatory cytokines, especially TNFα, play a central role in the pathogenesis of rheumatoid arthritis (RA). The available TNF inhibitors are only slightly different from one another in terms of clinical efficacy, at least at the group level, but their structures and modes of action are not identical. Infliximab (IFX) and etanercept (ETN) differ in their ability to induce antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, and in their ability to bind TNFß. The purpose of our study was to elucidate the different cytokine pathways through which these two drugs enact their clinical efficacy. METHODS: Serum from 44 RA patients treated with IFX and 24 patients treated with ETN was studied. All patients had been given these biologics at identical dosages and intervals for one year. The concentrations of 11 inflammatory cytokines and their receptors (IL-1ß, IL-2, IL-6, IL-6R, IL-8, IL-10, IL-12, TNFα, TNFß, IFNγ, and GM-CSF) were measured at weeks 0, 22, and 54 using a high-sensitivity electro-chemiluminescence assay. Cytokine profiles were analyzed along with clinical efficacy. RESULTS: IL-6 was significantly decreased in the ETN+MTX and IFX+MTX groups, although not in the ETN-only group; this change was consistent with changes in disease activity. IFNγ was gradually increased only in the non-remission subgroup of the IFX group, and not at all in the ETN group. TNFß increased after starting IFX regardless of clinical efficacy. CONCLUSION: IL-6 inhibition is a pathway affected by both IFX and ETN. In addition, IFNγ increase is a distinctive feature of the inefficacy of IFX.

Tocilizumab is clinically, functionally, and radiographically effective and safe either with or without low-dose methotrexate in active rheumatoid arthritis patients with inadequate responses to DMARDs and/or TNF inhibitors: a single-center retrospective cohort study (KEIO-TCZ study) at week 52.

OBJECTIVES: To explore the effectiveness and safety of tocilizumab (TCZ) with or without methotrexate (MTX) in active rheumatoid arthritis (RA) patients showing inadequate responses to DMARDs and/or TNF inhibitors in clinical practice. METHODS: We observed consecutive 115 RA patients initiating TCZ treatment in Keio University Hospital, dividing them into two groups with (TCZ + MTX group) or without MTX (TCZ group), and evaluated clinical, functional and structural outcomes besides safety at week 52. RESULTS: Overall mean age, RA duration, and DAS28-ESR were 55.4, 8.4 years, and 5.0, respectively. Proportions of the prior use of TNF inhibitors and concomitant MTX were 45.5% and 57.4%, respectively. Mean dose of concomitant MTX was 8.4 mg/week. Baseline characteristics were comparable between the groups. TCZ improved disease activity measured by DAS28-ESR to 2.1 at week 52 overall, without significant difference between the groups. Clinical (DAS28-ESR < 2.6), functional (HAQ-DI ≤ 0.5), and structural (ΔTSS ≤ 0.5) remission rates in the TCZ group and the TCZ + MTX group were 79.1%/63.8% (P = 0.10), 62.8%/54.4% (P = 0.40), and 70.0%/53.8% (P = 0.61), respectively. Retention rates were 81.0% in the TCZ + MTX group and 88.5% in the TCZ group (P = 0.47). The rate of serious adverse events was comparable between the groups. CONCLUSIONS: TCZ was clinically, functionally, and radiographically effective and safe either with or without low-dose MTX.

Modifications of azoxymethane-induced carcinogenesis and 90-day oral toxicities of 2-tetradecylcyclobutanone as a radiolytic product of stearic acid in F344 rats.

A 90-day oral toxicity test in rats was performed to evaluate the toxicity of 2-tetradecylcyclobutanone (2-tDCB), a unique radiolytic product of stearic acid. Six-week-old male and female F344 rats (n=15/group) were given 2-tDCB at concentrations of 0, 12, 60 and 300 ppm in a powder diet for 13 weeks. Slight dose-dependent increases in serum total protein and albumin in male rats were found, but these changes were not considered to be a toxic effect. The fasting, but not non-fasting, blood glucose levels of the male rats in the 300 ppm group and female rats in the 60 and 300 ppm groups were lower than those of the controls. Gas chromatography-mass spectrometry analysis showed dose-dependent accumulation of 2-tDCB in adipose tissue, notably in males. Next, we performed an azoxymethane (AOM)-induced two-stage carcinogenesis study. After injection of 6-week-old male F344 rats (n=30/group) once a week for 3 weeks, the animals received 2-tDCB at concentrations of 0, 10, 50 and 250 ppm in a powder diet for 25 weeks. The incidences of colon tumors for the 2-tDCB dosages were 34%, 45%, 40% and 37%, respectively, and were not statistically significant. These data suggest that 2-tDCB shows no toxic or tumor-modifying effects under the present conditions, and that the no-observed-adverse-effect level for 2-tDCB is 300 ppm in both sexes, equivalent to 15.5 mg/kg b.w./day in males and 16.5 mg/kg b.w./day in females.

