Antibody predictors of mortality and lung function trends in myositis spectrum interstitial lung disease.

OBJECTIVES: The impact of autoantibody profiles on prognosis of idiopathic inflammatory myositis associated interstitial lung disease (IIM-ILD) and myositis spectrum ILD with Myositis Specific Antibodies (MSA) remains unclear. This retrospective cohort study examines whether serological profiles are associated with mortality and longitudinal lung function change. METHODS: Baseline clinical/demographic characteristics and follow-up lung function of consecutive adult patients with IIM-ILD or Interstitial Pneumonia with Autoimmune Features (IPAF) positive for MSAs were extracted from three hospitals. Univariate and multi-variate Cox-Proportional Hazards analyses were used to compare mortality between autoantibodies. Regression models were used to analyse lung function trends. RESULTS: Of 430 included patients, 81% met IIM criteria, 19% were IPAF-MSA. On univariate analysis, risk factors associated with mortality included higher age, Charlson Co-morbidity Index and CRP; and lower BMI, baseline TLCO% and FEV1%. Compared to anti-MDA5-negativity, anti-MDA5-positivity (MDA5+) was associated with high mortality in the first 3 months (HR 65.2. 95%CI 14.1, 302.0), while no significant difference was seen thereafter (HR 0.55, 95%CI 0.14, 2.28). On multi-variate analysis, combined anti-synthetase antibodies carried a reduced risk of mortality (HR 0.63), although individually, mortality was reduced in anti-Jo1 + (HR 0.61, 95%CI 0.4-0.87) and increased in anti-PL7+ patients (HR 2.07, 95%CI 1.44-2.99). Anti-MDA5+ was associated with slow improvement in %FVC over the first 3 years, while anti-PL7+ was linked with a slow decline from 12 months onwards. CONCLUSIONS: Among autoantibody profiles in myositis spectrum disorders, anti-MDA5+ and anti-PL7+ confer higher mortality risks. Survivors of an early peak of mortality in anti-MDA5+ disease appear to have a favourable prognosis.

UBE2L3 regulates TLR7-induced B cell autoreactivity in Systemic Lupus Erythematosus.

Both TLR7 and NF-κB hyperactivity are known to contribute to pathogenesis in Systemic Lupus Erythematosus (SLE), driving a pro-interferon response, autoreactive B cell expansion and autoantibody production. UBE2L3 is an SLE susceptibility gene which drives plasmablast/plasma cell expansion in SLE, but its role in TLR7 signalling has not been elucidated. We aimed to investigate the role of UBE2L3 in TLR7-mediated NF-κB activation, and the effect of UBE2L3 inhibition by Dimethyl Fumarate (DMF) on SLE B cell differentiation in vitro. Our data demonstrate that UBE2L3 is critical for activation of NF-κB downstream of TLR7 stimulation, via interaction with LUBAC. DMF, which directly inhibits UBE2L3, significantly inhibited TLR7-induced NF-κB activation, differentiation of memory B cells and plasmablasts, and autoantibody secretion in SLE. DMF also downregulated interferon signature genes and plasma cell transcriptional programmes. These results demonstrate that UBE2L3 inhibition could potentially be used as a therapy in SLE through repurposing of DMF, thus preventing TLR7-driven autoreactive B cell maturation.

A Systematic Review and Metaanalysis of Predictors of Mortality in Idiopathic Inflammatory Myopathy-Associated Interstitial Lung Disease.

OBJECTIVE: Idiopathic inflammatory myopathy (IIM)-associated interstitial lung disease (ILD) can range from rapidly progressive disease with high mortality to indolent disease with minimal morbidity. This systematic review and metaanalysis describe immunological, clinical, and radiographical predictors of mortality in IIM-ILD. METHODS: MEDLINE and Embase database searches were completed on October 18, 2021, to identify articles providing survival data according to baseline characteristics in patients with concurrent IIM and ILD. Prognostic factors common to more than 5 papers were included in the metaanalysis using a random-effects model to report odds ratios (ORs) for binary variables and Hedges g for continuous variables. Risk of bias was assessed using the Newcastle-Ottawa Scale score and the Egger test for publication bias. RESULTS: From 4433 articles, 62 papers were suitable for inclusion; among these studies, 38 different variables were considered. The OR for risk of death regarding the presence of anti-melanoma differentiation-associated protein 5 (MDA5) antibodies was 6.20 (95% CI 3.58-10.71), and anti-tRNA synthetase antibodies were found to be protective (OR 0.24, 95% CI 0.14-0.41). Neither antinuclear antibodies, anti-52-kDa Ro antigen antibodies, nor SSA significantly altered mortality, nor was MDA5 titer predictive. Examples of prognostic factors that are significantly associated with mortality in this study include the following: age; male sex; acute/subacute onset; clinically amyopathic dermatomyositis; dyspnea; ulceration; fever; raised C-reactive protein, ferritin, lactate dehydrogenase, alveolar to arterial O2 (A-aO2) gradient, ground-glass opacity on high-resolution computed tomography (HRCT), and overall HRCT score; and reduced albumin, lymphocytes, ratio of partial pressure of oxygen in the arterial blood to fraction of inspired oxygen (PF ratio), percentage predicted transfer factor for carbon monoxide, and percentage predicted forced vital capacity. Baseline surfactant protein-D and Krebs von den Lungen-6 levels were not predictors of mortality. CONCLUSION: Many mortality risk factors were identified, though heterogeneity was high, with a low quality of evidence and a risk of publication bias. Studies regarding anti-MDA5 antibody-positive disease and and those from East Asia predominate, which could mask risk factors relevant to other IIM subgroups or populations.

