Examination of Prognostic Factors in Anti-Melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis.

OBJECTIVE: This study investigated the prognostic factors of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis (MDA5-DM). METHODS: This study analysed 34 MDA5-DM cases (20 and 14 in the survival and death groups, respectively) encountered at Kurume University between 2008 and 2021. The clinical, physiological, and computed tomography findings, pulmonary function, and serological results were retrospectively evaluated for each MDA5-DM case during the first visit and throughout the next 12 weeks. RESULTS: In the death group, the mean age of patients was higher (47.6 vs. 61.8 years), while the duration from symptom onset to consultation was shorter (110 vs. 34.9 days). During the first visit, the death group demonstrated a significantly higher serum C-reactive protein (CRP) level (0.52 vs. 1.99) and a significantly lower albumin level (3.23 vs. 2.63) than the survival group; this persisted throughout the next 12 weeks. Poor prognosis was associated with CRP and albumin levels above 0.19 mg/dL and below 2.3 g/dL, respectively, 4 weeks after starting treatment. CONCLUSION: Four weeks after beginning treatment, serum CRP and albumin levels of patients with MDA5-DM can be used to evaluate treatment response and predict prognosis.

Periostin Is a Biomarker of Rheumatoid Arthritis-Associated Interstitial Lung Disease.

Periostin was investigated as a biomarker for rheumatoid arthritis-associated interstitial lung disease (RA-ILD). This prospective study measured serum monomeric and total periostin, Klebs von den Lungen-6 (KL-6), surfactant protein D (SP-D), and lactate dehydrogenase (LDH) in 19 patients with RA-ILD, 20 RA without ILD, and 137 healthy controls (HC). All biomarkers were higher in RA-ILD than HC or RA without ILD. KL-6 accurately detected ILD in RA patients (area under curve [AUC] = 0.939) and moderately detected SP-D and monomeric and total periostin (AUC = 0.803, =0.767, =0.767, respectively). Monomeric and total periostin were negatively correlated with normal lung area and positively correlated with honeycombing, reticulation, fibrosis score, and the traction bronchiectasis grade but not inflammatory areas. Serum levels of SP-D, KL-6, and LDH did not correlate with the extent of those fibrotic areas on high-resolution CT. Serum monomeric and total periostin were higher in patients with RA-ILD with definite usual interstitial pneumonia pattern compared with other ILD patterns. Immunohistochemical analyses of biopsy or autopsy lung tissues from RA-ILD during the chronic phase and acute exacerbation showed that periostin was expressed in fibroblastic foci but not inflammatory or dense fibrosis lesions. Periostin is a potential biomarker for diagnosis, evaluating fibrosis, and deciding therapeutic strategies for patients with RA-ILD.

Combination of Prednisolone and Calcineurin Inhibitors Prevents Lung Function Decline in Patients with Anti-aminoacyl-tRNA Synthetase Antibody-Positive Polymyositis/Dermatomyositis.

OBJECTIVE: Anti-aminoacyl-tRNA synthetase antibody-positive polymyositis/dermatomyositis-associ ated interstitial lung disease (ARS-ILD) has a good prognosis, with few cases progressing to respiratory failure. This study aimed to determine factors predictive of lung function changes in patients with ARS-ILD. METHODS: We retrospectively studied 49 patients with ARS-ILD treated at Kurume University Hospital Hospital between 2000 and 2018. We followed 30 patients for more than 2 years after prednisolone (PSL) therapy, with or without calcineurin inhibitors (CNIs), evaluating clinical, physiological, computed tomography, pulmonary func tion, and serological data. RESULTS: After treatment for 24 months, no significant differences were noted between clinical parameters and improvement in forced vital capacity (FVC), %FVC, % carbon monoxide diffusing capacity/alveolar volume (%DLCO), and %DLCO/alveolar volume. Conversely, the annual change of %FVC significantly correlated with the Medical Research Council dyspnea scale grade and %FVC at the first visit and treatment. Furthermore, the annual change of %DLCO/VA significantly correlated with the duration from the first visit to treatment initiation. CONCLUSION: Compared with PSL monotherapy, combining PSL and CNI showed greater mitigation of %FVC decline. The time from onset of ARS-ILD to the first visit is critical for preventing a decline in lung function, and as such, patients should be monitored carefully.

