Josep Maria Grau-Junyent

Usefulness of anti‐p155 autoantibody for diagnosing cancer‐associated dermatomyositis: A systematic review and meta‐analysis

OBJECTIVE Anti-p155 autoantibody, which was recently described in adult patients with dermatomyositis (DM), seems to be associated with cancer in this population. We performed a systematic review and meta-analysis to ascertain the accuracy of anti-p155 testing for the diagnosis of cancer-associated myositis. METHODS We searched relevant databases, with no restrictions on study design or language, for original studies that included adult patients with probable/definite DM or amyopathic DM who were evaluated for neoplasm and anti-p155 status. Pooled sensitivity and specificity were calculated using a bivariate model. We computed the diagnostic odds ratio (OR), likelihood ratios (LRs) for positive and negative test results, positive and negative predictive values, and the summary receiver operating characteristic (SROC) curve. Statistical heterogeneity between studies was assessed using the I(2) statistic, and 95% confidence intervals (95% CIs) were computed for the parameters studied. RESULTS Six studies including a total of 312 adult patients with DM were selected. The pooled sensitivity of anti-p155 for diagnosing cancer-associated DM was 78% (95% CI 45-94%), and specificity was 89% (95% CI 82-93%). The diagnostic OR was 27.26 (95% CI 6.59-112.82), and LRs for positive and negative test results were 6.79 (95% CI 4.11-11.23) and 0.25 (95% CI 0.08-0.76), respectively. Heterogeneity was substantial except with regard to the LR for a positive test result. The area under the SROC curve was 0.91 (95% CI 0.88-0.93). Taking the pooled prevalence of 17% as pretest probability, anti-p155 had a positive predictive value of 58% and a negative predictive value of 95%. CONCLUSION Our findings indicate that anti-p155 autoantibody determination is useful for diagnosing cancer-associated myositis and guiding disease management.

On the relationship between nociceptive evoked potentials and intraepidermal nerve fiber density in painful sensory polyneuropathies

&NA; This study analyzed the relationship between the density of intraepidermal nerve fibers (IENF) and the characteristics of either nociceptive laser‐evoked potentials (LEPs) or contact heat‐evoked potentials (CHEPs) in patients with painful sensory polyneuropathy with the aim to determine which parameters of LEPs and CHEPs more reliably reflect IENF loss. A total of 96 patients and 35 healthy volunteers took part in the study. Based on clinical examination, nerve conduction tests, and quantitative sensory testing, we identified 52 patients with small‐fiber neuropathy (SFN), 40 with mixed (small‐fiber and large‐fiber) neuropathy (MFN), and 4 who were excluded from the analysis because of no evidence of involvement of small fibers. The latency of the N2 was delayed for both LEPs and CHEPs in patients with MFN and for CHEPs only in patients with SFN. The amplitude of the vertex N2/P2 potential was similarly reduced in both types of neuropathy, but LEPs were more frequently absent than CHEPs in MFN patients (68% vs 40%). In general, latency and amplitude of LEPs and CHEPs were well correlated with IENF density. SFN patients were characterized by abnormal EPs and slightly decreased but morphologically abnormal IENF. MFN patients were characterized by frequently absent LEPs and CHEPs and a rather severe IENF loss. The correlation between nociceptive evoked potentials (laser‐evoked potentials and contact heat‐evoked potentials) and skin biopsy aids in the diagnosis of painful neuropathies.

Epidermal Langerhans cells in small fiber neuropathies.

Summary Subjects with painful small fiber neuropathy, specially in the context of diabetics, had an increased number of the proinflammatory Langerhans cells at the skin. ABSTRACT We quantified the immune histiocytic Langerhans cells (LCs) in skin biopsy samples of patients with distal small fiber neuropathy (SFN). Patients were divided according to the presence or absence of neuropathic pain (burning pain) assessed by a visual analogue scale (VAS). We studied 13 diabetic patients (pain‐DSFN), 7 nondiabetic patients (pain‐SFN) who reported relevant neuropathic pain (VAS ⩾3), and 6 nondiabetic patients without neuropathic pain (no‐pain‐SFN). Using double immunofluorohistochemistry with the PGP 9.5 and the langerin/CD207, we quantified the intraepidermal nerve fibers density (IENFD) and LCs per square millimeter in the epidermis. A group of 10 skin samples from healthy subjects served as controls. Confocal analysis was performed to evaluate LC PGP 9.5‐immunoreactivity. We found a mean value of 334.3 LC/mm2 in controls, 310.2 LC/mm2 in no‐pain‐SFN, 329.6 LC/mm2 in pain‐SFN and 484.3 LC/mm2 in pain‐DSFN (analysis of variance; P = .01). In patients, analysis of covariance adjusted by different covariables showed that the presence of diabetes (F = 5.2, P = .03) was associated with an increased number of LC/mm2. There was a negative correlation between the IENFD and the number of LCs (r2 = −0.13, P = .03). No statistically significant differences were found among groups of subjects either for the co‐localization or for the number of LCs that were PGP 9.5‐immunoreactive (analysis of variance; P > .05). These results indicate that patients with neuropathic pain in the context of SFN, specially those who had diabetes (DSFN), had an increased number of LCs in the epidermis that may play a role in the generation or maintenance of neuropathic pain.

