Bone marrow edema detection for diagnostic support of axial spondyloarthritis using MRI.

PURPOSE: This study proposes a process for detecting slices with bone marrow edema (BME), a typical finding of axSpA, using MRI scans as the input. This process does not require manual input of ROIs and provides the results of the judgment of the presence or absence of BME on a slice and the location of edema as the rationale for the judgment. METHODS: First, the signal intensity of the MRI scans of the sacroiliac joint was normalized to reduce the variation in signal values between scans. Next, slices containing synovial joints were extracted using a slice selection network. Finally, the BME slice detection network determines the presence or absence of the BME in each slice and outputs the location of the BME. RESULTS: The proposed method was applied to 86 MRI scans collected from 15 hospitals in Japan. The results showed that the average absolute error of the slice selection process was 1.49 slices for the misalignment between the upper and lower slices of the synovial joint range. The accuracy, sensitivity, and specificity of the BME slice detection network were 0.905, 0.532, and 0.974, respectively. CONCLUSION: This paper proposes a process to detect the slice with BME and its location as the rationale of the judgment from an MRI scan and shows its effectiveness using 86 MRI scans. In the future, we plan to develop a process for detecting other findings such as bone erosion from MR scans, followed by the development of a diagnostic support system.

A Systemic Lupus Erythematosus Patient with Cutaneous Mycobacterium haemophilum Infection under Belimumab Treatment: A Case Report.

A 38-year-old female with systemic lupus erythematosus (SLE) initiated belimumab treatment. One month later, she presented with a reddish painful swelling on her right lower leg. She was treated with ceftriaxone and vancomycin. However, novel erythematous papules and indurated nodules appeared on both her lower legs. Skin biopsy revealed microabscess formation with mixed cell granuloma surrounded by inflammatory cell infiltration within the dermis with subcutaneous fat tissue. A large number of acid-fast bacilli were observed with Ziehl-Neelsen staining. DNA sequencing of both the hsp65 and the 16S rRNA sequences showed a 100% match with the corresponding region of Mycobacterium haemophilum. Mycobacterial culture revealed satellite growth enhancement on Middlebrook 7H11 agar plates around a paper strip containing hemin. She was treated with levofloxacin, rifabutin, and ethambutol. Within 13 months, her cutaneous lesions improved markedly without any side effects. The B cell-targeted biologic belimumab, a fully humanized IgG1γ monoclonal antibody that inactivates B lymphocyte stimulator, has been considered to be beneficial for active SLE. However, this therapy could increase the risk for the development of biologic therapy-associated mycobacterial infections, both tuberculosis and nontuberculous mycobacteria infections.

Polyarteritis nodosa diagnosed in a young male after COVID-19 vaccine: A case report.

In response to the coronavirus disease 2019 pandemic, the coronavirus disease 2019 vaccine was rapidly developed and the effectiveness of the vaccine has been established. However, various adverse effects have been reported, including the development of autoimmune diseases. We report a case of new-onset polyarteritis nodosa in a 32-year-old male following the coronavirus disease 2019 vaccination. The patient developed limb pain, fever, pulmonary embolism, multiple subcutaneous nodules, and haematomas. Skin biopsy revealed necrotising inflammation accompanied by fibrinoid necrosis and high inflammatory cell infiltration in the walls of medium to small arteries. The symptoms resolved following corticosteroid treatment. Although it is difficult to prove a relationship between the vaccine and polyarteritis nodosa, similar cases have been reported and further reports and analyses are therefore necessary.

Clinical characteristics of patients with spondyloarthritis and inflammatory bowel disease versus inflammatory bowel disease-related arthritis.

