Comparison of clinical features between patients with anti-synthetase syndrome and dermatomyositis: Results from the MYONET registry.

OBJECTIVES: To compare clinical characteristics, including the frequency of cutaneous, extramuscular manifestations, and malignancy, between adults with anti-synthetase syndrome (ASyS) and dermatomyositis (DM). METHODS: Using data regarding adults from the MYONET registry, a cohort of DM patients with anti-Mi2/-TIF1É£/-NXP2/-SAE/-MDA5 autoantibodies, and a cohort of ASyS patients with anti-tRNA synthetase autoantibodies (anti-Jo1/-PL7/-PL12/-OJ/-EJ/-Zo/-KS) were identified. Patients with DM sine dermatitis or with discordant dual autoantibody specificities were excluded. Sub-cohorts of patients with ASyS with or without skin involvement were defined based on presence of DM-type rashes (heliotrope rash, Gottron's papules/sign, violaceous rash, shawl sign, V sign, erythroderma, and/or periorbital rash). RESULTS: In total 1,054 patients were included (DM, n = 405; ASyS, n = 649). In ASyS cohort, 31% (n = 203) had DM-type skin involvement (ASyS-DMskin). A higher frequency of extramuscular manifestations, including Mechanic's hands, Raynaud's phenomenon, arthritis, interstitial lung disease, and cardiac involvement differentiated ASyS-DMskin from DM (all p< 0.001), whereas higher frequency of any of four DM-type rashes: heliotrope rash (n = 248, 61% vs n = 90, 44%), violaceous rash (n = 166, 41% vs n = 57, 9%), V sign (n = 124, 31% vs n = 28, 4%), and shawl sign (n = 133, 33% vs n = 18, 3%) differentiated DM from ASyS-DMskin (all p< 0.005). Cancer-associated myositis (CAM) was more frequent in DM (n = 67, 17%) compared with ASyS (n = 21, 3%) and ASyS-DMskin (n = 7, 3%) cohorts (both p< 0.001). CONCLUSION: DM-type rashes are frequent in patients with ASyS; however, distinct clinical manifestations differentiate these patients from classical DM. Skin involvement in ASyS does not necessitate increased malignancy surveillance. These findings will inform future ASyS classification criteria and patient management.

Investigating characteristics of idiopathic inflammatory myopathy flares using daily symptom data collected via a smartphone app.

OBJECTIVE: The objective of this study was to use daily data collected via a smartphone app for characterization of patient-reported and symptom-based (using an a priori definition) flares in an adult idiopathic inflammatory myopathy (IIM) cohort. METHODS: UK adults with an IIM answered patient-reported outcome measurements (PROMs) daily via a smartphone app during a 91-day study. Daily symptom PROMs addressed global activity, overall pain, myalgia, fatigue, and weakness (on a 0-100 visual analogue scale). Patient-reported flares were recorded via a weekly app question. Symptom-based flares were defined via an a priori definition related to increase in daily symptom data from the previous 4-day mean. RESULTS: Twenty participants (65% female) participated. Patient-reported flares occurred on a median of 5 weeks (IQR 3, 7) per participant, out of a possible 13. The mean of each symptom score was significantly higher in flare weeks, compared with non-flare weeks (e.g. mean flare week myalgia score 34/100, vs 21/100 during non-flare week, t test P-value <0.01). Fatigue accounted for the most symptom-based flares [incidence-rate 23/100 person-days (95% CI 19, 27)], and myalgia the fewest [incidence rate 13/100 person-days (95% CI 11, 16)]. Symptom-based flares typically resolved after 3 days, although fatigue-predominant flares lasted 2 days. The majority (69%) of patient-reported flare weeks coincided with at least one symptom-based flare. CONCLUSIONS: IIM flares are frequent and associated with increased symptom scores. This study has demonstrated the ability to identify and characterize patient-reported and symptom-based flares (based on an a priori definition), using daily app-collected data.

A systematic review and meta-analysis to inform cancer screening guidelines in idiopathic inflammatory myopathies.

