Magnetic Resonance Imaging Patterns Revealing Muscle Pathology and Clinical Features in Idiopathic Inflammatory Myopathies.

OBJECTIVE: Idiopathic inflammatory myopathies (IIMs) are autoimmune disorders significantly impacting skeletal muscles; however, the precise correlation between muscle magnetic resonance imaging (MRI) findings, muscle pathology, disease subtypes, and clinical characteristics remains uncertain. Thus, we investigated the association of muscle MRI findings in IIMs with muscle pathology and clinical features. METHODS: New-onset IIM patients underwent proximal upper and/or lower limb muscle MRI. Patterns of muscle oedema on MRI were categorised into fascial, honeycomb, peripheral, foggy, dense, or coarse dot patterns and compared with inflammatory cell infiltration sites in corresponding muscle biopsies. The incidence of MRI patterns was examined in patient subgroups using myositis-specific antibodies (MSAs) and 2017 EULAR/ACR classification criteria. Univariate and multivariate analyses were conducted to determine the odds ratios (ORs) of MRI findings for clinical characteristics. RESULTS: Fifty-six of 85 patients underwent muscle biopsy. Foggy, honeycomb, and fascial patterns at biopsy sites correlated with inflammatory cell infiltration in the endomysium (OR 11.9, p= 0.005), perimysium (OR 6.0, p= 0.014), and fascia (OR 16.9, p< 0.001), respectively. Honeycomb and foggy patterns were characteristic of patients with anti-TIF1γ or anti-Mi2 antibodies and MSA-negative dermatomyositis, and those with anti-SRP or anti-HMGCR antibodies and MSA-negative polymyositis (PM), respectively. The honeycomb pattern positively correlated with malignancy (OR 6.87, p< 0.001) and Gottron sign (OR 8.05, p= 0.002); the foggy pattern correlated with muscle weakness (OR 11.24, p= 0.005). The dense dot pattern was associated with dysphagia (OR 6.27, p= 0.006) and malignancy (OR 8.49, p= 0.002). CONCLUSION: Muscle MRI holds promise in predicting muscle pathology, disease subtypes, and clinical manifestations of IIMs.

Intramuscular lesions in musculoskeletal MRI as a favourable prognostic sign in patients with anti-MDA5 antibody-positive dermatomyositis.

OBJECTIVES: Anti-differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis, which has been described as clinically amyopathic dermatomyositis, complicates rapidly progressive interstitial lung disease (ILD). Owing to the absence of significant muscle symptoms, musculoskeletal MRI is often not performed. In this study, we aimed to devise a simple evaluation method using musculoskeletal MRI findings to elucidate the relationship between MRI findings and ILD prognosis and development. METHODS: The medical records and MRI scans of the proximal muscles at the time of diagnosis were retrospectively reviewed for 28 patients with anti-MDA5 antibody-positive dermatomyositis who were admitted to The Jikei University Hospital and The Jikei University Kashiwa Hospital between January 2008 and March 2022. Three observers evaluated nine proximal muscles for high signals on either short-tau inversion recovery images and/or fat-saturated gadolinium-enhanced T1-weighted images in the fascia and/or in the margins of the muscles in contact with the fascia (fascial pattern), and/or high signals in the muscles away from the fascia (intramuscular pattern), and a consensus was reached. RESULTS: Of the 28 patients, 15 presented with 'radiological myositis', where an intramuscular pattern was observed at any site. Patients with radiological myositis had significantly higher survival rates than those without radiological myositis, despite the lower rate of triple therapy with prednisolone, calcineurin inhibitors and cyclophosphamide. The spread of ILD on chest CT negatively and significantly correlated with the proportion of intramuscular lesions. CONCLUSION: The detection of intramuscular lesions on musculoskeletal MRI using our novel evaluation method could be clinically useful as a favourable prognostic marker.

Sustained microglial activation in the area postrema of collagen-induced arthritis mice.

