Pathological autoantibody internalisation in myositis.

OBJECTIVES: Autoantibodies targeting intracellular proteins are common in various autoimmune diseases. In the context of myositis, the pathologic significance of these autoantibodies has been questioned due to the assumption that autoantibodies cannot enter living muscle cells. This study aims to investigate the validity of this assumption. METHODS: Confocal immunofluorescence microscopy was employed to localise antibodies and other proteins of interest in myositis muscle biopsies. Bulk RNA sequencing was used to examine the transcriptomic profiles of 669 samples, including those from patients with myositis, disease controls and healthy controls. Additionally, antibodies from myositis patients were introduced into cultured myoblasts through electroporation, and their transcriptomic profiles were analysed using RNA sequencing. RESULTS: In patients with myositis autoantibodies, antibodies accumulated inside myofibres in the same subcellular compartment as the autoantigen. Bulk RNA sequencing revealed that muscle biopsies from patients with autoantibodies targeting transcriptional regulators exhibited transcriptomic patterns consistent with dysfunction of the autoantigen. For instance, in muscle biopsies from patients with anti-PM/Scl autoantibodies recognising components of the nuclear RNA exosome complex, an accumulation of divergent transcripts and long non-coding RNAs was observed; these RNA forms are typically degraded by the nuclear RNA exosome complex. Introducing patient antibodies into cultured muscle cells recapitulated the transcriptomic effects observed in human disease. Further supporting evidence suggested that myositis autoantibodies recognising other autoantigens may also disrupt the function of their targets. CONCLUSIONS: This study demonstrates that, in myositis, autoantibodies are internalised into living cells, causing biological effects consistent with the disrupted function of their autoantigen.

Age-Related Changes in Upper Airway Anatomy Via Ultrasonography in Pediatric Patients.

PURPOSE: Ultrasonography is a portable, noninvasive tool that may be used to evaluate the upper airway. The purpose of our study was to present a systematic approach to identify salient features of the pediatric airway and determine whether ultrasonography can identify anatomical changes that occur with growth and development. METHODS: We present a prospective, observational trial where patients included were between 1 day and 10 years of age presenting for elective surgery who had no known history of unfavorable airway pathology. We sequentially obtained 5 ultrasound views under anesthesia: (1) sagittal sternal notch view of the trachea, (2) sagittal longitudinal view of trachea (LT), (3) axial view at the level of the vocal cords (AVC), (4) axial view at the level of the cricoid membrane (AC), and (5) sagittal longitudinal submental space view (SM). A broadband linear array transducer was used to identify airway structures and perform measurements. RESULTS: Eighty-four percent of enrolled patients underwent airway imaging and were analyzed using multiple regression and Spearman correlation (ρ). In view 1, tracheal diameter via sagittal sternal notch view was immeasurable because of air disturbance. In the LT view, the distance from the skin to the cricothyroid membrane (LT1) did not statistically increase with age in days (P = 0.06); however, the distance from the cricoid to thyroid cartilage (LT2) did correlate to age (P < 0.001; 99% confidence interval [CI], 1.8 × 10-5, 7.7 × 10-5; ρ = 0.77, P = 0.001). We found a statistically significant relationship between age and the distance between the anterior and posterior commissures (AVC2; P < 0.001; 99% CI, 1.0 × 10-4, 1.7 × 10-4; ρ = 0.80, P < 0.001), the distance from the skin to the posterior commissure (AVC3; P < 0.001; 99% CI, 9.6 × 10-5, 2.0 × 10-4; ρ = 0.73, P < 0.001), the distance to the cricoid cartilage (AC; P < 0.001; 99% CI, 2.0 × 10-5, 7.7 × 10-5; ρ = 0.66, P < 0.001), and the distance from the tongue base to the soft palate (SM2; P < 0.001; 9% CI, 1.8 × 10-4, 3.9 × 10-4; ρ = 0.85, P < 0.001). There were no significant relationships between age and AVC1 (P = 0.16) and SM1 (P = 0.44). CONCLUSIONS: Airway ultrasound is a feasible tool to evaluate the pediatric airway in children younger than 10 years; however, the detection of age-related changes of certain structures is limited to select measurements.

Pathogenesis of inclusion body myositis.

