A novel ultrastructural finding in statin-exposed patients with inflammatory myositis

Ultrastructural defects of ciliary structure have been known to cause recurrent sino-respiratory infection concurrent with Kartagener's syndrome. (1,2,3) These defects are also known to cause infertility in both males and females. (4) Overall, the defects are defined as the Immotile, or Dyskinetic Cilia Syndrome (DCS). Several ultrastructural findings have been described, including decreased number of cilia, multidirection orientation, fused and compound cilia, membrane blebs, excess matrix in the axoneme, missing outer tubular doublets, translocated doublets, defective radial spokes and dynein arms. A rare but noteworthy ultrastructural finding in DCS is the predominance of microvilli-like structures on the luminal surface of the respiratory epithelium. (5,6) These permanent surface modifications of the apical respiratory epithelium no longer resemble cilia but reflect the ultrastructure of stereocilia, similar to that found in the epidydimal epithelium. Like microvilli, stereocilia are devoid of microtubular ultrastructure in comparison with true cilia.

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P170 The validity and utility of the SLE-key® rule-out serological test when applied in a selected cohort of patients with SLE and other connective tissue diseases

Rheumatology ◽

10.1093/rheumatology/keab247.165 ◽

2021 ◽

Vol 60 (Supplement_1) ◽

Author(s):

Sheilla Achieng ◽

John A Reynolds ◽

Ian N Bruce ◽

Marwan Bukhari

Keyword(s):

Linear Regression ◽

Connective Tissue ◽

Connective Tissue Disease ◽

Negative Correlation ◽

Connective Tissue Diseases ◽

Inflammatory Myositis ◽

The Mean ◽

Negative Rule ◽

Spearman’S Correlation ◽

Rule Out

Abstract Background/Aims We aimed to establish the validity of the SLE-key® rule-out test and analyse its utility in distinguishing systemic lupus erythematosus (SLE) from other autoimmune rheumatic connective tissue diseases. Methods We used data from the Lupus Extended Autoimmune Phenotype (LEAP) study, which included a representative cross-sectional sample of patients with a variety of rheumatic connective tissue diseases, including SLE, mixed connective tissue disease (MCTD), inflammatory myositis, systemic sclerosis, primary Sjögren’s syndrome and undifferentiated connective tissue disease (UCTD). The modified 1997 ACR criteria were used to classify patients with SLE. Banked serum samples were sent to Immune-Array’s CLIA- certified laboratory Veracis (Richmond, VA) for testing. Patients were assigned test scores between 0 and 1 where a score of 0 was considered a negative rule-out test (i.e. SLE cannot be excluded) whilst a score of 1 was assigned for a positive rule-out test (i.e. SLE excluded). Performance measures were used to assess the test’s validity and measures of association determined using linear regression and Spearman’s correlation. Results Our study included a total of 155 patients of whom 66 had SLE. The mean age in the SLE group was 44.2 years (SD 13.04). 146 patients (94.1%) were female. 84 (54.2%) patients from the entire cohort had ACR SLE scores of ≤ 3 whilst 71 (45.8%) had ACR SLE scores ≥ 4. The mean ACR SLE total score for the SLE patients was 4.85 (SD 1.67), ranging from 2 to 8, with mean disease duration of 12.9 years. The Sensitivity of the SLE-Key® Rule-Out test in diagnosing SLE from other connective tissue diseases was 54.5%, specificity was 44.9%, PPV 42.4% and NPV 57.1 %. 45% of the SLE patients had a positive rule-out test. SLE could not be ruled out in 73% of the MCTD patients whilst 51% of the UCTD patients had a positive Rule-Out test and >85% of the inflammatory myositis patients had a negative rule-out test. ROC analysis generated an AUC of 0.525 illustrating weak class separation capacity. Linear regression established a negative correlation between the SLE-key Rule-Out score and ACR SLE total scores. Spearman’s correlation was run to determine the relationship between ACR SLE total scores and SLE-key rule-out score and showed very weak negative correlation (rs = -0.0815, n = 155, p = 0.313). Conclusion Our findings demonstrate that when applied in clinical practice in a rheumatology CTD clinic setting, the SLE-key® rule-out test does not accurately distinguish SLE from other CTDs. The development of a robust test that could achieve this would be pivotal. It is however important to highlight that the test was designed to distinguish healthy subjects from SLE patients and not for the purpose of differentiating SLE from other connective tissue diseases. Disclosure S. Achieng: None. J.A. Reynolds: None. I.N. Bruce: Other; I.N.B is a National Institute for Health Research (NIHR) Senior Investigator and is funded by the NIHR Manchester Biomedical Research Centre. M. Bukhari: None.