BACKGROUND: Central nervous system (CNS)-mediated symptoms, such as fatigue, depression, and hyperalgesia, are common complications among patients with rheumatoid arthritis (RA). However, it remains unclear how the peripheral pathology of RA spreads to the brain. Accumulated evidence showing an association between serum cytokine levels and aberrant CNS function suggests that humoral factors participate in this mechanism. In contrast to the well-known early responses of microglia (CNS-resident immune cells) in the area postrema [AP; a brain region lacking a blood-brain barrier (BBB)] to experimental inflammation, microglial alterations in the AP during chronic inflammation like RA remain unclear. Therefore, to determine whether microglia in the AP can react to persistent autoimmune-arthritis conditions, we analyzed these cells in a mouse model of collagen-induced arthritis (CIA). METHODS: Microglial number and morphology were analyzed in the AP of CIA and control mice (administered Freund's adjuvant or saline). Immunostaining for ionized calcium-binding adaptor molecule-1 was performed at various disease phases: "pre-onset" [post-immunization day (PID) 21], "establishment" (PID 35), and "chronic" (PID 56 and 84). Quantitative analyses of microglial number and morphology were performed, with principal component analysis used to classify microglia. Interleukin-1ß (IL-1ß) mRNA expression was analyzed by multiple fluorescent in situ hybridization and real-time polymerase chain reaction. Behavioral changes were assessed by sucrose preference test. RESULTS: Microglia in the AP significantly increased in density and exhibited changes in morphology during the establishment and chronic phases, but not the pre-onset phase. Non-subjective clustering classification of cell morphology (CIA, 1,256 cells; saline, 852 cells) showed that the proportion of highly activated microglia increased in the CIA group during establishment and chronic phases. Moreover, the density of IL-1ß-positive microglia, a hallmark of functional activation, was increased in the AP. Sucrose preferences in CIA mice negatively correlated with IL-1ß expression in brain regions containing the AP. CONCLUSIONS: Our findings demonstrate that microglia in the AP can sustain their activated state during persistent autoimmune arthritis, which suggests that chronic inflammation, such as RA, may affect microglia in brain regions lacking a BBB and have various neural consequences.

Immune recognition of lysyl-tRNA synthetase and isoleucyl-tRNA synthetase by anti-OJ antibody-positive sera.

OBJECTIVE: Anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies are useful for identifying a clinical subset of patients with idiopathic inflammatory myopathies (IIMs). Anti-OJ antibodies, which recognize multi-enzyme synthetase complexes including isoleucyl-tRNA synthetase (IARS) and lysyl-tRNA synthetase (KARS), are among the anti-ARS antibodies. Although testing antibodies to other ARSs have been used clinically, no validated immunoassays for detecting anti-OJ antibodies are available. We aimed to establish an anti-OJ ELISA. METHODS: Serum samples were collected from 279 patients with IIMs and 22 patients with idiopathic interstitial pneumonia. Sixty-four of the samples that had been confirmed to be negative for anti-OJ by standard immunoprecipitation were used as the negative control, and 12 anti-OJ-positive reference sera were used as the positive control. Antibodies to IARS and KARS were assayed by ELISA using biotinylated recombinant proteins generated by in vitro transcription/translation. RESULTS: The anti-OJ-positive sera strongly reacted with the KARS and IARS recombinant proteins in ELISA. Although all 12 reference sera were positive in the anti-KARS ELISA, 4 of the 64 anti-OJ-negative sera were also weakly positive. The sensitivity and the specificity were 100% and 93.8%, respectively. Since our anti-KARS ELISA performed well, showing a high agreement with the results for immunoprecipitation (Cohen's κ > 0.8), the remaining 237 samples were also tested. Thirteen anti-KARS-positive sera were newly found by ELISA, all of which were anti-OJ positive by immunoprecipitation. CONCLUSION: Immunoassays for detecting anti-OJ antibodies using KARS and IARS recombinant proteins were developed. Our ELISAs performed well, with very high agreement of the results by immunoprecipitation and can be applied to the first reliable, easy-to-use measurement assays for anti-OJ antibodies.

How do neuropathic pain-like symptoms affect health-related quality of life among patients with rheumatoid arthritis?: A comparison of multiple pain-related parameters.

Objectives: Rheumatoid arthritis (RA) pain is thought to be nociceptive. However, recent studies indicate that RA also involves the neuropathic pain (NP) mechanism. We examined pain features and the effect of NP-like symptoms on health-related quality of life (HRQOL) among patients with RA.Methods: The painDETECT questionnaire (PDQ) was used to evaluate NP-like symptoms among 145 outpatients with RA. Disease activity, pain quality, and HRQOL were evaluated. We compared clinical parameters between patients with and without NP-like symptoms and analyzed pain features and the effect of NP-like symptoms on HRQOL, along with multiple other pain-related parameters.Results: Thirty (20.7%) patients had NP-like symptoms (PDQ ≥13). Patient global assessment and evaluator global assessment diverged for patients with RA who had NP-like symptoms. Of the examined pain-related parameters, PDQ score (p = .038, ß = -.173) was associated with the Short-Form 36-Item Health Survey role-social component summary score, but not with the physical or mental component summary scores.Conclusion: NP-like symptoms affected HRQOL among patients with RA. There was discordance between global assessments by patients and by evaluators for patients with RA who had NP-like symptoms. Therefore, NP-like symptoms should be given somewhat more attention when treating patients with RA.