The purpose of this study was to clarify the clinical characteristics of spondyloarthritis (SpA) patients with inflammatory bowel disease (IBD) compared to those without IBD. Furthermore, among patients with SpA and IBD, we aimed to clarify what clinical characteristics lead rheumatologists to diagnose "IBD-related arthritis." Utilizing SpA and psoriatic arthritis (PsA) patients' data from an international, cross-sectional, observational study, we analyzed information on demographics and disease characteristics, dichotomizing patients by IBD status. The presence or absence of IBD was determined based on data collection of treating rheumatologists. Patients with SpA (including PsA) and IBD were also categorized based on treating rheumatologists' definitive diagnosis in regard to SpA type, and compared by whether the patients had IBD-related arthritis or not. Among 4465 SpA patients, 287 (6.4%, 95%CI 5.7-7.2%) were identified with IBD. Compared to SpA patients without IBD, patients with SpA and IBD had a longer diagnostic delay (5.1 vs. 2.9 years, p < 0.001). In patients with SpA and IBD, 111 (38.7%, 95%CI 33.0-44.6%) were diagnosed with IBD-related arthritis. Multivariable analyses showed that HLA-B27 positivity [OR = 0.35, (95%CI 0.15-0.80)], psoriasis [OR = 0.14, (95%CI 0.04-0.50)], IBD as first symptom of SpA [OR = 3.32, (95%CI 1.84-6.01)], and need for IBD-specific treatment [OR = 5.41, (95%CI 2.02-14.50)] were independently associated with the definitive diagnosis of IBD-related arthritis. Collaboration with gastroenterologists is needed to shorten the diagnostic delay in patients with SpA and IBD. The recognition of the factors for the diagnosis of "IBD-related arthritis" may lead to the elucidation of the pathogenesis.

Expanding the spectrum of reactive arthritis (ReA): classic ReA and infection-related arthritis including poststreptococcal ReA, Poncet's disease, and iBCG-induced ReA.

Reactive arthritis (ReA) is a form of sterile arthritis that occurs secondary to an extra-articular infection in genetically predisposed individuals. The extra-articular infection is typically an infection of the gastrointestinal tract or genitourinary tract. Infection-related arthritis is a sterile arthritis associated with streptococcal tonsillitis, extra-articular tuberculosis, or intravesical instillation of bacillus Calmette-Guérin (iBCG) therapy for bladder cancer. These infection-related arthritis diagnoses are often grouped with ReA based on the pathogenic mechanism. However, the unique characteristics of these entities may be masked by a group classification. Therefore, we reviewed the clinical characteristics of classic ReA, poststreptococcal ReA, Poncet's disease, and iBCG-induced ReA. Considering the diversity in triggering microbes, infection sites, and frequency of HLA-B27, these are different disorders. However, the clinical symptoms and intracellular parasitism pathogenic mechanism among classic ReA and infection-related arthritis entities are similar. Therefore, poststreptococcal ReA, Poncet's disease, and iBCG-induced ReA could be included in the expanding spectrum of ReA, especially based on the pathogenic mechanism.

Amelioration of rheumatoid arthritis in a breast cancer patient treated with palbociclib: a case report.

Rheumatoid arthritis is a common autoimmune disease that requires new therapeutic agents. Cyclin-dependent kinase 4/6 inhibitors have recently been approved for metastatic breast cancer patients and have also been reported to improve the arthritis score in collagen-induced arthritis mouse models. We report a 56-year-old woman who had previously been diagnosed with rheumatoid arthritis and treated with methotrexate. At age 40, she underwent surgery with curative intent for breast cancer but subsequently developed lung metastases. Palbociclib, a cyclin-dependent kinase 4/6 inhibitor, was administered in combination with fulvestrant (anti-oestrogen drug) for metastatic breast cancer. One month later, serum matrix metalloproteinase-3 and C-reactive protein levels were markedly decreased, and her rheumatoid arthritis symptoms, which had worsened just prior to the detection of metastatic lung disease, showed amelioration. Methotrexate, which had been used to treat her rheumatoid arthritis, could subsequently be administered in a reduced dose. The cyclin-dependent kinase 4/6 inhibitor was also effective for the metastatic breast cancer, and, to date, the patient's disease has remained stable for more than one year. Based on the results of basic research, cyclin-dependent kinase 4/6 inhibitors are promising new therapeutic agents for rheumatoid arthritis patients, although these drugs have not, as yet, been used in a clinical setting. To the best of our knowledge, this is the first report to describe a patient whose rheumatoid arthritis responded to a cyclin-dependent kinase 4/6 inhibitor administered for metastatic breast cancer.

