Collaborative research in myositis-related disorders: MIHRA, a global shared community model.

Myositis International Health and Research Collaborative Alliance (MIHRA) is a newly formed purpose-built non-profit charitable research organization dedicated to accelerating international clinical trial readiness, global professional and lay education, career development and rare disease advocacy in IIM-related disorders. In its long form, the name expresses the community's scope of engagement and intent. In its abbreviation, MIHRA, conveys linguistic roots across many languages, that reflects the IIM community's spirit with meanings such as kindness, community, goodness, and peace. MIHRA unites the global multi-disciplinary community of adult and pediatric healthcare professionals, researchers, patient advisors and networks focused on conducting research in and providing care for pediatric and adult IIM-related disorders to ultimately find a cure. MIHRA serves as a resourced platform for collaborative efforts in investigator-initiated projects, consensus guidelines for IIM assessment and treatment, and IIM-specific career development through connecting research networks.MIHRA's infrastructure, mission, programming and operations are designed to address challenges unique to rare disease communities and aspires to contribute toward transformative models of rare disease research such as global expansion and inclusivity, utilization of community resources, streamlining ethics and data-sharing policies to facilitate collaborative research. Herein, summarises MIHRA operational cores, missions, vision, programming and provision of community resources to sustain, accelerate and grow global collaborative research in myositis-related disorders.

Disease spectrum of myopathies with elevated aldolase and normal creatine kinase.

BACKGROUND AND PURPOSE: Elevation of serum creatine kinase (CK) or hyperCKemia is considered a biological marker of myopathies. However, selective elevation of serum aldolase with normal CK has been reported in a few myopathies, including dermatomyositis, immune-mediated myopathy with perimysial pathology and fasciitis with associated myopathy. The aim was to investigate the disease spectrum of myopathies with isolated aldolase elevation. METHODS: Medical records were reviewed to identify patients >18 years old seen between December 1994 and June 2020 who had pathologically proven myopathies with elevated aldolase and normal CK level. Patients with alternative causes of aldolase elevation were excluded. RESULTS: Thirty-four patients with various types of myopathies were identified. Myopathies were treatable in 27 patients. The three most common etiologies were dermatomyositis (n = 8), overlap myositis (n = 4) and nonspecific myopathy (n = 4). Perimysial pathology comprising inflammation, fragmentation, vasculitis, calcified perimysial vessels or extracellular amyloid deposition was found in 17/34 patients (50%). Eight dermatomyositis patients with selective elevated aldolase were compared to 24 sex- and age-matched patients with dermatomyositis and hyperCKemia. Dermatomyositis patients with normal CK significantly (p < 0.05) had less frequent cutaneous involvement (50.0% vs. 100.0%) and fibrillation potentials (50.0% vs. 90.5%) but higher median erythrocyte sedimentation rate (33.5 vs. 13.5 mm/h) and more common perifascicular mitochondrial pathology (37.5% vs. 4.2%). CONCLUSION: Isolated aldolase elevation can be found in a greater variety of myopathies than initially thought and most were treatable. Dermatomyositis is the most common myopathy with selective elevation of aldolase in our cohort, which features some unique characteristics compared to dermatomyositis with hyperCKemia.

Clinical Outcomes With and Without Plasma Exchange in the Treatment of Rapidly Progressive Interstitial Lung Disease Associated With Idiopathic Inflammatory Myopathy.

BACKGROUND/OBJECTIVE: A subset of patients with idiopathic inflammatory myopathy (IIM) develops highly fatal, rapidly progressive interstitial lung disease (RP-ILD). Treatment strategies consist of glucocorticoid and adjunctive immunosuppressive therapies. Plasma exchange (PE) is an alternative therapy, but its benefit is unclear. In this study, we aimed to determine whether PE benefited outcomes for patients with RP-ILD. METHODS: In this medical records review study, we compared baseline characteristics and clinical outcomes for 2 groups of patients with IIM-related RP-ILD: those who received and did not receive PE. RESULTS: Our cohort consisted of 15 patients, 9 of whom received PE. Baseline demographic characteristics and severity of lung, skin, and musculoskeletal disease between the 2 groups of patients were not significantly different. Five patients required mechanical ventilation (2, PE; 3, no PE). Plasma exchange was generally a third-line adjunctive treatment option. The PE group had a longer median (interquartile range) hospitalization (27.0 [23.0-36.0] days) than the non-PE group (12.0 [8.0-14.0] days) ( p = 0.02). There was a potential benefit in 30-day mortality improvement in those receiving PE (0% vs 33%, p = 0.14), with a statistically significant improvement in 2 important composite end points including 30-day mortality or need for lung transplant (0% vs 50%, p = 0.04) and 1-year mortality or need for lung transplant or hospital readmission for RP-ILD in those receiving PE (22% vs 83%, p = 0.04). CONCLUSIONS: Plasma exchange may be an underutilized, safe salvage therapy for patients with IIM-related RP-ILD when other immunosuppressive therapies fail.