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.

Positive Autoantibody Is Associated with Malignancies in Patients with Idiopathic Interstitial Pneumonias.

Various autoantibodies are associated with clinical outcomes in patients with idiopathic interstitial pneumonias (IIPs). We retrospectively analyzed the association between autoantibodies and malignancies in IIP patients. Comprehensive analyses of autoantibodies were performed using immunoprecipitation and enzyme-linked immunosorbent assays in 193 consecutive IIP patients. Cancer-related factors were analyzed using logistic regression analysis. In total, 22 of 193 patients (11.4%) with IIP had malignant disease. In univariate analysis, positivity for any autoantibody (odds ratio (OR), 3.1; 95% confidence interval (CI), 1.2-7.7; p = 0.017) and antinuclear antibody titer ≥1:320 (OR, 3.4; CI, 1.2-9.8; p = 0.024) were significantly associated with malignancies. Positive anti-aminoacyl tRNA synthetase (ARS) (OR, 3.7; CI, 0.88-15.5; p = 0.074) and anti-Ro52 antibody (OR, 3.2; CI, 0.93-11.2; p = 0.065) tended to be associated with malignancies. In multivariate analysis, independent risk factors were male sex (OR, 3.7; CI, 1.0-13.5; p = 0.029) and positivity for any autoantibody (OR, 3.9; CI, 1.5-10.1; p = 0.004) in model 1, and male sex (OR, 3.9; CI, 1.0-15.3; p = 0.049), antinuclear antibody titer ≥1:320 (OR, 4.2; CI, 1.4-13.3; p = 0.013), and positivity for anti-ARS antibody (OR, 6.5; CI, 1.2-34.1; p = 0.026) in model 2. Positivity for any autoantibody, antinuclear and anti-ARS antibodies, and male sex were independent risk factors for malignancies in IIP patients. Testing autoantibodies in IIP patients might help the early diagnosis of malignancies.

Clinical Characteristics of Anti-TIF-1γ Antibody-Positive Dermatomyositis Associated with Malignancy.

We retrospectively analyzed the clinical and laboratory data of patients diagnosed with anti-transcriptional intermediary factor 1 (TIF-1γ) antibody-positive polymyositis (PM)/dermatomyositis (DM) to clarify the characteristics of this disease. We identified 14 patients with TIF-1γ antibody-positive DM (TIF-1γ DM), 47 with anti-aminoacyl-tRNA synthetase antibody (ARS)-positive PM/DM, and 24 with anti-melanoma differentiation-associated gene 5 antibody (MDA-5)-positive PM/DM treated at the Kurume University Hospital between 2002 and 2020. Patients with TIF-1γ DM were significantly older than the other two groups. Nine patients with TIF-1γ DM were female, thirteen patients had DM, and one had clinically amyopathic DM. Primary malignant lesions were lung (3), uterus (2), colon (2), breast (2), ovary (1), lymphoma (1), and unknown (2). Cutaneous manifestation and dysphagia were the most common symptoms in TIF-1γ DM. Erythema (9/14), the V-neck sign (8/14), heliotrope (9/14), and nailfold telangiectasia (14/14) were significantly more common in TIF-1γ DM. Furthermore, no patients with TIF-1γ DM had interstitial lung abnormality on high-resolution CT. In patients with TIF-1γ DM, the frequency of dysphagia and unusual erythema, particularly that which spreads from the trunk, and nailfold telangiectasia, were characteristic findings. In most patients with TIF-1γ DM, it is necessary to administer other immunosuppressive drugs along with glucocorticoids.