Elevated cerebrospinal fluid levels of total protein in patients with secondary central nervous system vasculitis and giant cell arteritis.

Objectives: Secondary central nervous system vasculitis (SCNSV) is an extremely rare, refractory, and fatal disease in patients with giant cell arteritis (GCA). We compared the characteristics of GCA patients with and without SCNSV.Methods: This retrospective, single-center, observational cohort study included 35 patients with GCA admitted to Juntendo University Hospital from April 2009 to March 2019. The primary outcome was all-cause mortality.Results: We diagnosed four patients with GCA and SCNSV (SCNSV group) and 31 patients with GCA but no SCNSV (non-SCNSV group). The mortality rate of the SCNSV and non-SCNSV groups was 100% and 10%, respectively (p = .001). The SCNSV group had lower serum levels of C-reactive protein at the time of GCA diagnosis and higher cerebrospinal fluid (CSF) levels of total protein (102 mg/dL vs. 38 mg/dL, p = .008) and albumin (66 mg/dL vs. 21 mg/dL, p = .008) at the time of SCNSV diagnosis.Conclusion: At the time of SCNSV diagnosis, GCA patients had elevated CSF total protein and albumin levels. CSF examination in GCA patients suspected of having SCNSV may be useful for early diagnosis of SCNSV.

Successful treatment of anti-MDA5 antibody-positive refractory interstitial lung disease with plasma exchange therapy.

OBJECTIVES: We examined the effectiveness of plasma exchange (PE) therapy to reduce the mortality of rapidly progressive interstitial lung disease (RP-ILD) in patients positive for anti-melanoma differentiation-associated gene 5 (MDA5) antibodies. METHODS: Among 142 patients newly diagnosed with PM/DM or clinically amyopathic DM from 2008 to 2019 at our hospital, 10 were diagnosed with refractory RP-ILD and were positive for anti-MDA5 antibodies. PE was used as an adjunct to standard therapy and consisted of fresh frozen plasma as replacement solution. The primary outcome was non-disease-specific mortality. RESULTS: Anti-MDA5 antibodies were detected in 28 patients, of whom 21 were diagnosed with RP-ILD and 10 were refractory to intensive immunosuppressive therapy. Six patients received PE (PE group) and four did not (non-PE group). The 1-year survival rate of the PE group was higher than that of the non-PE group (100% and 25%, respectively, P = 0.033). Regarding adverse events associated with PE, two patients had anaphylactic shock, one had high fever due to fresh frozen plasma allergy and one had a catheter infection. All adverse events resolved with appropriate treatment. CONCLUSION: We evaluated the association between 1-year survival rate and PE for refractory RP-ILD in patients positive for anti-MDA5 antibodies. Intensive immunosuppressive therapy improved the survival rate in RP-ILD patients with anti-MDA5 antibodies, but 20-30% of cases were still fatal. PE could be administered to patients with active infectious disease who were immunocompromised by intensive immunosuppressive therapy. PE may be considered in refractory RP-ILD patients positive for anti-MDA5 antibodies.

Clinical Characteristics of Patients with Spondyloarthritis in Japan in Comparison with Other Regions of the World.

OBJECTIVE: To delineate clinical characteristics of patients with spondyloarthritis (SpA) in Japan in comparison to other areas of the world. METHODS: Using the ASAS-COMOSPA (Assessment of Spondyloarthritis international Society-COMOrbidities in SPondyloArthritis) data, an international cross-sectional observational study of patients with SpA, we analyzed information on demographics, disease characteristics, comorbidities, and risk factors. Patients were classified by region: Japan, other Asian countries (China, Singapore, South Korea, Taiwan), and non-Asian countries (Europe, the Americas, Africa). Patient characteristics, including diagnosis and treatment, were compared. RESULTS: Among 3984 patients included in the study, 161 were from centers in Japan, 933 from other Asian countries, and 2890 from other regions. Of patients with SpA in Japan, 42 (26.1%) had peripheral SpA, substantially more than in other countries. This trend was explained by the predominance of psoriatic arthritis (PsA) among Japanese patients with SpA. In contrast to the relatively low number in Japan, 54% of patients from other Asian countries had pure axial SpA (axSpA) without peripheral features. HLA-B27 testing, considered an integral part of the classification of axSpA, was performed in only 63.6% of Japanese patients with axSpA. More than half of Japanese patients with axSpA were classified using imaging criteria. CONCLUSION: In our study, there was a more substantial number of peripheral SpA cases observed in Japan compared to other parts of Asia and other regions of the world. Aside from ethnic differences, increasing recognition of PsA in Japan, as well as a potential underdiagnosis of axSpA due to the insufficient use of HLA-B27 testing, may partly explain regional discrepancies.