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Inflammatory Myositis Secondary to Anti-Retroviral Therapy in a Child; Case Report and Review of the Literature

Journal of Neuromuscular Diseases ◽

10.3233/jnd-210669 ◽

2021 ◽

pp. 1-7

Author(s):

Marie Monaghan ◽

Charlotte Loh ◽

Stephen Jones ◽

Agyepong Oware ◽

Kathryn Urankar ◽

...

Keyword(s):

Drug Regimen ◽

Dramatic Improvement ◽

Strand Transfer ◽

Inflammatory Myositis ◽

Once Daily ◽

Immune Mediated ◽

Show Evidence ◽

Transfer Inhibitor ◽

Integrase Strand Transfer Inhibitor

Here, we describe a five year old girl with congenital HIV who had a six-week onset of rapidly deteriorating mobility and progressive proximal muscle weakness, associated with a raised Creatine Kinase (CK) level of 4330 U/L [25–200 U/L], subsequently diagnosed with an inflammatory myositis. Potential causes were investigated by paediatric neurology and immunology teams. Her viral load had been undetectable over the preceding two years, excluding a primary HIV myositis. While MRI scanning did not show evidence of definite myositis, a muscle biopsy showed evidence of an inflammatory process, comprising a moderate endomysial, perimysial and perivascular mononuclear (CD8 + T cell) infiltrate with increased MHC expression. No particular features of dermatomyositis or immune-mediated necrotising myopathy were identified and there were no features of an inclusion body myositis. Given the absence of active HIV infection, the role of anti-retroviral medications was considered. She had had a recent switch in medication, from twice daily Raltegravir (an Integrase Strand Transfer Inhibitor, INSTI) to once daily Dolutegravir (an INSTI) while continuing on an established daily protocol of Abacavir and Lamivudine (Nucleoside Reverse Transcriptase Inhibitors). Changing the Dolutegravir back to Raltegravir, in combination with continuing Lamivudine and Abacavir for two months made no difference to her weakness or CK levels. Moreover, this drug regimen had been well-tolerated over the preceding 19 month period. Changing the anti-retroviral regime completely to a single drug class (Protease Inhibitors) of Ritonavir and Darunavir, resulted in a dramatic improvement in her symptomatology. Within ten days she regained the ability to stand and walk, with a reduction in her CK from 1700 U/L at time of switch to 403 U/L [25–200]. This case highlights the potential risk of developing inflammatory myositis from anti-retrovirals even 19 months into treatment.

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Inflammatory myositis in cancer patients receiving immune checkpoint inhibitors

Arthritis & Rheumatology ◽

10.1002/art.41714 ◽

2021 ◽

Author(s):

Sudhakar Tummala ◽

Xerxes Pundole ◽

Jeffrey Aldrich ◽

Maria E. Suarez‐Almazor

Keyword(s):

Cancer Patients ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Inflammatory Myositis

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SAT0290 HIGH SERUM MYOSTATIN LEVELS SUGGEST ACCELERATED MUSCLE SENESCENCE IN ACTIVE IDIOPATHIC INFLAMMATORY MYOSITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5641 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1089.2-1090

Author(s):

A. Anuja ◽

M. Singh ◽

M. K. Rai ◽

H. Singh ◽

V. Agarwal ◽

...

Keyword(s):