Incidence, Prevalence, and Mortality of Dermatomyositis: A Population-Based Cohort Study.

OBJECTIVE: We aimed to determine the population-based incidence, prevalence, and mortality of dermatomyositis (DM) using European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) criteria. METHODS: This population-based cohort study included incident DM from January 1, 1995 to December 31, 2019. We manually reviewed all individuals with at least 1 code for DM or polymyositis to determine if they met EULAR/ACR criteria, subspecialty physician diagnosis, and/or Bohan and Peter criteria. We age- and sex-adjusted incidence and prevalence estimates to the US non-Hispanic White year 2000 population and estimated prevalence on January 1, 2015. Standardized mortality ratios (SMRs) with 95% confidence intervals (95% CIs) compared observed to expected mortality adjusting for age, sex, and year. RESULTS: We identified 40 cases of verified DM, with 29 cases incident in Olmsted County from 1995 to 2019. The mean age was 57 years, 26 (90%) were female, and 12 (41%) had clinically amyopathic DM (CADM). The median follow-up time was 8.2 years. The overall adjusted incidence of DM was 1.1 (95% CI 0.7-1.5) per 100,000 person-years, and prevalence was 13 (95% CI 6-19) per 100,000. The SMR was significantly elevated among the myopathic DM cases (3.1 [95% CI 1.1-6.8]) but not CADM cases (1.1 [95% CI 0.2-3.3]). The positive predictive value of ≥2 DM codes was only 40 of 82 (49%). CONCLUSION: This population-based study found that DM incidence and prevalence were higher than previously reported. Mortality was significantly elevated for myopathic DM but not for CADM.

Symptomatic myopathies in sarcoidosis: disease spectrum and myxovirus resistance protein A expression.

OBJECTIVES: Symptomatic myopathy in sarcoidosis patients is not always due to sarcoid myopathy (ScM). We investigated the clinical and pathological spectrum including myxovirus resistance protein A (MxA) expression among sarcoidosis patients. METHODS: We reviewed the Mayo Clinic database (May 1980-December 2020) to identify sarcoidosis patients with myopathic symptoms and pathological evidence of myopathy. RESULTS: Among 5885 sarcoidosis patients, 21 had symptomatic myopathy. Eight carried a diagnosis of sarcoidosis 5.5 years (median) prior to myopathy onset. Eleven patients had ScM. The remaining had non-sarcoid myopathies (five IBM, one immune-mediated necrotizing myopathy, one non-specific myositis, two non-specific myopathy and one steroid myopathy). Estimated frequency of IBM is 85 per 100 000 sarcoidosis patients. The following features were associated with non-sarcoid myopathies (P < 0.05): (i) predominant finger flexor and quadriceps weakness, (ii) modified Rankin scale (mRS) >2 at time of diagnosis, (iii) creatine kinase >500 U/l, and (iv) absence of intramuscular granulomas. Sarcoplasmic MxA expression was observed in scattered myofibres in three patients, two of whom were tested for DM-specific autoantibodies and were negative. Immunosuppressive therapy led to improvement in mRS ≥1 in 5/10 ScM, none of the five IBM, and 3/3 remaining patients with non-sarcoid myopathies. DISCUSSION: Symptomatic myopathy occurred in 0.36% of sarcoidosis. IBM was the second most common cause of myopathies after ScM. Frequency of IBM in sarcoidosis is higher than in the general population. Recognition of features suggestive of alternative aetiologies can guide proper treatment. Our findings of abnormal MxA expression warrant a larger study.