Alterations of voluntary behavior in the course of disease progress and pharmacotherapy in mice with collagen-induced arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovitis and bone destruction at the joints, causing pain and motor disturbance. Despite the better control of inflammation and joint deformity afforded by modern disease-modifying anti-rheumatic drugs, many patients with RA remain dissatisfied with their treatment, primarily because of sensory-emotional distress. Pre-clinical tests that can evaluate not only the symptoms of arthritis but also the associated pain as sensory-emotional experience are urgently needed. METHODS: Here, we introduce two types of novel methods for evaluation of voluntary behavior in a commonly used model of RA (collagen-induced arthritis; CIA) in male mice. First, spontaneous motor activity was assessed with a running wheel placed in home cages and the number of rotations was continuously recorded in a 12:12-h light environment. Second, temperature preference was assessed by measuring the time spent in either of the floor plates with augmenting (25 to 49 °C) or fixed temperature (25 °C). We also evaluated the effects of tofacitinib on CIA-associated changes in voluntary wheel running and temperature preference. RESULTS: We detected a significant decrease in voluntary wheel running, a significant shift in the distribution of movement in the dark phase, and a significant increase in the time spent in warmer environments than the room temperature in the mice with CIA. These alterations in voluntary behavior have never been described with conventional methods. We also revealed tofacitinib-resistant significant changes in the voluntary behavior and choice of temperature despite significant mitigation of the symptoms of arthritis. CONCLUSIONS: We described for the first time significant alterations of the voluntary behavior of the mice with CIA during the clinical periods, indicating that the overall physical/motivational states and its circadian variation, as well as the specific preference to a certain environmental temperature, are modified in the mice with CIA, as observed in human patients. Some of these did not parallel with the conventional arthritis scores, particularly during the pharmacotherapy suggesting that mice with CIA show not only the peripheral symptoms but also the central consequences. The use of these approaches would also help clarify the biological mechanisms underlying physician-patient discordance in the assessment of RA.

Prokineticin 2 antagonist, PKRA7 suppresses arthritis in mice with collagen-induced arthritis.

BACKGROUND: Prokineticin 2 (PK2) expression is upregulated in mice with collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis. The purpose of our study was to investigate the effects of PK2 inhibition on CIA. METHODS: PK2, prokineticin receptor (PKR) 1, and PKR2 mRNA transcripts in the joints of CIA mice were measured by real-time PCR on Days 21, 28, and 35 (n = 15/day). Localization of PKR1 and PKR2 proteins was examined immunohistochemically. PKRA7, a PK2 antagonist, was administered intraperitoneally for 2 weeks to CIA mice, and the severity of arthritis was compared between treated (n = 12) and untreated (n = 12) mice. The gene expression levels of inflammatory cytokines IL-1ß, IL-6, TNF-α, and VEGF were also measured by real-time PCR and compared between treated (n = 6) and untreated (n = 6) CIA mice. The data was statistically analyzed, and P values of less than 0.05 were considered significant. RESULTS: In the thickened synovial membrane, PKR1 protein was expressed in infiltrating neutrophils, while PKR2 expression was found in macrophage-like mononuclear cells. PK2 gene expression was significantly more pronounced on Days 28 and 35 than on Day 21 (2.15 and 2.03 versus 1.00, P = 0.0311 and 0.0247; Dunn's multiple comparison). PKR2 gene expression levels were significantly higher on Days 28 and 35 compared to Day 21 (25.4 and 39.3 versus 1.0, P = 0.002 and < 0.0001; Dunn's multiple comparison). Administration of PKRA7 suppressed the severity of arthritis (P < 0.001; two-way analysis of variance). A gene expression analysis of inflammatory cytokines revealed significantly reduced IL-1ß and lL-6 expression in the joints of PKRA7-treated mice compared to untreated mice (0.1 versus 1.0, P = 0.0043 and 0.04 versus 1.0, P = 0.0022, respectively; Mann-Whitney test). CONCLUSIONS: PK2 inhibition suppressed arthritis in mice with CIA.