OBJECTIVES: To identify clinical factors associated with cancer risk in the idiopathic inflammatory myopathies (IIMs) and to systematically review the existing evidence related to cancer screening. METHODS: A systematic literature search was carried out on Medline, Embase and Scopus. Cancer risk within the IIM population (i.e. not compared with the general population) was expressed as risk ratios (RR) for binary variables and weighted mean differences (WMD) for continuous variables. Evidence relating to cancer screening practices in the IIMs were synthesized via narrative review. RESULTS: Sixty-nine studies were included in the meta-analysis. DM subtype (RR 2.21), older age (WMD 11.19), male sex (RR 1.53), dysphagia (RR 2.09), cutaneous ulceration (RR 2.73) and anti-transcriptional intermediary factor-1 gamma positivity (RR 4.66) were identified as being associated with significantly increased risk of cancer. PM (RR 0.49) and clinically amyopathic DM (RR 0.44) subtypes, Raynaud's phenomenon (RR 0.61), interstitial lung disease (RR 0.49), very high serum creatine kinase (WMD -1189.96) or lactate dehydrogenase (WMD -336.52) levels, and anti-Jo1 (RR 0.45) or anti-EJ (RR 0.17) positivity were identified as being associated with significantly reduced risk of cancer. Nine studies relating to IIM-specific cancer screening were included. CT scanning of the thorax, abdomen and pelvis appeared to be effective in identifying underlying asymptomatic cancers. CONCLUSION: Cancer risk factors should be evaluated in patients with IIM for risk stratification. Screening evidence is limited but CT scanning could be useful. Prospective studies and consensus guidelines are needed to establish cancer screening strategies in IIM patients.

Long-term strength and functional status in inclusion body myositis and identification of trajectory subgroups.

INTRODUCTION: Objective information on longitudinal disease progression in inclusion body myositis (IBM) is lacking. METHODS: Longitudinal dynamometry and functional status data were collated from a cohort of IBM patients. Annual change was calculated by means of linear modeling. Trajectories of change in grip, knee extension, IBM Functional Rating Scale (IBM-FRS) and Neuromuscular Symptom Score (NSS) were identified by means of latent growth mixture modeling. RESULTS: Data were collated from 75 IBM patients (348 person-years follow-up). Annual strength loss was greatest for pinch (-10%) and knee extension (-4%). Functional deterioration was greatest for males. Three distinct trajectory groups were identified. Rapid deterioration trajectory for grip strength was associated with younger diagnosis age. Rapid deterioration for knee extension strength was associated with older age of diagnosis. DISCUSSION: This study has quantified strength change in IBM and identified distinct trajectory groups, which will aid prognostication and stratification for inclusion into future clinical trials.

The performance of the European League Against Rheumatism/American College of Rheumatology idiopathic inflammatory myopathies classification criteria in an expert-defined 10 year incident cohort.

OBJECTIVES: To assess the performance of the EULAR/ACR idiopathic inflammatory myopathies (IIMs) classification criteria in a cohort of incident IIM cases and examine how criteria-assigned IIM subtype correlates with expert opinion. METHODS: Adults with newly diagnosed IIM attending Salford Royal NHS Foundation Trust were identified over a 10 year period. A retrospective review of all putative cases was performed and those fulfilling a consensus expert opinion diagnosis of IIM were included. Clinical, serological and histological data were collected and each case was assigned a single IIM subtype. The EULAR/ACR classification criteria were then applied and sensitivity, specificity and positive and negative predictive values were calculated, presented with 95% CIs. RESULTS: A total of 1637 cases were screened, with 255 consensus expert opinion IIM cases ultimately identified. Applying the EULAR/ACR classification criteria, the sensitivity to diagnose an IIM was 99.6% (95% CI 97.2, 100) and 80.9% (95% CI 76.0, 85.8) for the criteria cut-points of probable and definite diagnoses, respectively. In 94/255 cases the IIM subtype differed between consensus expert opinion and classification criteria, most strikingly in the group subtyped as PM by the EULAR/ACR criteria, where there was discrepancy in the majority (i.e. in 87/161). CONCLUSION: The EULAR/ACR criteria performed with high sensitivity in identifying IIM in this external cohort of incident IIM. However, substantial disagreements arose between consensus expert opinion and the criteria regarding IIM subtype assignments, resulting in a large proportion of criteria-assigned cases of PM having heterogeneous features. These results may have important implications for future use of these criteria in subsequent research.