Clinical manifestations and long-term outcome of anti-Jo1 antisynthetase patients in a large cohort of Spanish patients from the GEAS-IIM group

OBJECTIVE To evaluate the clinical manifestations, long-term clinical outcome and longitudinal pulmonary function in a large cohort of Spanish patients with anti-Jo1 antibodies. METHODS We retrospectively analyzed the clinical data and lung function parameters of 148 anti-Jo1 patients recruited from a multicentre registry including 18 Spanish hospitals. A composite endpoint was defined, comprising death due to respiratory failure directly related to antisynthetase syndrome (ASS), the need for long-term oxygen therapy or lung transplantation. RESULTS Median follow-up was 78.3 months. Clinical presentation patterns at onset are as follows: isolated interstitial lung disease (ILD) (32.4%), isolated myositis (26.9%), concomitant myositis and ILD (22.8%), and isolated polyarthritis (17.9%). Myositis with ILD was the most frequent final clinical phenotype (67.6%). In most ASS patients, ILD was a non-progressive disease, tending to stabilize with therapy. The endpoint was reached in a significantly larger number of ILD patients with dyspnea at onset than those with paucisymptomatic or asymptomatic forms (p = 0.01). A steady FVC decrease was the hallmark of patients with end-stage lung disease. Estimated survival rates were 87.7% and 75.4% at 5 and 10 years, respectively. Cancer (p = 0.02) and advanced age at ASS diagnosis (p < 0.0001) were related to poorer survival. Mortality was significantly higher than in the general Spanish population, with a standardised mortality ratio (95% CI) of 4.03 (2.79-5.64). CONCLUSIONS Anti-Jo1 ASS is a heterogeneous syndrome. ILD in ASS under immunosuppressive therapy is mainly a non-progressive disease. Dyspnea at ILD onset and a steady FVC decrease over time were related to a poorer respiratory prognosis.

Axonal fluorescence quantitation provides a new approach to assess cutaneous innervation.

We present a novel approach to quantify skin innervation by measuring the PGP 9.5 immunoreactive (PGP-ir) fluorescence corresponding to axons within the epidermis and dermis. The skin biopsies from 35 controls and 45 small fiber neuropathy (SFN) patients were included. In 50-μm free-floating sections, we determined the intraepidermal nerve fiber density (IENFD) by direct fluorescence visualization and captured 2-μm thick individual optical sections using the same confocal microscope and magnification. We measured the fluorescence of the PGP-ir axons in both, epidermal and dermal area by using the ImageJ software. There was good interobserver and intraobserver reliability of PGP-ir measures, similar than for IENFD. The PGP-ir axons were found decreased in patients with SFN (1.1‰ and 9.0‰ respectively for epidermal and dermal area in contrast to 2.2‰ and 16.0‰, respectively to controls). The area under the ROC curve was 0.90 for the IENFD, 0.84 for epidermal PGP-ir axons and 0.70 for dermal PGP-ir axons. There was a positive correlation between the IENFD and the PGP-ir axons at epidermis (Spearman Rho=0.66, p<0.001) as well as for the dermal nerve length and the PGP-ir axons at dermis (Spearman Rho=0.45, p<0.05). This method is also particularly adequate for the quantitation of dermal nerve fibers. We conclude that quantifying the fluorescent PGP-ir axons could help to assess skin innervation (dermal and epidermal nerve fibers) in patients with SFN.

Inflammatory myopathy: diagnosis and clinical course, specific clinical scenarios and new complementary tools

Idiopathic inflammatory myopathies are a heterogeneous group of rare autoimmune diseases characterized by symmetric proximal muscle weakness and inflammatory infiltrates on muscle biopsy. A meticulously collected combination of clinical, serological, and pathological data is essential to correctly diagnose and classify myositis patients, often a considerable challenge for clinicians. This article provides a comprehensive overview of the most useful tools for the diagnosis and follow-up of patients with myositis. Capillaroscopy, serological biomarkers (particularly the autoantibody profile) and imaging techniques, such as muscle magnetic resonance and chest ultrasound, are of great aid in diagnosing, classifying and managing these patients. Relevant clinical scenarios, such as interstitial lung disease, associated cancer and pregnancy are also addressed in this review. Myositis registries, identification of new autoantibodies, and genetic studies will enhance our understanding of the pathogenesis of these conditions and help to define new diagnostic and therapeutic approaches.