PURPOSE OF REVIEW: To review the pathogenesis of inclusion body myositis (IBM). RECENT FINDINGS: IBM is an autoimmune disease. Multiple arms of the immune system are activated, but a direct attack on muscle fibers by highly differentiated T cells drives muscle destruction. SUMMARY: Further understanding of the pathogenesis of IBM guides rational approaches to developing therapeutic strategies.

Inclusion-body myositis and primary Sjögren syndrome: mechanisms for shared etiologies.

Herein we report a case of sporadic inclusion-body myositis (sIBM) occurring at an unusually young age in a patient with primary Sjögren syndrome, and use the case to explore possible shared mechanisms for disease susceptibility. Possible factors may include the association of both conditions with the 8.1 ancestral haplotype; the presence of anti-cN1A antibodies, which, although considered specific for sIBM, are also seen in pSS; and the shared association with T-cell large granular lymphocyte leukemia (T-LGLL). Further evaluation of this patient did in fact reveal underlying T-LGLL and mechanisms by which T cells in sIBM may escape immune regulation and contribute to disease phenotype are explored. Despite myofiber infiltration with CD8-positive T cells in sIBM, and, although sIBM is traditionally considered treatment-refractory, we report a significant response to the anti-CD20 monoclonal antibody, rituximab, and discuss possible mechanisms by which this response may be mediated.

Highly differentiated cytotoxic T cells in inclusion body myositis.

Inclusion body myositis is a late onset treatment-refractory autoimmune disease of skeletal muscle associated with a blood autoantibody (anti-cN1A), an HLA autoimmune haplotype, and muscle pathology characterized by cytotoxic CD8+ T cell destruction of myofibres. Here, we report on translational studies of inclusion body myositis patient muscle compared with a diverse set of other muscle disease samples. Using available microarray data on 411 muscle samples from patients with inclusion body myositis (n = 40), other muscle diseases (n = 265), and without neuromuscular disease (normal, n = 106), we identified a signature of T-cell cytotoxicity in inclusion body myositis muscle coupled with a signature of highly differentiated CD8 T-cell effector memory and terminally differentiated effector cells. Further, we examined killer cell lectin-like receptor G1 (KLRG1) as a marker of this population of cells, demonstrated the correlation of KLRG1 gene expression with lymphocyte cytotoxicity across 28 870 human tissue samples, and identified the presence of KLRG1 on pathogenic inclusion body myositis muscle invading T cells and an increase in KLRG1 expressing T cells in inclusion body myositis blood. We examined inclusion body myositis muscle T-cell proliferation by Ki67 immunohistochemistry demonstrating that diseased muscle-invading T cells are minimally or non-proliferative, in accordance with known properties of highly differentiated or terminally differentiated T cells. We found low expression of KLRG1 on infection-protective human lymphoid tissue central memory T cells and autoimmune-protective human blood regulatory T cells. Targeting highly differentiated cytotoxic T cells could be a favourable approach to treatment of inclusion body myositis.

Cytotoxic KLRG1 expressing lymphocytes invade portal tracts in primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease with an immunopathogenesis that includes highly differentiated cytotoxic T cell infiltration in portal areas. We have taken advantage of a large and well-defined cohort of patients with PBC, AIH, chronic hepatitis virus, and healthy controls to study for the presence of highly differentiated T cells which express the killer cell lectin-like receptor G1 (KLRG1). Such studies were performed using both liver and peripheral blood mononuclear cells. In particular, gene expression data (GSE79850) from 16 PBC patients stratified according to future risk of liver transplantation were analyzed for markers of highly differentiated cytotoxic T cells. Liver biopsy samples from 44 PBC patients were studied by immunohistochemistry and a separate cohort of PBC blood samples were studied by flow cytometry. Gene expression data demonstrated correlation of increased KLRG1 and cytotoxic lymphocyte molecules, such as granzyme B (GZMB) and perforin (PRF1), to disease severity as measured by future risk of liver transplantation. Immunohistochemistry demonstrated abundant infiltration of KLRG1+ cells into liver portal areas (mean of 45% of infiltrating cells, range 25-75%) positively correlated with hepatic inflammatory (r = 0.47, p = 0.001) and hepatic fibrosis (r = 0.34, p = 0.021) scores. KLRG1+ lymphocyte liver portal area infiltration was positively correlated with serum alkaline phosphatase (r = 0.45, p = 0.005) and GGT (r = 0.40, p = 0.014), and AST (r = 0.35, p = 0.033) levels. Mononuclear blood flow cytometry studies showed KLRG1+ lymphocytes had greater levels of cytotoxic molecules (granzyme B and perforin), inflammatory cytokines (IFN-γ and TNF-α) and inflammatory chemokine receptors (CCR5 and CX3CR1) than KLRG1-counterparts. However, clearly the most significant data was that found in liver with the intense portal infiltrates that are unique to PBC. Conclusion: Highly cytotoxic KLRG1+ lymphocytes have invaded PBC liver portal areas. Liver KLRG1 gene expression and the abundance of KLRG1+ lymphocytes are positively correlated with disease biomarkers used as clinical trial outcome measures (liver transplantation and serum alkaline phosphatase), suggesting the targeting of KLRG1+ lymphocytes as a rational approach for PBC therapeutic drug development.

Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS.

Algorithms designed to identify canonical yeast prions predict that around 250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbour a distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here we define pathogenic mutations in PrLDs of heterogeneous nuclear ribonucleoproteins (hnRNPs) A2B1 and A1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and in one case of familial amyotrophic lateral sclerosis. Wild-type hnRNPA2 (the most abundant isoform of hnRNPA2B1) and hnRNPA1 show an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a 'steric zipper' motif in the PrLD, which accelerates the formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Notably, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant steric zipper motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs should therefore be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone.

Association of inclusion body myositis with T cell large granular lymphocytic leukaemia.

SEE HOHLFELD AND SCHULZE-KOOPS DOI101093/BRAIN/AWW053 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Inclusion body myositis and T cell large granular lymphocytic leukaemia are rare diseases involving pathogenic cytotoxic CD8+ T cells. After encountering four patients with both disorders, we prospectively screened 38 patients with inclusion body myositis for the presence of expanded large granular lymphocyte populations by standard clinical laboratory methods (flow cytometry, examination of blood smears, and T cell receptor gene rearrangements), and performed muscle immunohistochemistry for CD8, CD57, and TIA1. Most (22/38; 58%) patients with inclusion body myositis had aberrant populations of large granular lymphocytes in their blood meeting standard diagnostic criteria for T cell large granular lymphocytic leukaemia. These T cell populations were clonal in 20/20 patients and stably present on follow-up testing in 15 patients a median of 350 days later. T cell aberrant loss of CD5 or gain of expression of CD16 and CD94 were common (19/42, 45%). In comparison, 2/15 (14%) age-matched patients with dermatomyositis, polymyositis, or necrotizing myopathy, and 0/20 (0%) age-matched healthy subjects had large granular lymphocyte expansions, with none of these patients having T cell aberrant expression of CD5, CD16 or CD94. Reduced blood CD4/CD8 ratio, increased blood CD8 count, and lymphocytosis were additional biomarkers highly correlated with flow cytometry-measured large granular lymphocyte expansions. Cross-sectional data suggested more aggressive disease in patients with such expansions than without. Muscle immunohistochemistry demonstrated invasion of large granular lymphocytes into muscle in 15/15 inclusion body myositis patients but in only 1/28 patients with dermatomyositis or polymyositis. The extent of CD8+ and CD57+ cells in inclusion body myositis muscle correlated with the size of blood large granular lymphocyte populations. Myofibre-invading cells expressed CD57, a marker of persistent T cell exposure to antigen and T cell aggressiveness. In many patients with inclusion body myositis, the autoimmune T cell expansion has evolved into a neoplastic-like or overtly neoplastic disorder, perhaps contributing to its relative refractoriness to immune-directed therapies previously reported.

Severe motor neuropathy or neuronopathy due to nitrous oxide toxicity after correction of vitamin B12 deficiency.

INTRODUCTION: Nitrous oxide (N2 O) toxicity can cause a sensory predominant myeloneuropathy identical to subacute combined degeneration caused by vitamin B12 deficiency. We describe a patient with a typical vitamin B12 deficiency syndrome after N2 O abuse who recovered and then developed a severe lower motor neuron syndrome following vitamin B12 correction. This suggests N2 O toxicity independent of functional vitamin B12 deficiency. METHODS: Electrophysiological, serological, and clinical evaluations were undertaken in the evaluation of this patient. RESULTS: A 22-year-old man abused N2 O and presented with a dorsal column syndrome with low vitamin B12 and high homocysteine serum levels. He recovered with treatment but presented later with profound motor axonal degeneration and normal vitamin B12, homocysteine, and methlymalonic acid levels. CONCLUSIONS: This case illustrates that N2 O-associated severe motor neuropathy or neuronopathy can develop separately from typical vitamin B12 deficiency dorsal column myelopathy. This syndrome can present when functional measures of vitamin B12 deficiency have normalized.