Role of platelet-derived growth factor/platelet-derived growth factor receptor axis in the trafficking of circulating fibrocytes in pulmonary fibrosis.

Circulating fibrocytes have been reported to migrate into the injured lungs, and contribute to fibrogenesis via CXCL12-CXCR4 axis. In contrast, we report that imatinib mesylate prevented bleomycin (BLM)-induced pulmonary fibrosis in mice by inhibiting platelet-derived growth factor receptor (PDGFR), even when it was administered only in the early phase. The goal of this study was to test the hypothesis that platelet-derived growth factor (PDGF) might directly contribute to the migration of fibrocytes to the injured lungs. PDGFR expression in fibrocytes was examined by flow cytometry and RT-PCR. The migration of fibrocytes was evaluated by using a chemotaxis assay for human fibrocytes isolated from peripheral blood. The numbers of fibrocytes triple-stained for CD45, collagen-1, and CXCR4 were also examined in lung digests of BLM-treated mice. PDGFR mRNA levels in fibrocytes isolated from patients with idiopathic pulmonary fibrosis were investigated by real-time PCR. Fibrocytes expressed both PDGFR-α and -ß, and migrated in response to PDGFs. PDGFR inhibitors (imatinib, PDGFR-blocking antibodies) suppressed fibrocyte migration in vitro, and reduced the number of fibrocytes in the lungs of BLM-treated mice. PDGF-BB was a stronger chemoattractant than the other PDGFs in vitro, and anti-PDGFR-ß-blocking antibody decreased the numbers of fibrocytes in the lungs compared with anti-PDGFR-α antibody in vivo. Marked expression of PDGFR-ß was observed in fibrocytes from patients with idiopathic pulmonary fibrosis compared with healthy subjects. These results suggest that PDGF directly functions as a strong chemoattractant for fibrocytes. In particular, the PDGF-BB-PDGFR-ß biological axis might play a critical role in fibrocyte migration into the fibrotic lungs.

Exogenous fatty acid binding protein 4 promotes human prostate cancer cell progression.

Epidemiologic studies have found that obesity is associated with malignant grade and mortality in prostate cancer. Several adipokines have been implicated as putative mediating factors between obesity and prostate cancer. Fatty acid binding protein 4 (FABP4), a member of the cytoplasmic fatty acid binding protein multigene family, was recently identified as a novel adipokine. Although FABP4 is released from adipocytes and mean circulating concentrations of FABP4 are linked with obesity, effects of exogenous FABP4 on prostate cancer progression are unclear. In this study, we examined the effects of exogenous FABP4 on human prostate cancer cell progression. FABP4 treatment promoted serum-induced prostate cancer cell invasion in vitro. Furthermore, oleic acid promoted prostate cancer cell invasion only if FABP4 was present in the medium. These promoting effects were reduced by FABP4 inhibitor, which inhibits FABP4 binding to fatty acids. Immunostaining for FABP4 showed that exogenous FABP4 was taken up into DU145 cells in three-dimensional culture. In mice, treatment with FABP4 inhibitor reduced the subcutaneous growth and lung metastasis of prostate cancer cells. Immunohistochemical analysis showed that the number of apoptotic cells, positive for cleaved caspase-3 and cleaved PARP, was increased in subcutaneous tumors of FABP4 inhibitor-treated mice, as compared with control mice. These results suggest that exogenous FABP4 might promote human prostate cancer cell progression by binding with fatty acids. Additionally, exogenous FABP4 activated the PI3K/Akt pathway, independently of binding to fatty acids. Thus, FABP4 might be a key molecule to understand the mechanisms underlying the obesity-prostate cancer progression link.