Validation of methods to identify people with idiopathic inflammatory myopathies using hospital episode statistics.

Objective: Hospital episode statistics (HES) are routinely recorded at every hospital admission within the National Health Service (NHS) in England. This study validates diagnostic ICD-10 codes within HES as a method of identifying cases of idiopathic inflammatory myopathies (IIMs). Methods: All inpatient admissions at one NHS Trust between 2010 and 2020 with relevant diagnostic ICD-10 codes were extracted from HES. Hospital databases were used to identify all outpatients with IIM, and electronic care records were reviewed to confirm coding accuracy. Total hospital admissions were calculated from NHS Digital reports. The sensitivity and specificity of each code and code combinations were calculated to develop an optimal algorithm. The optimal algorithm was tested in a sample of admissions at another NHS Trust. Results: Of the 672 individuals identified by HES, 510 were confirmed to have IIM. Overall, the positive predictive value (PPV) was 76% and sensitivity 89%. Combination algorithms achieved PPVs between 89 and 94%. HES can also predict the presence of IIM-associated interstitial lung disease (ILD) with a PPV of 79% and sensitivity of 71%. The optimal algorithm excluded children (except JDM code M33.0), combined M33.0, M33.1, M33.9, M36.0, G72.4, M60.8 and M33.2, and included M60.9 only if it occurred alongside an ILD code (J84.1, J84.9 or J99.1). This produced a PPV of 88.9% and sensitivity of 84.2%. Retesting this algorithm at another NHS Trust confirmed a high PPV (94.4%). Conclusion: IIM ICD-10 code combinations in HES have high PPVs and sensitivities. Algorithms tested in this study could be applied across all NHS Trusts to enable robust and cost-effective whole-population research into the epidemiology of IIM.

Skeletal muscles and Covid-19: a systematic review of rhabdomyolysis and myositis in SARS-CoV-2 infection.

OBJECTIVES: Myalgia is a widely publicised feature of Covid-19, but severe muscle injury can occur. This systematic review summarises relevant evidence for skeletal muscle involvement in Covid-19. METHODS: A systematic search of OVID and Medline databases was conducted on 16/3/2021 and updated on 28/10/2021 to identify case reports or observational studies relating to skeletal muscle manifestations of Covid-19 (PROSPERO: CRD42020198637). Data from rhabdomyolysis case reports were combined and summary descriptive statistics calculated. Data relating to other manifestations were analysed for narrative review. RESULTS: 1920 articles were identified. From these, 61 case reports/series met inclusion criteria, covering 86 rhabdomyolysis cases. Median age of rhabdomyolysis patients was 50 years, (range 6-89). 49% had either hypertension, diabetes mellitus or obesity. 77% were male. Symptoms included myalgia (74%), fever (69%), cough (59%), dyspnoea (68%). Median peak CK was 15,783U/L. 28% required intravenous haemofiltration and 36% underwent mechanical ventilation. 62% recovered to discharge and 30% died. Dyspnoea, elevated CRP and need for intravenous haemofiltration increased risk of fatal outcome. Additional articles relating to skeletal muscular pathologies include 6 possible concomitant diagnoses or relapses of idiopathic inflammatory myopathies and 10 reports of viral-induced muscle injuries without rhabdomyolysis. Localised myositis and rhabdomyolysis with SARS-CoV-2 vaccination have been reported. CONCLUSIONS: Rhabdomyolysis is an infrequent but important complication of Covid-19. Increased mortality was associated with a high CRP, renal replacement therapy and dyspnoea. The idiopathic inflammatory myopathies (IIM) may have viral environmental triggers. However, to date the limited number of case reports do not confirm an association with Covid-19.

Improved monitoring of clinical response in Systemic Lupus Erythematosus by longitudinal trend in soluble vascular cell adhesion molecule-1.