TAFRO Syndrome That Responded to Prednisolone-only Treatment: Evaluating Changes in IL-6.

Thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome is a systemic inflammatory disorder characterized by the above-mentioned symptoms. Because of the similarity in phenotypes between TAFRO syndrome and decompensated liver cirrhosis, an accurate diagnosis is often difficult. We herein report a 62-year-old Japanese patient with TAFRO syndrome who was misdiagnosed with intractable ascites associated with liver cirrhosis. Improvement of symptoms after treatment with prednisolone was associated with interleukin-6 rather than C-reactive protein. The pathogenesis of TAFRO syndrome, which has similar clinical manifestations to liver cirrhosis, remains unclear, and our findings may help elucidate the concept of this condition.

Mast cells can produce transforming growth factor ß1 and promote tissue fibrosis during the development of Sjögren's syndrome-related sialadenitis.

OBJECTIVES: This study investigated the associations of mast cells with immune-mediated inflammation and fibrosis in patients with primary Sjögren's syndrome (pSS); it also explored the underlying pathophysiology of pSS-related sialadenitis. METHODS: Twenty-two patients with pSS and 10 patients with sicca (control individuals) underwent labial salivary gland biopsies. Sections were subjected to staining and immunofluorescence analyses. HMC-1 human mast cells were cocultured with fibroblasts in vitro; fibroblasts were also grown in HMC-1 conditioned medium. mRNA levels of collagen Type I (Col1a) and transforming growth factor (TGF)ß1 were analysed in cultured cells. RESULTS: Mast cell numbers in labial salivary glands were significantly greater in patients with pSS than in control individuals. In salivary glands from patients with pSS, mast cell number was significantly correlated with fibrosis extent; moreover, mast cells were located near fibrous tissue and expressed TGFß1. Col1a and TGFß1 mRNAs were upregulated in cocultured fibroblasts and HMC-1 cells, respectively. Fibroblasts cultured in HMC-1 conditioned medium exhibited upregulation of Col1a mRNA; this was abrogated by TGFß1 neutralizing antibodies. CONCLUSIONS: Mast cell numbers were elevated in patients with pSS-related sialadenitis; these cells were located near fibroblasts and expressed TGFß1. TGFß1 could induce collagen synthesis in fibroblasts, which might contribute to fibrosis.

Subcutaneous Cheek Nodule Associated with Granulomatosis with Polyangiitis.

We herein report an unusual case of granulomatosis with polyangiitis (GPA) in a 65-year-old man in whom relapsed disease manifested as an anterior cheek nodule. Magnetic resonance imaging indicated the differential diagnoses of the subcutaneous nodule in the patient's anterior cheek to be inflammatory granulomatous lesions with GPA, malignancy, or infectious disease. A histopathological examination ruled out malignancy and infectious diseases, and necrotizing vasculitis was suspected. The subcutaneous nodule was successfully treated using rituximab, suggesting that it was associated with GPA, secondary to vasculitis. Clinicians should be aware of the possibility of such a rare manifestation of GPA.

Possible Roles of tRNA Fragments, as New Regulatory ncRNAs, in the Pathogenesis of Rheumatoid Arthritis.

Understanding the pathophysiology of rheumatoid arthritis (RA) has led to the successful development of molecule-targeted drugs for the treatment of RA. However, some RA patients are refractory to these treatments, suggesting that the pathological mechanism of the disease is not entirely understood. Genome and transcriptome analysis is essential for understanding the unknown pathophysiology of human diseases. Rapid and more comprehensive gene analysis technologies have revealed notable changes in the expression of coding RNA and non-coding RNA in RA patients. This review focuses on the current state of non-coding RNA research in relation to RA, especially on tRNA fragments. Interestingly, it has been found that tRNA fragments repress translation and are antiapoptotic. The association between tRNA fragments and various diseases has been studied, and this article reviews the possible role of tRNA fragments in RA.