Statin-induced myalgia and myositis: an update on pathogenesis and clinical recommendations

ABSTRACT Introduction: Musculoskeletal manifestations are well-recognized side effects of treatment with statins. New advances in this field have appeared in recent years. This review focuses on the diagnosis of these conditions and their underlying pathogenesis, in particular immune-mediated necrotizing myopathy. Areas covered: Clinical phenotypes including rhabdomyolysis, myalgia and/or mild hyperCKemia, self-limited toxin statin myopathy, and immune-mediated necrotizing myopathy are herein described. Therapeutic recommendations and a diagnostic algorithm in statin-associated myopathy are also proposed. The etiology and pathogenesis of statin-induced myopathy has mainly focused on the anti-HMGCR antibodies and the responsibility of the immune-mediated necrotizing myopathy is discussed. The fact that patients who have not been exposed to statins may develop statin-associated autoimmune myopathy with anti-HMGCR antibodies is also addressed. The literature search strategy included terms identified by searches of PubMed between 1969 and December 2017. The search terms ‘myositis’, ‘statin-induced autoimmune myopathy’, ‘immune-mediate necrotizing myopathy’, ‘statins’, ‘muscular manifestations’, and ‘anti-HMGCR antibodies’ were used. Expert commentary: Full characterization of the known phenotypes of statin toxicity and the specific role of the anti-HMGCR in those exposed and not exposed (i.e. juvenile forms) to statins and in some types of neoplasms is of paramount relevance.

Miopatías inflamatorias idiopáticas

Estudio descriptivo y retrospectivo de una serie de 35 pacientes con miopatia inflamatoria idiopatica, que a partir de la recogida de variables clinicas, de laboratorio y patologicas, se propone los siguientes objetivos: caracterizar a este grupo de enfermedades, clasificar a los pacientes en subgrupos en funcion de criterios histopatologicos y caracterizar los distintos subgrupos analizando que variables permiten diferenciar mejor cada categoria.

Classification and management of adult inflammatory myopathies

Inflammatory myopathies, collectively known as myositis, are heterogeneous disorders characterised by muscle inflammation, and frequently accompanied by extramuscular manifestations that affect the skin, lung, and joints. Patients with inflammatory myopathies were previously classified as having dermatomyositis if characteristic rashes accompanied the muscle involvement, and as having polymyositis if no rashes were present. Five main types of inflammatory myopathies are now widely recognised: dermatomyositis, immune-mediated necrotising myopathy, sporadic inclusion-body myositis, overlap myositis (including antisynthetase syndrome), and polymyositis. The discovery of autoantibodies that are specifically associated with characteristic clinical phenotypes has been instrumental to the understanding of inflammatory myopathies. Treatment is still largely based on expert opinion, but several studies have shown effectiveness of different therapies in various subsets of inflammatory myopathies. These advances will undoubtedly improve the outcomes of patients with inflammatory myopathies.

FRI0463 Survival and Mortality Analysis in a Large Cohort of Spanish Patients with Anti-JO1 Antisynthetase Syndrome from the Geas-IIM Group

Background Antisynthetase syndrome (ASS) can be a life-threatening condition. Patients with ASS in the context of idiopathic inflammatory myositis (IIM) have been described to have a worse prognosis compared to patients either with dermatomyositis (DM) or polymyositis (PM) alone. Objectives To evaluate survival and mortality in a large cohort of Spanish patients with anti-Jo1 ASS and compare it with mortality rates of Spanish general population. Methods From March 2011 to June 2014 we conducted a national multicentre study, including retrospective and prospective data, among members of the GEAS-IIM Group of the SEMI. Clinicians from 18 Spanish centers participated in the development of a registry of patients with Anti-Jo1 ASS. For data collection a specific electronic database including broad information about demographic and clinical data was developed. Continuous variables were compared by the t-student or non-parametric Mann-Whitney tests when appropriated, while X2 test were used to compare categorical variables. The Kaplan-Meier method and long-rank tests were used to compare survival between groups. The standardized mortality ratio (SMR) was calculated using the Spanish mortality registry. Results were expressed with its 95% interval confiance (IC). Results A total of 148 anti-Jo1 ASS patients, 90 women (60.8%), were included in the study. Mean (SD) age at diagnosis was 50.8 (16) years. Range follow-up was 1.3 to 412 months [mean (SD) 95 (76.4) months], with only 12 patients with a follow-up fewer than 12 months. Fifteen percent of patients had ILD as the unique main ASS clinical manifestation, other 15% had myositis and 69.3% had both ILD and myositis. Thirty seven patients (25%) died after a median follow-up of 70.3 months (range 4.9 – 308 months). The SMR (95%IC) was 4.77 (3.31-6.67). Main causes of death included respiratory failure (6.8%), cancer (6.1%), infection (4.1%), myositis (2.7%) and acute cardiovascular events (1.3%). A directly ASS-related death were considered in 18 patients (46.6%). Estimated survival rate (95% IC) was 87.5% (81.6% - 93.4%) and 75.4% (66.4% - 84.4%) at 5 and 10 years respectively. Median survival rate (95% IC) was 20.3 years (13.8-26.8 years). No difference in survival was found between patients with myositis (DM or PM) and those with ILD without associated myopathy. The presence of cancer (p=0.02) and an advanced age at ASS diagnosis (p<0.0001) were the unique clinical features significantly related to poorer survival rates. Conclusions Mortality in ASS patients is four-fold and a half higher than in the general population. Mortality can be directly attributed to ASS in near a half of the cases. Respiratory failure, cancer and infection are the main causes of death. Estimated survival rate at 10 years is around 75%. References Marie I. Morbidity and mortality in adult polymyositis and dermatomyositis. Curr Rheumatol Rep.2012;14:275-285. Disclosure of Interest None declared