The temporal relationship between cancer and adult onset anti-transcriptional intermediary factor 1 antibody-positive dermatomyositis.

OBJECTIVES: To characterize the 10 year relationship between anti-transcriptional intermediary factor 1 antibody (anti-TIF1-Ab) positivity and cancer onset in a large UK-based adult DM cohort. METHODS: Data from anti-TIF1-Ab-positive/-negative adults with verified diagnoses of DM from the UK Myositis Network register were analysed. Each patient was followed up until they developed cancer. Kaplan-Meier methods and Cox proportional hazard modelling were employed to estimate the cumulative cancer incidence. RESULTS: Data from 263 DM cases were analysed, with a total of 3252 person-years and a median 11 years of follow-up; 55 (21%) DM cases were anti-TIF1-Ab positive. After 10 years of follow-up, a higher proportion of anti-TIF1-Ab-positive cases developed cancer compared with anti-TIF1-Ab-negative cases: 38% vs 15% [hazard ratio 3.4 (95% CI 2.2, 5.4)]. All the detected malignancy cases in the anti-TIF1-Ab-positive cohort occurred between 3 years prior to and 2.5 years after DM onset. No cancer cases were detected within the following 7.5 years in this group, whereas cancers were detected during this period in the anti-TIF1-Ab-negative cases. Ovarian cancer was more common in the anti-TIF1-Ab-positive vs -negative cohort: 19% vs 2%, respectively (P < 0.05). No anti-TIF1-Ab-positive case <39 years of age developed cancer, compared with 21 (53%) of those ≥39 years of age. CONCLUSION: Anti-TIF1-Ab-positive-associated malignancy occurs exclusively within the 3 year period on either side of DM onset, the risk being highest in those ≥39 years of age. Cancer types differ according to anti-TIF1-Ab status, and this may warrant specific cancer screening approaches.

Recent developments in classification criteria and diagnosis guidelines for idiopathic inflammatory myopathies.

PURPOSE OF REVIEW: The aim of this review was to summarize key developments in classification and diagnosis of the idiopathic inflammatory myopathies (IIMs). RECENT FINDINGS: The recently published European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for the IIMs provide a comprehensive, accurate and data-driven approach to identification of IIM cases appropriate for inclusion in research studies. Further, recent studies have advanced understanding of clinical manifestations of the IIMs and delineated the role of imaging, particularly magnetic resonance. SUMMARY: The recent publication of the EULAR/ACR classification criteria will potentially greatly improve IIM research through more accurate case identification and standardization across studies.Future inclusion of newly recognized clinical associations with the MSAs may further improve the criteria's accuracy and utility. Clear and comprehensive understanding of associations between clinical manifestations, prognosis and multisystem involvement can aid diagnostic assessment; recent advances include delineation of such associations and expansion of the role of imaging.

Long-term persistence with rituximab in patients with rheumatoid arthritis.