BACKGROUND: To determine whether optimal use of serial measurements of serum levels of soluble cell adhesion molecules (CAM) can improve monitoring of disease activity in SLE. METHODS: Serum levels of soluble CAM and conventional SLE biomarkers were measured in serial samples (n = 80) from 21 SLE patients during and after flare and correlated in longitudinal analysis with disease activity determined by ECLAM score. Blood samples from a second cohort of 34 SLE patients were subject to flow cytometry to correlate serum biomarkers with B cell subsets. RESULTS: By adjusting for the baseline level (at the first visit), delta soluble vascular cell adhesion molecule-1 (sVCAM-1) showed stronger correlation with changes in ECLAM score and improved sensitivity and specificity for identifying SLE responders versus non-responders compared to conventional SLE biomarkers including anti-dsDNA antibody titre and complement C3. Multiple regression analysis identified delta sVCAM-1 as the best marker of SLE clinical response. sVCAM-1 levels were significantly correlated with CD95(+)CD27(+) activated memory B cells, CD95(+) plasmablasts and circulating plasma cell numbers in SLE patients. CONCLUSION: Subtracting a baseline level of sVCAM-1 for each individual substantially improved its utility as a biomarker. Delta sVCAM-1 was superior to conventional SLE biomarkers for monitoring changes in disease activity. This suggests that serial monitoring of serum sVCAM-1 trends should be considered in SLE patients to document responses to treatment. We hypothesise that the correlation between activated B cell subsets and circulating plasma cell numbers with soluble VCAM-1 serum levels in SLE may relate to the important role of VCAM-1 in B lymphocyte survival and maturation in bone marrow and secondary lymphoid tissues.

UBE2L3 polymorphism amplifies NF-κB activation and promotes plasma cell development, linking linear ubiquitination to multiple autoimmune diseases.

UBE2L3 is associated with increased susceptibility to numerous autoimmune diseases, but the underlying mechanism is unexplained. By using data from a genome-wide association study of systemic lupus erythematosus (SLE), we observed a single risk haplotype spanning UBE2L3, consistently aligned across multiple autoimmune diseases, associated with increased UBE2L3 expression in B cells and monocytes. rs140490 in the UBE2L3 promoter region showed the strongest association. UBE2L3 is an E2 ubiquitin-conjugating enzyme, specially adapted to function with HECT and RING-in-between-RING (RBR) E3 ligases, including HOIL-1 and HOIP, components of the linear ubiquitin chain assembly complex (LUBAC). Our data demonstrate that UBE2L3 is the preferred E2 conjugating enzyme for LUBAC in vivo, and UBE2L3 is essential for LUBAC-mediated activation of NF-κB. By accurately quantifying NF-κB translocation in primary human cells from healthy individuals stratified by rs140490 genotype, we observed that the autoimmune disease risk UBE2L3 genotype was correlated with basal NF-κB activation in unstimulated B cells and monocytes and regulated the sensitivity of NF-κB to CD40 stimulation in B cells and TNF stimulation in monocytes. The UBE2L3 risk allele correlated with increased circulating plasmablast and plasma cell numbers in SLE individuals, consistent with substantially elevated UBE2L3 protein levels in plasmablasts and plasma cells. These results identify key immunological consequences of the UBE2L3 autoimmune risk haplotype and highlight an important role for UBE2L3 in plasmablast and plasma cell development.

Immunosuppressant and immunomodulatory treatment for dermatomyositis and polymyositis.