Young Adults ◽

Elevated Serum ◽

High Serum ◽

Inactive Disease ◽

Healthy Controls ◽

Muscle Enzymes ◽

Inflammatory Myositis ◽

Idiopathic Inflammatory Myositis ◽

Healthy Control ◽

Accelerated Senescence

Background:Inflammation is the forerunner to fibrosis and premature ageing in various systemic diseases. Hence it seems plausible that idiopathic inflammatory myopathies (IIM) may exhibit accelerated senescence too.Objectives:Hence we investigated the Myostatin: Follistatin system in the serum as a reflection of early senescence in myositis as compared with healthy and diseased controls.Methods:Patients with inflammatory myositis (ACR/EULAR criteria) presenting to the wards and outpatient clinic between December 2017 to August 2019 were recruited. Those with active infection, pregnancy, renal dysfunction or chronic kidney disease were excluded. Apart from patient and disease variables, activity and damage were assessed using standard IMACS score set measures. Patients in inception cohort were additionally followed up at 1 and 6 months. Myostatin and Follistatin were estimated in sera using ELISA (R&D systems, USA). Juvenile myositis and young adults (18-40 years) were subsequently analyzed separately. Non-parametric tests were used for paired and unpaired analysis. Results expressed as median.Results:95 myositis (8 Juvenile myositis, 26 DM, 10 PM, 29 Overlap, 2 NAM 1 CAM and 19 ASS) patients (23 Male and 72 Female) with median age 38 (24.5-46.0) years and disease duration 0.9 (2.3-5.1) years were included. Serum Myostatin was lower in IIM than in healthy control (HC) (153.5 vs. 243.6 p<0.0001, Fig 1A) but higher in IIM as compared with disease controls (153.5 vs 86.1 p=0.0174 Fig. 1B). Serum myostatin was comparable between juvenile and adult myositis and in the various subsets of adult myositis (Fig. 1 C and D). Myostatin levels were higher in active as compared with inactive myositis in young adults (211.7 vs. 158.9, p=0.0149, Figure 1E). Serum Myostatin correlated with height (r 0.3, p=0.003) and weight (r 0.2, p=0.047) but not MMT8 or muscle enzymes.Figure 1.Serum Myostatin levels in IIM as compared with healthy controls (A) and disease controls (B). Levels in juvenile myositis as compared with adult IIM (C) and in various subsets of IIM (D). Serum Myostatin levels in active and inactive disease (E).Although Follistatin was lower in IIM than HC (198.4 vs 243.6, p=<0.0001), the neither Follistatin nor Myostatin: Follistatin ratios differ between subsets, and in active versus inactive disease Figure 2 A-D). On follow-up, the serial Myostatin estimation paralleled change in disease activity.Figure 2.Serum Follistatin levels in IIM as compared with healthy controls (A) and disease controls (C). Levels in juvenile and adult IIM (D) and in various subsets of IIM (D).Conclusion:Elevated serum Myostatin levels in active myositis raise the possibility of accelerated senescence in the inflamed muscle tissues which need further investigation.Acknowledgments: :Partly funded by APLAR and IRA research grants awarded to LG.Disclosure of Interests:None declared

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SAT0323 MYOSITIS-SPECIFIC AND MYOSITIS-ASSOCIATED AUTOANTIBODIES IN A LARGE INDIAN COHORT OF INFLAMMATORY MYOSITIS REVEAL NOVEL CLINICO-PHENOTYPIC PATTERNS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.315 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1107.1-1107

Author(s):

L. Gupta ◽

P. Gaur ◽

V. Agarwal ◽

R. Aggarwal ◽

R. Misra

Keyword(s):