HLA-B46 is associated with severe sacroiliitis in Japanese patients with psoriatic arthritis.

Objectives: The aim of the present study was to determine if the HLA phenotype is related to severe sacroiliitis in Japanese patients with psoriatic arthritis.Methods: This study was a single-center, retrospective, cross-sectional, observational study. We reviewed the clinical information and radiologic examinations of patients with psoriatic arthritis (PsA) who visited our hospital from January 2011 to December 2016. Radiographic changes in the sacroiliac joints were assessed by four independent investigators according to the recommendations of the Assessment of Spondyloarthritis International Society.Results: Of 113 PsA patients, 63 (55.8%) had sacroiliitis. The HLA phenotype was investigated in 39 patients. Ordered logistic regression analysis revealed that the presence of HLA-B46 was an independent risk factor for severe sacroiliitis in Japanese PsA patients (odds ratio 3.2; 95% confidence interval 1.16-9.81). Therefore, the clinical features were divided into two groups according to the presence of HLA-B46. Both the Nail Psoriasis Severity Index and grade of sacroiliitis were significantly higher in the HLA-B46-positive group (Mann-Whitney U test; p = .0003 and p = .028, respectively).Conclusion: HLA-B46 is considered a risk factor for severe sacroiliitis in Japanese patients with PsA.

A case of ankylosing spondylitis with concurrent Takayasu arteritis.

We herein report a case involving a 56-year-old man who had experienced neck and lower back pain since the age of 23 years. Ankylosing spondylitis (AS) was diagnosed at 41 years of age, and treatment with sulfasalazine was initiated. At 44 years of age, the patient developed respiratory distress on exertion and chest pain. Aortic regurgitation (AR) was diagnosed via echocardiography, and the patient presented to our hospital for close examination and treatment. Coronary computed tomography angiography revealed no lesions in the coronary artery; however, magnetic resonance angiography revealed stenotic lesions in the left common carotid artery and left subclavian artery. Based on the findings of a physical examination, fundus examination, and blood tests, the patient was diagnosed with AS with concurrent Takayasu arteritis (TA). Upon administration of steroids to alleviate inflammation caused by an autoimmune mechanism, the patient's chest symptoms and inflammatory findings improved. AR was treated with aortic valve replacement and prosthetic blood vessel replacement, after which the patient progressed well. Intraoperative aortic biopsy revealed findings pathologically consistent with TA. Although AS with concurrent AR is well described, AS with concurrent TA, as in the present case, is rare.

Clinical characteristics and change in the antibody titres of patients with anti-MDA5 antibody-positive inflammatory myositis.