Sustained autoimmune mechanisms in dermatomyositis.

Dermatomyositis is an autoimmune disease predominantly affecting skin and muscle. Its poorly understood pathogenesis is increasingly being linked to the overproduction of type 1 interferon-inducible gene transcripts and proteins. Mechanisms have been identified by which chronic sustained accumulation of these proteins might occur and thereby injure tissue in dermatomyositis.

A phase 1b clinical trial evaluating sifalimumab, an anti-IFN-α monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients.

OBJECTIVE: To assess the pharmacodynamic effects of sifalimumab, an investigational anti-IFN-α monoclonal antibody, in the blood and muscle of adult dermatomyositis and polymyositis patients by measuring neutralisation of a type I IFN gene signature (IFNGS) following drug exposure. METHODS: A phase 1b randomised, double-blinded, placebo controlled, dose-escalation, multicentre clinical trial was conducted to evaluate sifalimumab in dermatomyositis or polymyositis patients. Blood and muscle biopsies were procured before and after sifalimumab administration. Selected proteins were measured in patient serum with a multiplex assay, in the muscle using immunohistochemistry, and transcripts were profiled with microarray and quantitative reverse transcriptase PCR assays. A 13-gene IFNGS was used to measure the pharmacological effect of sifalimumab. RESULTS: The IFNGS was suppressed by a median of 53-66% across three time points (days 28, 56 and 98) in blood (p=0.019) and 47% at day 98 in muscle specimens post-sifalimumab administration. Both IFN-inducible transcripts and proteins were prevalently suppressed following sifalimumab administration. Patients with 15% or greater improvement from baseline manual muscle testing scores showed greater neutralisation of the IFNGS than patients with less than 15% improvement in both blood and muscle. Pathway/functional analysis of transcripts suppressed by sifalimumab showed that leucocyte infiltration, antigen presentation and immunoglobulin categories were most suppressed by sifalimumab and highly correlated with IFNGS neutralisation in muscle. CONCLUSIONS: Sifalimumab suppressed the IFNGS in blood and muscle tissue in myositis patients, consistent with this molecule's mechanism of action with a positive correlative trend between target neutralisation and clinical improvement. These observations will require confirmation in a larger trial powered to evaluate efficacy.

Cytosolic 5'-nucleotidase 1A autoimmunity in sporadic inclusion body myositis.

OBJECTIVE: We previously identified a circulating autoantibody against a 43 kDa muscle autoantigen in sporadic inclusion body myositis (IBM) and demonstrated the feasibility of an IBM diagnostic blood test. Here, we sought to identify the molecular target of this IBM autoantibody, understand the relationship between IBM autoimmunity and muscle degeneration, and develop an IBM blood test with high diagnostic accuracy. METHODS: IBM blood samples were screened using mass spectrometry and a synthetic human peptidome. Plasma and serum samples (N=200 patients) underwent immunoblotting assays, and results were correlated to clinical features. Muscle biopsy samples (n=30) were examined by immunohistochemistry and immunoblotting. Exome or whole genome sequencing was performed on DNA from 19 patients. RESULTS: Both mass spectrometry and screening of a 413,611 human peptide library spanning the entire human proteome identified cytosolic 5'-nucleotidase 1A (cN1A; NT5C1A) as the likely 43 kDa IBM autoantigen, which was then confirmed in dot blot and Western blot assays using recombinant cN1A protein. Moderate reactivity of anti-cN1A autoantibodies was 70% sensitive and 92% specific, and high reactivity was 34% sensitive and 98% specific for the diagnosis of IBM. One to 3 major cN1A immunodominant epitopes were identified. cN1A reactivity by immunohistochemistry accumulated in perinuclear regions and rimmed vacuoles in IBM muscle, localizing to areas of myonuclear degeneration. INTERPRETATION: Autoantibodies against cN1A are common in and highly specific to IBM among muscle diseases, and may provide a link between IBM's dual processes of autoimmunity and myodegeneration. Blood diagnostic testing is feasible and should improve early and reliable diagnosis of IBM.

Cytoplasmic 5'-nucleotidase autoantibodies in inclusion body myositis: Isotypes and diagnostic utility.