Surfactant protein D attenuates sub-epithelial fibrosis in allergic airways disease through TGF-ß.

BACKGROUND: Surfactant protein D (SP-D) can regulate both innate and adaptive immunity. Recently, SP-D has been shown to contribute to the pathogenesis of airway allergic inflammation and bleomycin-induced pulmonary fibrosis. However, in allergic airways disease, the role of SP-D in airway remodeling remains unknown. The objective of this study was to determine the contribution of functional SP-D in regulating sub-epithelial fibrosis in a mouse chronic house dust mite model of allergic airways disease. METHODS: C57BL/6 wild-type (WT) and SP-D-/- mice (C57BL/6 background) were chronically challenged with house dust mite antigen (Dermatophagoides pteronyssinus, Dp). Studies with SP-D rescue and neutralization of TGF-ß were conducted. Lung histopathology and the concentrations of collagen, growth factors, and cytokines present in the airspace and lung tissue were determined. Cultured eosinophils were stimulated by Dp in presence or absence of SP-D. RESULTS: Dp-challenged SP-D-/- mice demonstrate increased sub-epithelial fibrosis, collagen production, eosinophil infiltration, TGF-ß1, and IL-13 production, when compared to Dp-challenged WT mice. By immunohistology, we detected an increase in TGF-ß1 and IL-13 positive eosinophils in SP-D-/- mice. Purified eosinophils stimulated with Dp produced TGF-ß1 and IL-13, which was prevented by co-incubation with SP-D. Additionally, treatment of Dp challenged SP-D-/- mice with exogenous SP-D was able to rescue the phenotypes observed in SP-D-/- mice and neutralization of TGF-ß1 reduced sub-epithelial fibrosis in Dp-challenged SP-D-/- mice. CONCLUSION: These data support a protective role for SP-D in the pathogenesis of sub-epithelial fibrosis in a mouse model of allergic inflammation through regulation of eosinophil-derived TGF-ß.

Relation between abnormal synergy and gait in patients after stroke.

BACKGROUND: The abnormal synergy seen in patients after stroke is considered to limit the ability of these patients. However, in the lower extremity, antigravity torque generation rather than precise movement is needed for functions such as sit-to-stand movement and gait. Therefore, the ability to generate torque may be important either as a primary movement or as an abnormal synergy. We attempted to quantify the torque generation in the lower limb, selectively and as an abnormal synergy, and its relation with gait. METHODS: Selectively generated plantar flexion torque in the ankle and plantar flexion torque secondarily generated accompanying maximal hip extension (i.e., torque generated with abnormal synergy) were measured in subjects after stroke and control subjects. In subjects after stroke, secondary torque generation while controlling hip extension torque as 25%, 50%, and 75% of the maximal hip extension was also measured. The relation of torque generation with the gait speed and timed-up-and go test (TUG) was also analyzed. RESULTS: In subjects after stroke, there was no difference between the amount of plantar flexion torque generated secondarily and the selectively generated torque, whereas the selective torque was significantly greater in control subjects. Pearson product-moment correlation coefficient analysis revealed that TUG speed is related to secondarily generated torque accompanying maximal hip extension but not with selectively generated torque. CONCLUSION: Secondarily generated torque was found to be a factor that affects TUG speed, and the ability to generate torque even through abnormal synergy may help for gait ability in subjects after stroke.

Ensemble detection of hand joint ankylosis and subluxation in radiographic images using deep neural networks.

The modified total Sharp score (mTSS) is often used as an evaluation index for joint destruction caused by rheumatoid arthritis. In this study, special findings (ankylosis, subluxation, and dislocation) are detected to estimate the efficacy of mTSS by using deep neural networks (DNNs). The proposed method detects and classifies finger joint regions using an ensemble mechanism. This integrates multiple DNN detection models, specifically single shot multibox detectors, using different training data for each special finding. For the learning phase, we prepared a total of 260 hand X-ray images, in which proximal interphalangeal (PIP) and metacarpophalangeal (MP) joints were annotated with mTSS by skilled rheumatologists and radiologists. We evaluated our model using five-fold cross-validation. The proposed model produced a higher detection accuracy, recall, precision, specificity, F-value, and intersection over union than individual detection models for both ankylosis and subluxation detection, with a detection rate above 99.8% for the MP and PIP joint regions. Our future research will aim at the development of an automatic diagnosis system that uses the proposed mTSS model to estimate the erosion and joint space narrowing score.