Dermatomyositis-like eruptions and fasciitis with novel compound heterozygous MEFV mutations: Newly recognized features of a variant of familial Mediterranean fever.

Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by recurrent febrile attacks and serositis. The diagnosis of FMF has been based on clinical criteria, including frequent symptoms and good response to the treatment with colchicine. Some patients with FMF show skin or muscle manifestations, which may be confused with other cutaneous or muscle disorders. Here we report a female in her 40s with periodic fever, migratory myalgia, dermatomyositis-like dermatitis, arthralgia, pharyngalgia, and lymphadenopathy. The initial clinical differential diagnosis included dermatomyositis, malignant lymphoma, and adult-onset Still's disease. However, the following examinations could not explain her pathological condition with such diseases. In particular, findings from muscle and fascial biopsy demonstrated severe inflammatory cell infiltrate in the fascia, suggesting fasciitis as a possible cause of migratory myalgia. We examined the possibility of autoinflammatory diseases by genetic testing. Accordingly, she was found to have novel compound heterozygous mutations (L110P, E148Q, and P369S) in the MEFV gene. Given her genetic mutations and favorable response to colchicine, she was finally diagnosed as a variant of FMF with myalgia and previously unprecedented skin eruptions.

MEFV E148Q variant is more associated with familial Mediterranean fever when combined with other non-exon 10 MEFV variants in Japanese patients with recurrent fever.

OBJECTIVE: To investigate the genetic characteristics of one of the MEFV gene variants, p.Glu148Gln (E148Q), in patients with familial Mediterranean fever (FMF) and examine its significance in Japanese patients with recurrent fever. METHODS: The clinical phenotype and genomic variants of systemic autoinflammatory diseases (SAIDs), including MEFV, were analyzed in 211 Japanese patients with recurrent fever. Genetic analysis was performed via next-generation sequencing of exons, including exon-intron boundaries. RESULTS: Twelve patients met the diagnostic criteria for SAIDs other than FMF. Considering 199 patients with recurrent fever, 137 cases (68.8%) were clinically diagnosed with FMF. Although Bonferroni-adjusted p-value did not reach significance level, the group containing heterozygous E148Q and other variants tended to be at higher risk of developing the FMF phenotype (nominal p = .036) than the group with heterozygous E148Q only. Comparison between the group with heterozygous E148Q and other variants and the heterozygous group containing non-E148Q showed no statistically significant difference in FMF phenotype expression (nominal p = 1.00). CONCLUSION: Patients with heterozygous E148Q and other variants exhibited higher expression of FMF phenotype than those with heterozygous E148Q only, and suggested that other variants than E148Q as well as exon 10 variants might contribute to the FMF phenotype.

Clinical phenotypes and genetic analyses for diagnosis of systemic autoinflammatory diseases in adult patients with unexplained fever.

OBJECTIVE: To make an accurate diagnosis of systemic autoinflammatory diseases (SAIDs), clinical and genetic analyses were performed in patients with unexplained fever. METHODS: The clinical phenotype and genomic variants of 11 genes responsible for SAIDs were analyzed in 179 Japanese patients with unexplained fever. Genetic analysis was performed by next generation sequencing (NGS) on exons including exon-intron boundaries. RESULTS: Three cases met the diagnostic criteria for SAIDs other than familial Mediterranean fever (FMF). Considering 176 patients with unexplained fever, 43 cases (24.0%) were clinically diagnosed as FMF. Gene variants were found in 53 cases (30.1%) when searching for variants in the 10 disease genes other than the MEFV gene. Among them, the most frequently-identified genes were NLRP3, NOD2, NLRP12, NLRC4, and PLCG2, which accounted for 14, 7, 17, 7, and 6 cases, respectively. These variants were less than 1% of healthy individuals or novel variants, but not regarded as pathogenic since the patients did not meet the diagnostic criteria of SAIDs caused by their identified variants clinically. CONCLUSION: Twenty four percent of Japanese patients with unexplained fever were clinically diagnosed as FMF in this study. Low frequency but not pathogenic variants in genes other than MEFV were identified in 30.1% of the cases. It is not clear how much these gene variants contribute to the inflammatory phenotypes; therefore, further analysis would uncover their autoinflammatory phenotypes that cause fever.