Objectives: To investigate the long term persistence of rituximab (RTX) in a large observational RA cohort, investigate persistence of RTX when used as a first or second line biologic DMARD (bDMARD), to characterize subsequent bDMARD treatment following RTX. Methods: Patients with RA starting treatment with RTX (MabThera) between 2008 and 2011 were recruited into the British Society for Rheumatology Biologics Register for RA. Duration of RTX treatment over the first 4 years after initiation was estimated via Kaplan-Meier estimates and the reason for discontinuation was ascertained. Subsequent bDMARD use following RTX discontinuation was characterised. Treatment survival in bDMARD-naïve (first line RTX use) and experienced (second line RTX use) cohorts was described. Results: One thousand six hundred and twenty-nine patients were recruited (1371 bDMARD-experienced and 258 bDMARD-naïve). Sixty percent of the whole cohort remained on RTX after 4 years. Ineffectiveness (46%) and death (24%) were the most common reason for RTX discontinuation. RTX discontinuation was associated with RF negativity for the bDMARD-experienced cohort. Of those that discontinued RTX, 46% initiated treatment with another bDMARD, with tocilizumab being the most common. Conclusion: This large study of patients initiating RTX treatment for severe RA found that 60% persisted with treatment after 4 years. This study also identified that RTX is tolerated well when used as a first or second line bDMARD.

Frailty and bone health in European men.

Background: frailty is associated with an increased risk of fragility fractures. Less is known, however, about the association between frailty and bone health. Methods: men aged 40-79 years were recruited from population registers in eight European centres for participation in the European Male Aging Study. Subjects completed a comprehensive assessment which included quantitative ultrasound (QUS) scan of the heel (Hologic-SAHARA) and in two centres, dual-energy bone densitometry (dual-energy x-ray absorptiometry, DXA). Frailty was defined based on an adaptation of Fried's phenotype criteria and a frailty index (FI) was constructed. The association between frailty and the QUS and DXA parameters was determined using linear regression, with adjustments for age, body mass index and centre. Results: in total, 3,231 subjects contributed data to the analysis. Using the Fried categorisation of frailty, pre-frail and frail men had significantly lower speed of sound (SOS), broadband ultrasound attenuation (BUA) and quantitative ultrasound index (QUI) compared to robust men (P< 0.05). Similar results were seen using the FI after categorisation into 'high', 'medium' and 'low' levels of frailty. Using the Fried categorisation, frail men had lower femoral neck bone mineral density (BMD) compared to robust men (P < 0.05), but not lower lumbar spine BMD. Using the FI categorisation, a 'high' level of frailty (FI > 0.35) was associated with lower lumbar spine BMD (P < 0.05) when compared to those with low (FI < 0.2), but not lower femoral neck BMD. When analysed as a continuous variable, higher FI was linked with lower SOS, BUA and QUI (P < 0.05). Conclusions: optimisation of bone health as well as prevention of falls should be considered as strategies to reduce fractures in frail older people.

International Guideline for Idiopathic Inflammatory Myopathy-Associated Cancer Screening: an International Myositis Assessment and Clinical Studies Group (IMACS) initiative.

Adult-onset idiopathic inflammatory myopathy (IIM) is associated with an increased cancer risk within the 3 years preceding and following IIM onset. Evidence- and consensus-based recommendations for IIM-associated cancer screening can potentially improve outcomes. This International Guideline for IIM-Associated Cancer Screening provides recommendations addressing IIM-associated cancer risk stratification, cancer screening modalities and screening frequency. The international Expert Group formed a total of 18 recommendations via a modified Delphi approach using a series of online surveys. First, the recommendations enable an individual patient's IIM-associated cancer risk to be stratified into standard, moderate or high risk according to the IIM subtype, autoantibody status and clinical features. Second, the recommendations outline a 'basic' screening panel (including chest radiography and preliminary laboratory tests) and an 'enhanced' screening panel (including CT and tumour markers). Third, the recommendations advise on the timing and frequency of screening via basic and enhanced panels, according to risk status. The recommendations also advise consideration of upper or lower gastrointestinal endoscopy, nasoendoscopy and 18F-FDG PET-CT scanning in specific patient populations. These recommendations are aimed at facilitating earlier IIM-associated cancer detection, especially in those who are at a high risk, thus potentially improving outcomes, including survival.

Patient insights on living with idiopathic inflammatory myopathy and the limitations of disease activity measurement methods - a qualitative study.