Disease Duration ◽

Unique Feature ◽

Diagnostic Value ◽

Immunofluorescence Assay ◽

Major Influence ◽

Antibody Prevalence ◽

Research Support ◽

Inflammatory Myositis ◽

Idiopathic Inflammatory Myositis ◽

Physician Diagnosis

Background:Idiopathic Inflammatory Myositis (IIM) are heterogenous, with distinct autoantibodies reflecting upon possible clinical evolution and outcomes. Ethnicity has major influence on both antibody prevalence patterns as well as phenotypic behaviours linked to them.Objectives:Thus we sought prevalence and co-existence of myositis specific autoantibodies (MSAs) and myositis associated autoantibodies (MAAs) and associated clinical characteristics in a large cohort of patients with IIM.Methods:Adult patients with a physician diagnosis of IIM as per ACR/EULAR classification criteria were investigated for the presence of MSAs/MAAs by Line immunoassay (G4, Euro-Immune, Lubeck, Germany). Anti-Nuclear Antibody (ANA) was tested by Immunofluorescence assay (IFA), and patterns in various antibody subsets explored. Prevalence and associations of different antibodies were assessed in disease subsets and clinical phenotypes.Results:MSA and MAAs were tested in 250 IIM patients (F:M 3.8:1) of median age 37 (25-47) and disease duration 6 (3-17) years. Dermatomyositis (DM) was seen in most patients 83 (33.2%) followed by overlap myositis (OM), juvenile DM, Anti-synthetase syndrome (ASS), polymyositis (PM), and cancer associated myositis (CAM). MSAs/MAAs were found in 148 (59.2%) of patients, of which 95 (64.2%) had an MSA and 53 (35.8%) had MAAs (Fig, 1A). 93 (62.8%) of autoantibody positive patients were positive for a single antibody, and only 2 (0.8%) of total had more than one MSA (Table 1).Table 1.Multiple antibodies positive upon testing for MSA and MAA by the LIANote: ** PL-7 co-exists with Ku + Pm/Scl, **PL-12 co-exists with Pm/Scl + Ro52, **SRP co-exists with Pm/Scl + Ro52The most frequently detected MSA was anti-Jo-1 (8%), with a further 9 specificities each found in 0.5–7.0% of patients. Amongst the autoantibody positive patients, 21% (n=53) had isolated MAA positivity, anti-Ro52 (33, 62.3%) being the most common, followed by anti-Pm/Scl (11, 20.8%) and anti-Ku (9, 17.0%) (Fig. 1B).Figure 1.A. MSA and MAA in Indian cohort of myositis B. ANA patterns in myositis C. MSA in ANA negative IIMOn ANA, 76.0% (172 of 226) were positive, with speckled being the most common pattern (37%,Fig. 1C). Of those ANA negative (n=54), 61% had either MSA or MAA (Fig 1D). 18 (54.6%) had autoantibodies associated with cytoplasmic patterns suggesting that cytoplasmic ANA may be underreported.Clinical presentation akin to DM was seen with all MSA except anti-SRP. PM group was heterogenous, and included ASS, OM and necrotizing phenotype (Fig. 2A). On occasion, anti-SRP, anti-Mi-2 and anti-MDA5 presented with clinical phenotype of ASS. (Fig 2A,C). Patients with ARS or anti-SAE were often clinically amyopathic (Figure 2B,C)Figure 2.A. Phenotypic associated with various antibody subsets B,C,and D. MSA/MAA in muscle weakness, rash and ILD phenotype. E. Unique feature of eye-lid edema in some patients with MDA-5 positive myositisARS were associated with mechanic’s hand (p<0.0001,OR 7.6), ILD (p<0.0001,OR 4.4), and arthritis (p=.002,OR 2.6) though there was no difference between Jo-1 and non-Jo-1 ASS. Anti-MDA-5 associated with fever (p=0.003,OR 12) and weight loss (p=0.008,OR 10.2) and unique phenotype of eye-lid edema in some adults (Figure 2E) and arthritis in children (p=0.01, OR 11.5). Anti-TIF-1ɣ associated with alopecia (p=0.007,OR 5.9) and malignancy (p= <0.0001,OR 34) in adults but not children.Conclusion:Myositis autoantibodies are seen in two-thirds IIM and identify distinct clinical subsets as well as unique phenotypes. MSA/MAA are positive in two-thirds of those negative on ANA, adding diagnostic value. MSAs are nearly always mutually exclusive and thus useful as biomarkers for diagnosis.Acknowledgments:MSA testing supported by grants from APLAR and Association of Physicians of India.Disclosure of Interests:Latika Gupta: None declared, Priyanka Gaur: None declared, Vikas Agarwal: None declared, Rohit Aggarwal Grant/research support from: Pfizer, Genentech, BMS, Mallinckrodt, Consultant of: Pfizer, Genentech, BMS, Mallinckrodt, Bristol Myers-Squibb, octapharma, CSL Behring, AstraZeneca, Corbus, Kezar, Abbvie, Ramnath Misra: None declared

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AB0156 NMR-BASED MUSCLE METABOLOMICS IN INFLAMMATORY MYOSITIS- UNDERSTANDING CHANGES IN SERUM AS A REFLECTION OF THE MUSCLE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.316 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1378.2-1379

Author(s):

L. Gupta ◽

U. Kumar ◽

A. Anuja ◽

P. Sharma ◽

A. Guleria ◽

...

Keyword(s):