Objective: The aim of this study was to evaluate the clinical characteristics of patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive inflammatory myositis, and the change in anti-MDA5 antibody titres before and after onset. Method: For 105 PM/DM patients, newly diagnosed in our hospital within the period 2008-2016, serum anti-MDA5 antibody levels were measured at diagnosis and after treatment by ELISA using the MESACUP anti-MDA5 test. The relationships between anti-MDA5 antibody levels and clinical manifestations, laboratory data, and mortality were examined. Result: Compared with patients who were anti-MDA5 antibody negative, those who were antibody positive demonstrated more frequent dermatitis, clinically amyopathic DM, interstitial lung disease and rapid-progressive interstitial lung disease, as well as significantly higher serum ferritin, significantly lower creatine kinase and aldolase, and significantly less frequent ANA (⩾1:160) and anti-cytoplasmic pattern of ANA staining positivity. Anti-MDA5 antibody titres were examined before disease onset in two patients; one showed antibody positivity with low titres 2 years earlier, while both exhibited increased titres at onset. Anti-MDA5 antibody titres declined significantly less in survivors than in non-survivors after treatment; however, there was no significant difference between the two groups when the rate was compared at 2 months after treatment. Conclusion: An initial decrease in anti-MDA5 antibody titre after commencement of treatment was observed in most of the patients, including in fatal cases, suggesting that this may not necessarily be a useful marker for treatment of patients with DM.

Elevated serum levels of soluble CD146 in patients with systemic sclerosis.

CD146, a transmembrane glycoprotein member of the immunoglobulin superfamily, acts as an adhesion molecule that helps maintain the cell monolayer. Human endothelial cells expressing CD146 are involved in angiogenesis and inflammation. Recently, we developed a sandwich ELISA for detecting soluble CD146 (sCD146) in human serum specimens. The aim of this study is to determine serum levels of sCD146 in patients with systemic sclerosis (SSc) and to examine the relationship between sCD146 levels and clinical manifestations. We quantified serum sCD146 levels in 47 serum samples from patients fulfilling criteria for SSc, 23 serum samples from patients fulfilling criteria for rheumatoid arthritis (RA), and 25 healthy controls. We also investigated the relationship between sCD146 levels and various clinical characteristics with SSc patients. Levels of sCD146 were significantly higher in the 47 patients with SSc than in the 25 healthy controls and 23 patients with RA (12.50 vs. 6.91 vs. 9.95 ng/ml; p < 0.001). Serum sCD146 levels in SSc patients with pulmonary arterial hypertension (PAH) were lower than in SSc patients without PAH (10.12 vs.13.17 ng/ml; p < 0.01). The serum levels of sCD146 were elevated in patients with SSc. However, decreased sCD146 levels were observed in SSc patients with PAH. Further studies are necessary to elucidate the sources and the mechanisms.

Involvement of Mucosal-associated Invariant T cells in Ankylosing Spondylitis.

OBJECTIVE: Ankylosing spondylitis (AS) is characterized by chronic inflammation of the axial and peripheral joints and ligamentous attachments. Gut immunity is thought to be involved in AS, because a prominent coexistence of gut and joint inflammation has been observed in patients with AS. Mucosal-associated invariant T (MAIT) cells are preferentially located in the gut lamina propria and produce inflammatory cytokines such as interleukin 17 (IL-17) and tumor necrosis factor-α (TNF-α), which are therapeutic targets for AS. This study aimed to investigate the involvement of MAIT cells in AS. METHODS: The frequency of MAIT cells and their cytokine production were determined in patients with AS and healthy controls (HC). The expression of a MAIT cell activation marker (CD69) was analyzed in patients with AS by using flow cytometry. RESULTS: The frequency of MAIT cells in the peripheral blood was lower in patients with AS compared with HC. The levels of IL-17 produced by MAIT cells after activation were higher in patients with AS than in the HC. CD69 expression on MAIT cells correlated with the Ankylosing Spondylitis Disease Activity Score in patients with AS. CONCLUSION: These results suggest the involvement of MAIT cells in the pathogenesis of AS.

Usefulness of minor salivary gland biopsy in the diagnosis of IgG4-related disease: a case report.

Although considered essential for diagnosing IgG4-related disease (IgG4-RD), biopsy of target organs is often difficult to perform. Such was the case of a 56-year-old man admitted with general malaise and weight loss. Computed tomography revealed swelling of the submandibular gland, mild dilatation of the main pancreatic duct, renal involvement, periaortitis, and swelling of the lymph nodes in the abdominal cavity. Laboratory testing revealed elevated serum IgG4 level. These findings were suggestive of IgG4-RD; however, the patient refused consent for biopsy of the target organs for a definitive diagnosis for the invasiveness. Therefore, we tried to perform a biopsy from minor salivary gland, which revealed no sign of clinical abnormality because the biopsy is not an invasive diagnostic procedure. As a result, the biopsy revealed significant IgG4-positive plasma cell infiltration, allowing for definitive IgG4-RD diagnosis. Administration of oral prednisolone (30 mg/day) effectively improved all symptoms. These findings indicate that minor salivary gland biopsy is an effective means of IgG4-RD diagnosis in patients for whom biopsy of target organs is difficult even if there were no sign of clinical abnormality in appearance.