INTRODUCTION: Recent studies have identified circulating immunoglobulin (Ig) G autoantibodies against cytoplasmic 5'-nucleotidase 1A (cN1A; NT5C1A) in patients with inclusion body myositis (IBM), whose detection provides for an IBM blood diagnostic test. Whether or not anti-cN1A autoantibody isotypes other than IgG are present in IBM has not previously been reported. METHODS: Plasma and serum samples from 205 patients (50 with and155 without IBM) were studied for the presence of IgM and IgA, in addition to IgG, anti-cN1A autoantibodies using immunoblots and enzyme-linked immunoassays (ELISAs). RESULTS: IgM, IgA, and IgG anti-cN1A autoantibodies were detected by ELISA with similar sensitivities (49-53%) and specificities (94-96%), but with differing patterns of autoantibody isotype presence. Combination assays of all 3 autoantibody levels improved diagnostic sensitivity to 76%. CONCLUSIONS: In addition to previously recognized IgG anti-cN1A autoantibodies, IBM patients have circulating IgM and IgA anti-cN1A autoantibodies. Differing patterns of these isotypes may be present and useful for diagnosis.

Pathogenic autoantibody internalization in myositis.

Objectives: Myositis is a heterogeneous family of autoimmune muscle diseases. As myositis autoantibodies recognize intracellular proteins, their role in disease pathogenesis has been unclear. This study aimed to determine whether myositis autoantibodies reach their autoantigen targets within muscle cells and disrupt the normal function of these proteins. Methods: Confocal immunofluorescence microscopy was used to localize antibodies and other proteins of interest in myositis muscle biopsies. Bulk RNA sequencing was used to study the transcriptomic profiles of 668 samples from patients with myositis, disease controls, and healthy controls. Antibodies from myositis patients were introduced into cultured myoblasts by electroporation and the transcriptomic profiles of the treated myoblasts were studied by bulk RNA sequencing. Results: In patients with myositis autoantibodies, antibodies accumulated inside myofibers in the same subcellular compartment as the autoantigen. Each autoantibody was associated with effects consistent with dysfunction of its autoantigen, such as the derepression of genes normally repressed by Mi2/NuRD in patients with anti-Mi2 autoantibodies, the accumulation of RNAs degraded by the nuclear RNA exosome complex in patients with anti-PM/Scl autoantibodies targeting this complex, and the accumulation of lipids within myofibers of anti-HMGCR-positive patients. Internalization of patient immunoglobulin into cultured myoblasts recapitulated the transcriptomic phenotypes observed in human disease, including the derepression of Mi2/NuRD-regulated genes in anti-Mi2-positive dermatomyositis and the increased expression of genes normally degraded by the nuclear RNA exosome complex in anti-PM/Scl-positive myositis. Conclusions: In myositis, autoantibodies are internalized into muscle fibers, disrupt the biological function of their autoantigen, and mediate the pathophysiology of the disease.

KLRG1 Cell Depletion as a Novel Therapeutic Strategy in Patients with Mature T-Cell Lymphoma Subtypes.

PURPOSE: Develop a novel therapeutic strategy for patients with subtypes of mature T-cell and NK-cell neoplasms. EXPERIMENTAL DESIGN: Primary specimens, cell lines, patient-derived xenograft models, commercially available, and proprietary anti-KLRG1 antibodies were used for screening, target, and functional validation. RESULTS: Here we demonstrate that surface KLRG1 is highly expressed on tumor cells in subsets of patients with extranodal NK/T-cell lymphoma (ENKTCL), T-prolymphocytic leukemia (T-PLL), and gamma/delta T-cell lymphoma (G/D TCL). The majority of the CD8+/CD57+ or CD3-/CD56+ leukemic cells derived from patients with T- and NK-large granular lymphocytic leukemia (T-LGLL and NK-LGLL), respectively, expressed surface KLRG1. The humanized afucosylated anti-KLRG1 monoclonal antibody (mAb208) optimized for mouse in vivo use depleted KLRG1+ TCL cells by mechanisms of ADCC, ADCP, and CDC rather than apoptosis. mAb208 induced ADCC and ADCP of T-LGLL patient-derived CD8+/CD57+ cells ex vivo. mAb208 effected ADCC of subsets of healthy donor-derived KLRG1+ NK, CD4+, CD8+ Tem, and TemRA cells while sparing KLRG1- naïve and CD8+ Tcm cells. Treatment of cell line and TCL patient-derived xenografts with mAb208 or anti-CD47 mAb alone and in combination with the PI3K-δ/γ inhibitor duvelisib extended survival. The depletion of macrophages in vivo antagonized mAb208 efficacy. CONCLUSIONS: Our findings suggest the potential benefit of a broader treatment strategy combining therapeutic antibodies with PI3Ki for the treatment of patients with mature T-cell and NK-cell neoplasms. See related commentary by Varma and Diefenbach, p. 2300.