BACKGROUND: The idiopathic inflammatory myopathies (IIMs) are chronic autoimmune conditions, typically resulting in proximal muscle weakness and impacting upon quality of life. Accurate measurement of IIM disease activity is imperative for appropriate medical management and carrying out valid clinical trials. The International Myositis Assessment and Clinical Studies Group (IMACS) "Disease Activity Core Set Measures" are the current gold-standard of IIM disease activity assessment. Anecdotally, patients with an IIM report that the IMACS Core Set Measures and other available methods do not necessarily capture their perceived disease activity. Investigating the patient experiences of living with an IIM and their views on the accuracy of the IMACS Core Set Measures will provide valuable insights for both clinical and research purposes. METHODS: Eighteen interviews with patients with an IIM were carried out and analysed thematically, using a grounded theory approach. Experiences on living with an IIM and perceptions on the accuracy of disease activity measurement methods were explored. RESULTS: Interview analysis revealed four themes: 1) fatigue, 2) pain, 3) day-to-day symptom variation, 4) limitations of creatine kinase levels and manual muscle testing. CONCLUSIONS: This study has provided valuable insights into patient experiences of living with an IIM. Aspects of IIM disease activity perceived not to be wholly measured by the IMACS Core Set Measures have also been identified. These findings have implications for future IIM clinical care and research, in particular providing justification for research into pain, fatigue and symptom variation.

A review of accelerometer-derived physical activity in the idiopathic inflammatory myopathies.

BACKGROUND: The idiopathic inflammatory myopathies (IIMs) are a group of rare conditions characterised by muscle inflammation (myositis). Accurate disease activity assessment is vital in both clinical and research settings, however, current available methods lack ability to quantify associated variation of physical activity, an important consequence of myositis.This study aims to review studies that have collected accelerometer-derived physical activity data in IIM populations, and to investigate if these studies identified associations between physical and myositis disease activity. METHODS: A narrative review was conducted to identify original articles that have collected accelerometer-derived physical activity data in IIM populations. The following databases were searched from February 2000 until February 2019: Medline via PubMed, Embase via OVID and Scopus. RESULTS: Of the 297 publications screened, eight studies describing accelerometer use in 181 IIM cases were identified. Seven out of the eight studies investigated juvenile dermatomyositis (JDM) populations and only one reported on an adult-onset population. Population sizes, disease duration, accelerometer devices used, body placement sites, and study duration varied between each study.Accelerometer-derived physical activity levels were reduced in IIM cohorts, compared to healthy controls, and studies reported improvement of physical activity levels following exercise programme interventions, thus demonstrating efficacy.Higher levels of accelerometer-derived physical activity measurements were associated with shorter JDM disease duration, current glucocorticoid use and lower serum creatine kinase. However, no clear association between muscle strength and accelerometer-derived physical activity measures was identified. CONCLUSIONS: The use of accelerometer-derived physical activity in IIM research is in its infancy. Whilst knowledge is currently limited to small studies, the opportunities are promising and future research in this area has the potential to improve disease activity assessment for clinical and research applications.

Genetic background may contribute to the latitude-dependent prevalence of dermatomyositis and anti-TIF1-γ autoantibodies in adult patients with myositis.

BACKGROUND: The prevalence of dermatomyositis (DM) versus DM and polymyositis (PM) combined has been shown to be negatively associated with latitude. This observation has been attributed to increasing exposure to ultraviolet (UV) light towards the equator. In this study, we investigated whether differing genetic background in populations could contribute to this distribution of DM. METHODS: Case data derived from the MYOGEN (Myositis Genetics Consortium) Immunochip study (n = 1769) were used to model the association of DM prevalence and DM-specific autoantibodies with latitude. Control data (n = 9911) were used to model the relationship of human leucocyte antigen (HLA) associated with DM autoantibodies and DM or PM single-nucleotide polymorphisms (suggestive significance in the Immunochip project, P < 2.25 × 10- 5) in healthy control subjects with latitude. All variables were analysed against latitude using ordered logistic regression, adjusted for sex. RESULTS: The prevalence of DM, as a proportion of DM and PM combined, and the presence of anti-transcription intermediary factor 1 (anti-TIF1-γ) autoantibodies were both significantly negatively associated with latitude (OR 0.96, 95% CI 0.95-0.98, P < 0.001; and OR 0.95, 95% CI 0.92-0.99, P = 0.004, respectively). HLA alleles significantly associated with anti-Mi-2 and anti-TIF1-γ autoantibodies also were strongly negatively associated with latitude (OR 0.97, 95% CI 0.96-0.98, P < 0.001 and OR 0.98, 95% CI 0.97-0.99, P < 0.001, respectively). The frequency of five PM- or DM-associated SNPs showed a significant association with latitude (P < 0.05), and the direction of four of these associations was consistent with the latitude associations of the clinical phenotypes. CONCLUSIONS: These results lend some support to the hypothesis that genetic background, in addition to UV exposure, may contribute to the distribution of DM.