BACKGROUND: Idiopathic inflammatory myopathies are chronic diseases with significant mortality and morbidity. Whilst immunosuppressive and immunomodulatory therapies are frequently used, the optimal therapeutic regimen remains unclear. This is an update of a review first published in 2005. OBJECTIVES: To assess the effects of immunosuppressants and immunomodulatory treatments for dermatomyositis and polymyositis. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (August 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 3 2011), MEDLINE (January 1966 to August 2011), EMBASE (January 1980 to August 2011) and clinicaltrials.gov (August 2011). We checked the bibliographies of identified trials and wrote to disease experts. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) or quasi-RCTs involving participants with probable or definite dermatomyositis and polymyositis as defined by the criteria of Bohan and Peter, or definite, probable or mild/early by the criteria of Dalakas. In participants without a classical rash of dermatomyositis, inclusion body myositis should have been excluded by muscle biopsy. We considered any immunosuppressant or immunomodulatory treatment. The two primary outcomes were the change in a function or disability scale measured as the proportion of participants improving one grade, two grades etc, predefined based on the scales used in the studies after at least six months, and a 15% or greater improvement in muscle strength compared with baseline after at least six months. Other outcomes were: the International Myositis Assessment and Clinical Studies Group (IMACS) definition of improvement, number of relapses and time to relapse, remission and time-to-remission, cumulative corticosteroid dose and serious adverse effects. DATA COLLECTION AND ANALYSIS: Two authors independently selected papers, extracted data and assessed risk of bias in included studies. They collected adverse event data from the included studies. MAIN RESULTS: The review authors identified fourteen 14 relevant RCTs. They excluded four trials.The 10 included studies, four of which have been added in this update, included a total of 258 participants. Six studies compared an immunosuppressant or immunomodulator with placebo control, and four studies compared two immunosuppressant regimes with each other. Most of the studies were small (the largest had 62 participants) and many of the reports contained insufficient information to assess risk of bias.Amongst the six studies comparing immunosuppressant with placebo, one study, investigating intravenous immunoglobulin (IVIg), showed statistically significant improvement in scores of muscle strength in the IVIg group over three months. Another study investigating etanercept showed some evidence of a steroid sparing effect, a secondary outcome in this review, but no improvement in other assessed outcomes. The other four randomised placebo-controlled trials assessed either plasma exchange and leukapheresis, eculizumab, infliximab or azathioprine against placebo and all produced negative results.Three of the four studies comparing two immunosuppressant regimes (azathioprine with methotrexate, ciclosporin with methotrexate, and intramuscular methotrexate with oral methotrexate plus azathioprine) showed no statistically significant difference in efficacy between the treatment regimes. The fourth study comparing pulsed oral dexamethasone with daily oral prednisolone and found that the dexamethasone regime had a shorter median time to relapse but fewer side effects.Immunosuppressants were associated with significant side effects. AUTHORS' CONCLUSIONS: This systematic review highlights the lack of high quality RCTs that assess the efficacy and toxicity of immunosuppressants in inflammatory myositis.

Clinical and radiological features of rheumatoid arthritis in British black Africans.

The objective of this study was to determine whether radiographic damage is different in British black African patients with rheumatoid arthritis compared to Caucasian patients. Data on demographics, disease- and disability-related variables were obtained from all black African patients and their age-, gender- and disease-duration-matched Caucasian controls. After all features identifying the patients were concealed, X-rays of hands and feet were scored by using the Sharp/van der Heijde method. Data were analysed using Mann-Whitney U test, t test and chi (2) test. Sixty-four patients (32 in each ethnic group) were studied. The median age was 52 years and median disease duration 6 years. Seventy-two percent of patients were female. Black Africans and Caucasians did not differ significantly in rheumatoid factor positivity, disease-modifying anti-rheumatic drugs and biological treatment use. British black African patients had significantly more tender joints and disability. Joint space narrowing was significantly greater in Caucasian patients [48 (27-85) vs 56 (34-107), p = 0.01]. Caucasian patients had more number of erosions (172 vs 220) and higher erosion score; however, the difference in the erosion scores was not statistically significant [2 (0-48) vs 4.5 (0-46), p = 0.17]. Radiographic damage was less severe in black African patients with rheumatoid arthritis compared to their age-, gender- and disease-duration-matched Caucasian controls. A large prospective study is required to confirm the findings of this study and to establish the factors which might be accountable for any differences in the expression of rheumatoid arthritis in this ethnic group.

Presentation and prognosis of the shrinking lung syndrome in systemic lupus erythematosus.

BACKGROUND AND OBJECTIVES: Systemic lupus erythematosus (SLE) may affect all the components of the respiratory system, including upper airways, lung parenchyma, pulmonary vasculature, pleura, and respiratory muscles. The shrinking lung syndrome (SLS) is a rare complication of SLE. This study describes the presenting features, investigation findings, treatment measures, and outcome of 7 patients with SLE and SLS. METHODS: Five patients with SLE/SLE were chosen retrospectively by examination of patient records, and 2 patients were chosen prospectively. All patients attended St. Thomas' Hospital or the Royal London Hospital between 1984 and 2001, with a total population of 2650 patients with SLE. RESULTS: Clinical features included dyspnea and pleuritic chest pain. Chest x-ray films showed small but clear lung fields, or basal atelectasis, with diaphragmatic elevation. No evidence of major parenchymal lung or pleural disease was found on the computerized tomography scan. Lung volumes were reduced on pulmonary function testing (PFT) in a restrictive pattern. Treatment of SLS included theophylline, increase in corticosteroid dosage, and intensification of immunosuppressive medication to include methotrexate or cyclophosphamide. During follow-up, 5 of 7 patients showed objective evidence on PFT of stabilization or improvement. CONCLUSIONS: The long-term prognosis of our SLS patients was reasonable, highlighting the importance of establishing a correct diagnosis and in particular differentiating it from fibrosing lung disease. Immunosuppressive therapy was helpful in stabilizing SLS and improving respiratory symptoms and PFT in some cases. RELEVANCE: SLS represents a rare complication of SLE, and it is important to be aware of its presenting features and prognosis.