Trial of Intravenous Immune Globulin in Dermatomyositis.

BACKGROUND: Intravenous immune globulin (IVIG) for the treatment of dermatomyositis has not been extensively evaluated. METHODS: We conducted a randomized, placebo-controlled trial involving patients with active dermatomyositis. The patients were assigned in a 1:1 ratio to receive IVIG at a dose of 2.0 g per kilogram of body weight or placebo every 4 weeks for 16 weeks. The patients who received placebo and those without confirmed clinical deterioration while receiving IVIG could enter an open-label extension phase for another 24 weeks. The primary end point was a response, defined as a Total Improvement Score (TIS) of at least 20 (indicating at least minimal improvement) at week 16 and no confirmed deterioration up to week 16. The TIS is a weighted composite score reflecting the change in a core set of six measures of myositis activity over time; scores range from 0 to 100, with higher scores indicating greater improvement. Key secondary end points included at least moderate improvement (TIS ≥40) and major improvement (TIS ≥60), and change in score on the Cutaneous Dermatomyositis Disease Area and Severity Index. RESULTS: A total of 95 patients underwent randomization: 47 patients were assigned to the IVIG group, and 48 to the placebo group. At 16 weeks, 79% of the patients in the IVIG group (37 of 47) and 44% of those in the placebo group (21 of 48) had a TIS of at least 20 (difference, 35 percentage points; 95% confidence interval, 17 to 53; P<0.001). The results with respect to the secondary end points, including at least moderate improvement and major improvement, were generally in the same direction as the results of the primary end-point analysis, except for the change in creatine kinase level (an individual core measure of the TIS), which did not differ meaningfully between the two groups. Over 40 weeks, 282 treatment-related adverse events occurred in the IVIG group, including headache (in 42% of patients), pyrexia (in 19%), and nausea (in 16%). A total of 9 serious adverse events that were considered to be related to IVIG occurred, including 6 thromboembolic events. CONCLUSIONS: In this 16-week trial involving adults with dermatomyositis, the percentage of patients with a response of at least minimal improvement based on a composite score of disease activity was significantly greater among those who received IVIG than among those who received placebo. IVIG was associated with adverse events, including thromboembolism. (Funded by Octapharma Pharmazeutika; ProDERM ClinicalTrials.gov number, NCT02728752.).

Randomized Trial of Tocilizumab in the Treatment of Refractory Adult Polymyositis and Dermatomyositis.

OBJECTIVE: To assess the efficacy and tolerability of tocilizumab in a multicenter, randomized, double-blind, placebo-controlled trial in refractory adult patients with dermatomyositis (DM) and polymyositis (PM). METHODS: Thirty-six subjects with probable or definite DM/PM were enrolled in a 6-month phase 2B clinical trial and randomized 1:1 to receive tocilizumab (8 mg/kg intravenously) or placebo every 4 weeks for 24 weeks. Eligible subjects had either a DM rash, a myositis-associated autoantibody or an adjudicated PM diagnosis. Active disease was defined by at least three of six abnormal core set measures (CSMs), including a manual muscle testing (MMT)-8 score of less than 136/150. If the MMT-8 score was greater than 136, then a cutaneous score of 3 or more (10 cm visual analogue scale) was required along with three additional abnormal CSMs indicating disease activity. The primary endpoint compared the Total Improvement Score (TIS) between both arms from week 4 to 24. Secondary outcomes included time to meeting minimal TIS improvement, changes in CSMs, time to worsening, steroid-sparing effect, proportion of subjects meeting more stringent improvement criteria, and safety outcomes. RESULTS: There was no significant difference (P = 0.86) in the TIS over 24 weeks between tocilizumab and placebo arms. The secondary endpoints of time to improvement (minimal, moderate, or major), time to worsening, CSM changes, safety outcomes, and steroid-sparing effect were also not significantly different between arms. CONCLUSION: Tocilizumab was safe and well tolerated but did not meet the primary or secondary efficacy outcomes in refractory DM and PM in this 24-week phase 2B study.