Statistical Significance ◽

Muscle Disease ◽

P Value ◽

Healthy Controls ◽

Inflammatory Myositis ◽

Activity Assessment ◽

Muscle Tissues ◽

Low Levels ◽

Serum Metabolomics ◽

Research Grant

Background:We have previously found promise in NMR as a tool to distinguish sera of active from inactive inflammatory myositis (IIM)1. To understand the changes previously found in sera and urine we studied muscle tissue of patients with myositis.Objectives:To identify differences in metabolome on inflamed muscle tissues of patients with active myositis from that of healthy controls and infectious polymyositis.Methods:Muscle (n=17) from patients classifiable as myositis by the ACR-EULAR criteria [34 years (23.5 - 50.5 IQR), M/F 1:3] were compared with healthy controls [n=11, age= 44 (35-50) years, M/F-1:1]. Two disease controls with infectious polymyositis were also compared. Findings were applied to muscle biopsy tissues of two patients with established myositis and superadded infections (HBV, Histoplasmosis) to assess discriminatory potential.Metabolic profiles were obtained at 800 MHZ NMR spectrometer and compared using multivariate partial least-squares discriminant analysis (PLS-DA). The discriminatory metabolites were identified based on variable importance in projection (VIP) statistics and further evaluated for statistical significance (p-value <0.05). Paired T tests, ANNOVA and correlation of individual metabolites were done after normalizing for formate.Results:Metabolomics profiles in IIM were distinct from healthy controls (Fig. 1A).Of the various discriminatory metabolites (Fig. 1B), Succinate had the highest discriminatory potential (AUC 0.8, P=0.01) followed by citrate, glycine, glycerol, glucose, creatine and lactate. (Fig. 1C) Both glucose and creatine were decreased in IIM (Fig. 1D,E) and this was uniform across all types of IIM. However, glycine levels differed across different myositis subsets supporting the fact that they might differ in pathogenesis. (Fig. 1E) Amongst various serum biomarkers of muscle disease and damage, serum Aspartate Transaminase correlated with glutamate (r=0.6, p=0.01), and serum creatinine correlated negatively with glycerol (r-0.8, p=0.04),Biopsies of infectious polymyositis suggested difference in spectra from IIM (Fig. 2A). Trends were observed towards lower succinate and higher citrate levels suggesting metabolomics could possibly be useful to differentiate the two. Muscle of both patients with IIM with superadded infectious polymyositis also exhibited low succinate and elevated citrate.Conclusion:Muscle metabolomics of active myositis is distinctive. Amino acids and creatine are lower in diseases muscle suggesting active breakdown and loss, in turn explaining previous findings of low levels in serum in active disease. Certain metabolite composition differ in different types of myositis supporting different pathogenesis.Infectious polymyositis might exhibit different metabolome from IIM with potential as a biomarker though this needs to be confirmed in larger numbers.Disclosures:Funded by APLAR research grant 2017 awarded to Dr Latika Gupta.References:[1]Gupta L, Kumar D, Gulerai A, Kumar U, Misra R. “NMR-Based Serum, Urine and Muscle Metabolomics in Inflammatory Myositis for Diagnosis and Activity Assessment: Serum Metabolomics Can Differentiate Active from Inactive Myositis” Oral presentation at the ACR, Atlanta 2019.Acknowledgments:MSA and metabolomics supported by APLAR research grant.Disclosure of Interests:None declared

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Uveitis and Myositis as Immune Complications in Chemorefractory NK/T-Cell Nasal-Type Lymphoma Successfully Treated with Allogeneic Stem-Cell Transplant

Case Reports in Hematology ◽

10.1155/2016/7297920 ◽

2016 ◽

Vol 2016 ◽

pp. 1-5

Author(s):

Maria José Gómez-Crespo ◽

Aránzazu García-Raso ◽

Jose Luis López-Lorenzo ◽

Teresa Villaescusa ◽

María Rodríguez-Pinilla ◽

...

Keyword(s):

T Cell ◽

Lower Limbs ◽

Manuscript Preparation ◽

Cell Transplant ◽

Line Treatment ◽

First Line ◽

Inflammatory Myositis ◽

T Cell Lymphomas ◽

Nk T Cell ◽

First Line Treatment

NK/T-cell lymphomas are a group of clonal proliferations of NK- or, rarely, T-cell types and have peculiar clinicopathologic features. Most common site of involvement is the upper aerodigestive tract (nasal cavity, nasopharynx, paranasal sinuses, and palate). Association of autoimmune paraneoplastic disorders with NK/T-cell lymphomas is not well studied. Our patient was diagnosed with NK/T-cell lymphoma stage IV with skin involvement and treated frontline with CHOEP regimen. While he was under treatment, two immune complications presented: anterior uveitis of autoimmune origin refractory to steroids and myositis in lower limbs muscles. Autologous transplantation was rejected due to confirmed early relapse after first-line treatment, and the patient received second-line treatment according to the SMILE scheme, reaching complete response after four cycles. The patient underwent allogeneic transplantation and at the time of manuscript preparation is alive despite multiple complications. The disease should be suspected in patients with rhinitis or recurrent sinusitis, and early biopsy is recommended for all patients to avoid a delay in diagnosis. Our patient also presented symptoms of disease progression after first-line treatment, representing a paraneoplastic process, a very rare phenomenon in T-type lymphomas. This case is novel for the appearance of an inflammatory myositis, a histologically verified paraneoplastic phenomenon that responded to treatment for lymphoma.

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