Increasing incidence of adult idiopathic inflammatory myopathies in the City of Salford, UK: a 10-year epidemiological study.

OBJECTIVES: The aim was to identify and characterize all incident adult cases of idiopathic inflammatory myopathies (IIM) between 1 January 2007 and 31 December 2016 in the City of Salford, UK. METHODS: Adults first diagnosed with IIM within the study period were identified by: a Salford Royal NHS Foundation Trust (SRFT) inpatient episode IIM-specific ICD-10 coding search; all new patient appointments to SRFT neuromuscular outpatient clinics; and all Salford residents enrolled within the UKMYONET study. All patients with definite IIM by the 2017 EULAR/ACR classification criteria were included, as were probable cases if consensus expert opinion agreed. Cases were excluded if <18 years of age at disease onset, if they did not meet probable criteria or when probable but expert opinion concluded a non-IIM diagnosis. RESULTS: The multimodal case ascertainment identified 1156 cases which, after review and application of exclusion criteria, resulted in 32 incident cases during the study period. Twenty-three of 32 were female, with a mean age of 58.1 years. The mean incidence of adult IIM was 17.6/1 000 000 person years, and higher for females than for males (25.2 vs 10.0/1 000 000 person years, respectively). A significant incidence increase over time was apparent (13.6 vs 21.4/1 000 000 person years; P = 0.032). Using EULAR/ACR classification criteria, the largest IIM subtype (21/32) was PM, followed by DM (8/32), IBM (2/32) and amyopathic DM (1/32). Expert opinion subtype differed from EULAR/ACR classification criteria in 19/32 cases. CONCLUSION: The incidence of adult IIM in Salford is 17.6/1 000 000 person years, higher in females, and is increasing over time. Disagreement exists between EULAR/ACR-derived and expert opinion-derived IIM subtype assignments.

Drug-Induced Interstitial Lung Disease: A Systematic Review.

BACKGROUND: Drug-induced interstitial lung disease (DIILD) occurs as a result of numerous agents, but the risk often only becomes apparent after the marketing authorisation of such agents. METHODS: In this PRISMA-compliant systematic review, we aimed to evaluate and synthesise the current literature on DIILD. RESULTS: Following a quality assessment, 156 full-text papers describing more than 6000 DIILD cases were included in the review. However, the majority of the papers were of low or very low quality in relation to the review question (78%). Thus, it was not possible to perform a meta-analysis, and descriptive review was undertaken instead. DIILD incidence rates varied between 4.1 and 12.4 cases/million/year. DIILD accounted for 3⁻5% of prevalent ILD cases. Cancer drugs, followed by rheumatology drugs, amiodarone and antibiotics, were the most common causes of DIILD. The radiopathological phenotype of DIILD varied between and within agents, and no typical radiological pattern specific to DIILD was identified. Mortality rates of over 50% were reported in some studies. Severity at presentation was the most reliable predictor of mortality. Glucocorticoids (GCs) were commonly used to treat DIILD, but no prospective studies examined their effect on outcome. CONCLUSIONS: Overall high-quality evidence in DIILD is lacking, and the current review will inform larger prospective studies to investigate the diagnosis and management of DIILD.