Cancer and immune-mediated necrotizing myopathy: a longitudinal referral case-controlled outcomes evaluation.

OBJECTIVES: To investigate immune-mediated necrotizing myopathy (IMNM) association with cancer and its clinical implications. METHODS: IMNM cases were identified 1 January 2000 to 31 December 2020 matching sex and age controls (4:1). RESULTS: A total of 152 patients with IMNM were identified and among serologically tested, 60% (83/140) were HMGCR-IgG+, 14% (20/140) were SRP-IgG+ and 26% (37/140) were seronegative. Cancer rates were not significantly different between serological subgroups; 18.1% (15/83) HMGCR-IgG+, 25% (5/20) SRP-IgG+ and 30% (11/37) seronegative (P = 0.34). Cancer screening was performed within 12 months from IMNM diagnosis in 88% (134/152) (whole-body CT plus FDG-PET CT in 53, CT alone in 72 and FDG-PET alone in 9). FDG-PET/CT was positive in 73% (25/34) of cancers. Increasing age was the only risk associated with cancer (P = 0.02). The odds of developing cancer at ±3 or ±5 years from IMNM diagnosis was not higher than controls (OR = 0.49; CI: 0.325-0.76). Lifetime IMNM diagnosis of cancer was less compared with controls (OR = 0.5 CI: 0.33-0.78, P = 0.002). Most patients responded to treatment (137/147, P < 0.001). Death and treatment response did not significantly differ between cancer [23% (8/34); 88% (29/33)] and non-cancer patients [19% (23/118); 92% (108/118)]. In total, 13% (20/152) of patients died during follow-up compared with 14% (41/290) of medicine and 16% (46/290) of neurology controls (P = 0.8). Seropositives had greater life expectancy than seronegatives (P = 0.01). CONCLUSIONS: Greater cancer risk is not observed in IMNM vs controls. Cancer screening in IMNM should be individualized based on age-personal and family history, including consideration of FDG-PET/CT. Immune-treatment response did not differ with cancer.

Time to transition from psoriasis to psoriatic arthritis: A population-based study.

OBJECTIVE: To identify demographic and clinical characteristics associated with time between psoriasis and psoriatic arthritis (PsA). METHODS: A retrospective, population-based cohort of incident PsA patients ≥18 years (2000-17) from Olmsted County, MN was identified. PsA patients were divided into two groups: patients with concurrent psoriasis and PsA (within 1 year), and patients with psoriasis before PsA (>1 year). Patients with PsA prior to psoriasis were excluded. Age- and sex-adjusted logistic regression models were used to examine factors associated with the time between psoriasis and PsA diagnosis. RESULTS: Among 164 patients with incident PsA, 158 had a current or personal history of psoriasis. The mean (SD) age at PsA diagnosis was 46.3 (12.0) years, and 46% were females. The median (interquartile range) time from psoriasis to PsA was 35.5 (0.8-153.4) months. 64 patients (41%) patients had concurrent psoriasis and PsA while 94 (59%) had onset of psoriasis before PsA. The estimated age at onset of psoriasis symptom (OR per 10-year decrease = 1.63, 95% CI: 1.26-2.11) and psoriasis severity (OR = 3.65, 95% CI: 1.18-11.32 for severe vs. mild) were associated with having a psoriasis diagnosis more than one year prior to incident PsA. CONCLUSION: In this population-based study, approximately 60% of the patients had psoriasis before PsA, and the rest had concurrent psoriasis and PsA. Patients with lower age at psoriasis onset or severe psoriasis were more likely to have a longer time to transition from psoriasis to PsA.

Do histopathological features correlate with systemic manifestations in dermatomyositis? Analysis of 42 skin biopsy specimens from 22 patients.