Recent trends in use of nonbiologic DMARDs and evaluation of their continuation rates in single and dual combination therapies in rheumatoid arthritis patients in Japan.

OBJECTIVE: We aim to examine changes in usage of nonbiologic, disease-modifying antirheumatic drugs (DMARDs) and evaluate their continuation rates in Japan. METHODS: We analyzed DMARD treatment data for 3,734 patients with rheumatoid arthritis (RA) from 1998 to 2009 at Juntendo Hospital in Tokyo, Japan. The DMARD usage rate per month was determined to evaluate RA treatment history in the last decade. We also evaluated continuation rates of nonbiologic DMARDs in single and combination therapies and number of nonbiologic DMARD combination therapies used in each patient. RESULTS: We found that nonbiologic DMARD usage has dramatically changed in the last decade, with the most commonly used DMARD shifting from bucillamine to methotrexate (MTX). MTX showed the highest continuation rate; however, much lower continuation rate was observed when used alone rather than in combination treatments. Further, MTX was also used in the highest number of different combination therapies for a particular patient. CONCLUSIONS: These findings indicate that single MTX treatment may be unable to keep patients in clinical remission or lower disease activity compared with several combination therapies. Recent change in permitted maximum dosage of MTX from 8 to 16 mg/week may improve its efficacy and continuation rate in treating Japanese RA patients.

Single-center, retrospective analysis of efficacy and safety of tacrolimus as a second-line DMARD in combination therapy and the risk factors contributing to adverse events in 115 patients with rheumatoid arthritis.

To retrospectively evaluate the efficacy and safety of combination therapy with tacrolimus (TAC) and other disease-modifying antirheumatic drugs (DMARDs). One hundred fifteen rheumatoid arthritis (RA) patients treated with tacrolimus were enrolled in this retrospective analysis. We collected clinical information, including patient background, treatment efficacy (evaluated using the DAS score), and adverse events observed. Multiple logistic regression analysis was conducted to analyze factors contributing to clinical response and adverse effects. The disease activity score of 28 joints (DAS28) improved significantly at 24 weeks, and continuation rate at 1 year was 57.9%. There was no difference in continuation rate between different DMARD combinations, and not only methotrexate (MTX) but also bucillamine (BUC) and salazosulfapyridine (SSZ) were effective combination partners with TAC. No serious adverse events were observed, and no different inefficacy or safety was observed between non-elderly (<65 years old) and elderly (≥65 years old) RA patients. By conducting multiple logistic regression analysis, combination therapy with MTX and TAC, the number of baseline DMARDs (specifically, ≥3), and old age were identified as risk factors for adverse events. Our findings indicate that TAC is a valuable DMARD for second-line combination therapy in RA.

Genome wide analysis of TNF-inducible genes reveals that antioxidant enzymes are induced by TNF and responsible for elimination of ROS.

We recently showed that TNF induces accumulation of reactive oxygen species (ROS) that mediates necrosis in murine embryonic fibroblasts (MEFs) derived from TRAF2- and TRAF5-double deficient (DKO) mice. To elucidate the defects that subsequently cause accumulation of ROS in DKO MEFs, we compared gene expression profiles of wild-type and DKO MEFs before and after TNF stimulation using cDNA microarrays. Interestingly, many antioxidant enzymes are induced by TNF in wild-type MEFs, induction of these genes is impaired in DKO MEFs. Taken that TNF induces accumulation of ROS in DKO, but not wild-type MEFs, upregulation of antioxidant enzyme(s) might play a crucial role in elimination of ROS.