Biomarkers of inclusion body myositis.

PURPOSE OF REVIEW: Inclusion body myositis (IBM) is a poorly understood autoimmune and degenerative disorder of skeletal muscle. Here, pathophysiological and diagnostic biomarkers of IBM are reviewed. RECENT FINDINGS: Muscle histopathological biomarkers have been successful in stimulating the study of IBM pathophysiology for over three decades. Their use as diagnostic biomarkers, in contrast, has significant limitations. A blood biomarker, autoantibodies against a 43-kDa muscle protein reported in 2011, has now been identified as targeting cytoplasmic 5' nucleotidase (cN1A; NT5C1A), a protein involved in nucleic acid metabolism. Diagnostic testing for these autoantibodies is of high diagnostic performance for IBM. SUMMARY: Muscle biomarkers have suggested that IBM pathophysiology is linked to myonuclear degeneration and disordered nucleic acid metabolism. A blood biomarker has high diagnostic performance for IBM, and through identification of its target links, IBM autoimmunity and degeneration together, supporting the view that IBM pathophysiology includes abnormal nucleic acid metabolism.

Etiology of limb girdle muscular dystrophy 1D/1E determined by laser capture microdissection proteomics.

Limb girdle muscular dystrophy 1D/1E (OMIM nomenclature LGMD1D, Human Gene Nomenclature Committee LGMD1E), a skeletal and cardiac myopathy, has previously been linked to chromosome 6q23. We used laser capture microdissection to isolate cytoplasmic inclusions from skeletal muscle from a patient with LGMD1D/1E, performed mass spectrometry-based proteomics on these minute inclusions, and identified through bioinformatics desmin as their major constituent. Sequencing in this patient and family members identified the genetic basis of the previously reported 6q23 linked LGMD1D/1E to be due to an intron splice donor site mutation (IVS3+3A>G) of the desmin gene located on chromosome 2q35.

Imaging With PET/CT of Diffuse CD8 T-Cell Infiltration of Skeletal Muscle in Patients With Inclusion Body Myositis.

BACKGROUND AND OBJECTIVES: Inclusion body myositis (IBM) is a progressive autoimmune skeletal muscle disease in which cytotoxic CD8+ T cells infiltrate muscle and destroy myofibers. IBM has required a muscle biopsy for diagnosis. Here, we administered to patients with IBM a novel investigational PET tracer 89Zr-Df-crefmirlimab for in vivo imaging of whole body skeletal muscle CD8 T cells. This technology has not previously been applied to patients with autoimmune disease. METHODS: Four patients with IBM received 89Zr-Df-crefmirlimab followed by PET/CT imaging 24 hours later, and the results were compared with similar imaging of age-matched patients with cancer. Mean standardized uptake value (SUVmean) was measured for reference tissues using spherical regions of interest (ROIs). RESULTS: 89Zr-Df-crefmirlimab was safe and well-tolerated. PET imaging demonstrated diffusely increased uptake qualitatively and quantitatively in IBM limb musculature. Quantitation of 89Zr-Df-crefmirlimab intensity in ROIs demonstrated particularly increased CD8 T-cell infiltration in patients with IBM compared with patients with cancer in quadriceps (SUVmean 0.55 vs 0.20, p < 0.0001), biceps brachii (0.62 vs 0.26, p < 0.0001), triceps (0.61 vs 0.25, p = 0.0005), and forearm finger flexors (0.71 vs 0.23, p = 0.008). DISCUSSION: 89Zr-Df-crefmirlimab uptake in muscles of patients with IBM was present at an intensity greater than the comparator population. The ability to visualize whole body in vivo cytotoxic T-cell tissue infiltration in the autoimmune disease IBM may hold utility as a biomarker for diagnosis, disease activity, and therapeutic development and potentially be applicable to other diseases with cytotoxic T-cell autoimmunity.