Antifibrotic effects of focal adhesion kinase inhibitor in bleomycin-induced pulmonary fibrosis in mice.

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase involved in various biological functions, including cell survival, proliferation, migration, and adhesion. FAK is an essential factor for transforming growth factor ß to induce myofibroblast differentiation. In the present study, we investigated whether the targeted inhibition of FAK by using a specific inhibitor, TAE226, has the potential to regulate pulmonary fibrosis. TAE226 showed inhibitory activity of autophosphorylation of FAK at tyrosine 397 in lung fibroblasts. The addition of TAE226 inhibited the proliferation of lung fibroblasts in response to various growth factors, including platelet-derived growth factor and insulin-like growth factor I, in vitro. TAE226 strongly suppressed the production of type I collagen by lung fibroblasts. Furthermore, treatment of fibroblasts with TAE226 reduced the expression of α-smooth muscle actin induced by transforming growth factor ß, indicating the inhibition of differentiation of fibroblasts to myofibroblasts. Administration of TAE226 ameliorated the pulmonary fibrosis induced by bleomycin in mice even when used late in the treatment. The number of proliferating mesenchymal cells was reduced in the lungs of TAE226-treated mice. These data suggest that FAK signal plays a significant role in the progression of pulmonary fibrosis and that it can become a promising target for therapeutic approaches to pulmonary fibrosis.

Lymphotoxin signal promotes thymic organogenesis by eliciting RANK expression in the embryonic thymic stroma.

It has recently become clear that signals mediated by members of the TNFR superfamily, including lymphotoxin-ß receptor (LTßR), receptor activator for NF-κB (RANK), and CD40, play essential roles in organizing the integrity of medullary thymic epithelial cells (mTECs) required for the establishment of self-tolerance. However, details of the mechanism responsible for the unique and cooperative action of individual and multiple TNFR superfamily members during mTEC differentiation still remain enigmatic. In this study, we show that the LTßR signal upregulates expression of RANK in the thymic stroma, thereby promoting accessibility to the RANK ligand necessary for mTEC differentiation. Cooperation between the LTßR and RANK signals for optimal mTEC differentiation was underscored by the exaggerated defect of thymic organogenesis observed in mice doubly deficient for these signals. In contrast, we observed little cooperation between the LTßR and CD40 signals. Thus, the LTßR signal exhibits a novel and unique function in promoting RANK activity for mTEC organization, indicating a link between thymic organogenesis mediated by multiple cytokine signals and the control of autoimmunity.

Suppressive effect of RAS inhibitor manumycin A on aberrant crypt foci formation in the azoxymethane-induced rat colorectal carcinogenesis model.

BACKGROUND AND AIM: The chemopreventive effect of RAS inhibitors on colorectal cancer is unknown. Because aberrant crypt foci (ACF), earliest preneoplastic lesions, are highly positive for K-RAS mutation, RAS inhibitors are likely to be effective for chemoprevention. Therefore, in the present study, the suppressive effect of a RAS inhibitor, manumycin A, on ACF formation in an azoxymethane (AOM)-induced rat colorectal carcinogenesis model was investigated. METHODS: Rats injected with AOM were administered manumycin A (30 mg/kg) subcutaneously thrice weekly for 8 weeks or for 4 weeks (latter half), sacrificed at 8 weeks, and examined for ACF in the colorectum. Phosphorylated ERK and Ki-67 expression was evaluated by immunohistochemistry. Apoptosis was assessed by TUNEL staining. RESULTS: The mean number of ACF in the 8-week manumycin A group (72.9 ± 20.1) was significantly lower than in the vehicle group (155.6 ± 56.7, P < 0.01), and it was significantly lower even in the 4-week manumycin A group than in the vehicle group (92.2 ± 13.0 vs 222.3 ± 83.3, P < 0.01). The positive rate for phosphorylated ERK in the manumycin A group (13.5 ± 19.2%) was significantly lower than in the vehicle group (50.2 ± 19.8%, P < 0.01). The positive rate for Ki-67 in the manumycin A group (2.2 ± 3.4%) was significantly lower than in the vehicle group (14.7 ± 8.2%, P < 0.01). There were significantly more terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling-positive cells in tissue samples from the manumycin A group versus the vehicle group (8.6 ± 9.7% vs 2.9 ± 2.0%, P < 0.05). CONCLUSION: Manumycin A suppressed ACF formation in the AOM-induced colorectal carcinogenesis model, demonstrating that RAS inhibitors may be very effective for chemoprevention of colorectal cancers.