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.

Clinical and Genetic Analysis of 22 Japanese Patients with Familial Mediterranean Fever: An Examination of MEFV and 10 Other Genes Related to Autoinflammatory Syndromes.

Objective Familial Mediterranean Fever (FMF) is the most frequent autoinflammatory syndrome, and its frequency is reported to be increasing in Japan. We studied the clinical features and genetic background of patients with FMF in our hospital. Methods We analyzed the clinical features and genomic variants of MEFV, as well as 10 genes related to other autoinflammatory syndromes, in 22 Japanese patients with FMF. A genetic analysis was performed with a next generation sequencer. Results The patients were classified into the typical FMF (n=16) and atypical FMF (n=6) groups. Fever, abdominal pain, thoracic pain, and arthralgia were observed in 22, 12, 8, and 10 patients, respectively. MEFV variants were found in 19 patients (86.4%). Two cases had no MEFV variants and one case only had a variant in the 3' untranslated region (3'-UTR) of MEFV. Genomic variants were found in genes other than MEFV in 7 patients (31.8%); however, none met the diagnostic criteria for autoinflammatory syndromes with disease-related gene variants, and all were classified as typical FMF. Moreover, none of the 6 patients with atypical FMF had any variants among the 10 disease-related genes. All cases in which the onset occurred before 20 years of age were classified as typical FMF. Conclusion The clinical features of FMF recorded in our hospital coincided with those from the Japanese national epidemiological survey of FMF in Japan. More than 30% of the patients with FMF had non-MEFV genes, related to other autoinflammatory syndromes, thereby suggesting that variants of these genes may act as a disease-modifier in FMF.

ISSAID/EMQN Best Practice Guidelines for the Genetic Diagnosis of Monogenic Autoinflammatory Diseases in the Next-Generation Sequencing Era.

BACKGROUND: Monogenic autoinflammatory diseases are caused by pathogenic variants in genes that regulate innate immune responses, and are characterized by sterile systemic inflammatory episodes. Since symptoms can overlap within this rapidly expanding disease category, accurate genetic diagnosis is of the utmost importance to initiate early inflammation-targeted treatment and prevent clinically significant or life-threatening complications. Initial recommendations for the genetic diagnosis of autoinflammatory diseases were limited to a gene-by-gene diagnosis strategy based on the Sanger method, and restricted to the 4 prototypic recurrent fevers (MEFV, MVK, TNFRSF1A, and NLRP3 genes). The development of best practices guidelines integrating critical recent discoveries has become essential. METHODS: The preparatory steps included 2 online surveys and pathogenicity annotation of newly recommended genes. The current guidelines were drafted by European Molecular Genetics Quality Network members, then discussed by a panel of experts of the International Society for Systemic Autoinflammatory Diseases during a consensus meeting. RESULTS: In these guidelines, we combine the diagnostic strength of next-generation sequencing and recommendations to 4 more recently identified genes (ADA2, NOD2, PSTPIP1, and TNFAIP3), nonclassical pathogenic genetic alterations, and atypical phenotypes. We present a referral-based decision tree for test scope and method (Sanger versus next-generation sequencing) and recommend on complementary explorations for mosaicism, copy-number variants, and gene dose. A genotype table based on the 5-category variant pathogenicity classification provides the clinical significance of prototypic genotypes per gene and disease. CONCLUSIONS: These guidelines will orient and assist geneticists and health practitioners in providing up-to-date and appropriate diagnosis to their patients.