BACKGROUND: Understanding whether specific histopathologic features on skin biopsy are predictive of systemic associations in dermatomyositis (DM) would be useful to guide clinical screening. METHODS: Through retrospective medical record search, clinical and laboratory findings of patients with DM were documented. Existing skin biopsy slides were re-reviewed blindly. RESULTS: Of all biopsy specimens (n = 42), the most frequent histopathological finding was vacuolar interface dermatitis (95%). Other features included perivascular lymphocytic infiltrate (71%), increased dermal mucin (40%), vessel wall thickening (12%), follicular plugging (9.5%), and dermal sclerosis (7%). Neutrophilic infiltrate was observed in three biopsies from a patient with adalimumab-associated DM. Vasculitis was not observed. There was no statistically significant difference in the presence of any histopathological feature and that of various systemic manifestations (i.e., myopathy, interstitial lung disease [ILD] and malignancy). However, we observed that dense lichenoid infiltrate rather than pauci-inflammatory changes correlated with severe itching (p < 0.001). Patients with MDA-5 antibodies were significantly more likely to have vasculopathy than those without (p = 0.029*). CONCLUSIONS: No dermatopathologic feature was reliably predictive of myopathy, ILD, or malignancy. This finding implies that, regardless of histopathologic findings, patients should be screened for associated conditions as clinically indicated.

Survival and associated comorbidities in inclusion body myositis.

OBJECTIVE: To evaluate survival and associated comorbidities in inclusion body myositis (IBM) in a population-based, case-control study. METHODS: We utilized the expanded Rochester Epidemiology Project medical records-linkage system, including 27 counties in Minnesota and Wisconsin, to identify patients with IBM, other inflammatory myopathies (IIM), and age/sex-matched population-controls. We compared the frequency of various comorbidities and survival among groups. RESULTS: We identified 50 IBM patients, 65 IIM controls and 294 population controls. Dysphagia was most common in IBM (64%) patients. The frequency of neurodegenerative disorders (dementia/parkinsonism) and solid cancers was not different between groups. Rheumatoid arthritis was the most common rheumatic disease in all groups. A total of 36% of IBM patients had a peripheral neuropathy, 6% had Sjögren's syndrome and 10% had a haematologic malignancy. T-cell large granular lymphocytic leukaemia was only observed in the IBM group. None of the IBM patients had hepatitis B or C, or HIV. IBM patients were 2.7 times more likely to have peripheral neuropathy, 6.2 times more likely to have Sjögren's syndrome and 3.9 times more likely to have a haematologic malignancy than population controls. IBM was associated with increased mortality, with a 10-year survival of 36% from index, compared with 67% in IIM and 59% in population controls. Respiratory failure or pneumonia (44%) was the most common cause of death. CONCLUSIONS: IBM is associated with lower survival, and higher frequency of peripheral neuropathy, Sjögren's syndrome and haematologic malignancies than the general population. Close monitoring of IBM-related complications is warranted.

Single-cell expression quantitative trait loci (eQTL) analysis of SLE-risk loci in lupus patient monocytes.

BACKGROUND: We performed expression quantitative trait locus (eQTL) analysis in single classical (CL) and non-classical (NCL) monocytes from patients with systemic lupus erythematosus (SLE) to quantify the impact of well-established genetic risk alleles on transcription at single-cell resolution. METHODS: Single-cell gene expression was quantified using qPCR in purified monocyte subpopulations (CD14++CD16- CL and CD14dimCD16+ NCL) from SLE patients. Novel analysis methods were used to control for the within-person correlations observed, and eQTLs were compared between cell types and risk alleles. RESULTS: The SLE-risk alleles demonstrated significantly more eQTLs in NCLs as compared to CLs (p = 0.0004). There were 18 eQTLs exclusive to NCL cells, 5 eQTLs exclusive to CL cells, and only one shared eQTL, supporting large differences in the impact of the risk alleles between these monocyte subsets. The SPP1 and TNFAIP3 loci were associated with the greatest number of transcripts. Patterns of shared influence in which different SNPs impacted the same transcript also differed between monocyte subsets, with greater evidence for synergy in NCL cells. IRF1 expression demonstrated an on/off pattern, in which expression was zero in all of the monocytes studied from some individuals, and this pattern was associated with a number of SLE risk alleles. We observed corroborating evidence of this IRF1 expression pattern in public data sets. CONCLUSIONS: We document multiple SLE-risk allele eQTLs in single monocytes which differ greatly between CL and NCL subsets. These data support the importance of the SPP1 and TNFAIP3 risk variants and the IRF1 transcript in SLE patient monocyte function.

Amyloid arthropathy in smoldering myeloma: Do not take it lightly.