Allergic disorders and their risk factors in primary Sjögren's syndrome.

Objective: This study aimed to evaluate the prevalence of allergic disorders in patients with primary Sjögren's syndrome (pSS), compare it with that of patients with rheumatoid arthritis (RA), and examine the risk factors in patients with pSS. Methods: We retrospectively examined the records of patients diagnosed with pSS and RA who regularly visited our department between 2010 and 2020. Allergic disorders included drug allergy, food allergy, allergic contact dermatitis (ACD), allergic rhinitis (AR)/allergic conjunctivitis (AC), and asthma. Results: Patients with pSS (292 patients) had a higher prevalence of food allergy, drug allergy, and AR/AC than those with RA (413 patients). The multivariate analysis revealed that patients with pSS who had drug allergy had a higher prevalence of food allergy, higher eosinophil levels, and higher positivity rates of anti-SS-related antigen A (SSA) antibodies than those without drug allergy; those with food allergy had a higher rate of ACD than those without food allergy and vice versa; those with AR/AC had a higher rate of ACD and asthma and higher eosinophil levels than those without AR/AC; those with asthma had a higher rate of AR/AC than those without asthma. Conclusions: Patients with pSS had a higher prevalence of allergic disorders than those with RA. Among patients with pSS, the risk factors for drug allergy were food allergy, higher eosinophil levels, and positivity for anti-SSA antibodies, the risk factor for food allergy was ACD and vice versa, the risk factors for AR/AC were ACD, asthma, and high eosinophil levels, and the risk factor for asthma was AR/AC.

Successful treatment of PR3-ANCA-positive interstitial pneumonia with a moderate dose of glucocorticoid and rituximab.

Antineutrophil cytoplasmic antibody (ANCA)-positive interstitial pneumonia (IP) is reported as IP that is ANCA-positive and does not involve organ damage associated with vasculitis other than the lungs. While the combination of glucocorticoid and rituximab is effective in ANCA-associated vasculitis, the treatment strategy for ANCA-positive IP has not been established. Here, we report the first case of successful treatment of proteinase 3 (PR3)-ANCA-positive IP with a moderate dose of glucocorticoid and rituximab. The patient was an 80-year-old male who presented with subacute dry cough and dyspnoea. Blood tests revealed elevated levels of C-reactive protein, Krebs von den Lungen 6 (KL-6), and PR3-ANCA. Chest computed tomography (CT) showed interstitial shadows and infiltrates around honeycomb cysts. 18F-fluorodeoxyglucose (FDG) positron emission tomography CT revealed an uptake of FDG in the IP area. After starting treatment with a moderate dose of prednisolone and rituximab, the patient's clinical symptoms disappeared, C-reactive protein and KL-6 turned to be normal, and infiltrates around the cysts of honeycomb lungs disappeared. Prednisolone was gradually decreased to 2 mg, and no relapse or adverse events were observed during the course of treatment. Our case suggests that early treatment with a moderate dose of glucocorticoid and rituximab is effective for PR3-ANCA-positive IP.

Successful treatment with tofacitinib for relapse of rapidly progressive interstitial lung disease in anti-melanoma differentiation-associated gene 5 antibody-positive clinically amyopathic dermatomyositis.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody is associated with clinically amyopathic dermatomyositis (CADM) with rapidly progressive interstitial lung disease (RP-ILD). Recently, several studies have reported that tofacitinib (TOF), a Janus kinase inhibitor, might be effective for cases of new or refractory RP-ILD in anti-MDA5 antibody-positive CADM; however, it is unknown whether TOF can also be effective for relapsed cases. We herein report a relapsed case of RP-ILD in anti-MDA5 antibody-positive CADM, which was successfully treated by combination therapy with TOF (5 mg twice daily). Our case suggests that TOF may also be a potential treatment option for relapsed cases of this disease.