We report a case of smoldering multiple myeloma patient who developed signs and symptoms consistent with polyarthritis. A PET-CT demonstrated marked FDG activity in multiple joints, concerning for inflammatory arthritis. Arthrocentesis from the glenohumeral joint was consistent with inflammatory synovial fluid with no evidence for infection or crystals. Congo-red stain of the synovial fluid was positive, and mass-spectrometry based amyloid typing was consistent with wild-type transthyretin type. The patient responded instantly to glucocorticoids. This case reports highlights the feasibility of non-tissue diagnosis of amyloidosis using body fluids and underscores the importance of accurate typing to avoid erroneous treatment.

Epidemiology and Natural History of Inclusion Body Myositis: A 40-Year Population-Based Study.

OBJECTIVES: To determine the prevalence and natural history of sporadic inclusion body myositis (sIBM) and to test the hypothesis that patients with sIBM have higher cancer or mortality rates than the general population. METHODS: We sought patients with sIBM defined by the 2011 European Neuromuscular Centre (ENMC) diagnostic criteria among Olmsted County, Minnesota, residents in 40-year time period. RESULTS: We identified 20 patients (10 clinicopathologically defined, 9 clinically defined, and 1 probable) according to the ENMC criteria and 1 patient with all features of clinicopathologically defined sIBM except for symptom onset at <45 years of age. The prevalence of sIBM in 2010 was 18.20 per 100,000 people ≥50 years old. Ten patients developed cancers. The incidence of cancers in sIBM did not differ from that observed in the general population (odds ratio 1.89, 95% confidence interval [CI] 0.639-5.613, p = 0.24). Two-thirds of patients developed dysphagia, and half required a feeding tube. Nine patients required a wheelchair. The median time from symptom onset to wheelchair dependence was 10.5 (range 1-29) years. Overall life expectancy was shorter in the sIBM group compared to the general population (84.1 [95% CI 78-88.4] vs 87.5 [95% CI 85.2-89.5] years, p = 0.03). Thirteen patients died; 9 deaths were sIBM related (7 respiratory and 2 unspecified sIBM complications). Female sex (p = 0.03) and dysphagia (p = 0.05) were independent predictors of death. CONCLUSION: Olmsted County has the highest prevalence of sIBM reported to date. Patients with sIBM have similar risk of cancer, but slightly shorter life expectancy compared to matched patients without sIBM. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that patients with sIBM have similar risks of cancers and slightly shorter life expectancy compared to controls.

The Epidemiology of Psoriatic Arthritis Over Five Decades: A Population-Based Study.

OBJECTIVE: To determine the incidence of psoriatic arthritis (PsA) in a US population and describe trends in incidence and mortality over 5 decades. METHODS: The previously identified population-based cohort that included Olmsted County, Minnesota residents ≥18 years of age who fulfilled PsA criteria during 1970-1999 was extended to include patients with incident PsA during 2000-2017. Age- and sex-specific incidence rates and point prevalence, adjusted to the 2010 US White population, were reported. RESULTS: There were 164 incident cases of PsA in 2000-2017 (mean ± SD age 46.4 ± 12.0 years; 47% female). The overall age- and sex-adjusted annual incidence of PsA per 100,000 population was 8.5 (95% confidence interval [95% CI] 7.2-9.8) and was higher in men (9.3 [95% CI 7.4-11.3]) than women (7.7 [95% CI 5.9-9.4]) in 2000-2017. Overall incidence was highest in the 40-59 years age group. The incidence rate was relatively stable during 2000-2017, with no evidence of an overall increase or an increase in men only (but a modest increase of 3% per year in women), compared to 1970-1999 when a 4%-per-year increase in incidence was observed. Point prevalence was 181.8 per 100,000 population (95% CI 156.5-207.1) in 2015. The percentage of women among those with PsA increased from 39% in 1970-1999 and 41% in 2000-2009 to 54% in 2010-2017 (P = 0.08). Overall survival in PsA did not differ from the general population (standardized mortality ratio 0.85 [95% CI 0.61-1.15]). CONCLUSION: The incidence of PsA in this predominantly White US population was stable in 2000-2017, in contrast to previous years. However, an increasing proportion of women with PsA was found in this study.