Clinical spectrum time course in non-Asian patients positive for anti-MDA5 antibodies.

OBJECTIVES: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. METHODS: We conducted a multicentre, international, retrospective cohort study. RESULTS: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. CONCLUSIONS: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern.

An Italian Multicenter Study on Anti-NXP2 Antibodies: Clinical and Serological Associations.

The identification of anti-NXP2 antibodies is considered a serological marker of dermatomyositis (DM), with calcinosis, severe myositis and, in some reports, with cancer. Historically, these associations with anti-NXP2 antibodies have been detected by immunoprecipitation (IP), but in the last few years commercial immunoblotting assays have been released. The aim of this collaborative project was to analyse the clinical features associated to anti-NXP2 antibodies, both with commercial line blot (LB) and IP. Myositis-specific and myositis-associated autoantibodies were detected in single centres by commercial line blot (LB); available sera were evaluated in a single centre by protein and RNA immunoprecipitation (IP), and IP-Western blot. Sixty patients anti-NXP2+ (NXP2+) positive by LB were compared with 211 patients anti-NXP2 negative with idiopathic inflammatory myositis (IIM). NXP2+ showed a younger age at IIM onset (p = 0.0014), more frequent diagnosis of dermatomyositis (p = 0.026) and inclusion-body myositis (p = 0.009), and lower rate of anti-synthetase syndrome (p < 0.0001). As for clinical features, NXP2+ more frequently develop specific skin manifestations and less frequently features related with overlap myositis and anti-synthetase syndrome. IP confirmed NXP2 positivity in 31 of 52 available sera (62%). Most clinical associations were confirmed comparing NXP2 LB+/IP+ versus NXP2-negative myositis, with the following exceptions: inclusion-body myositis diagnosis was not detected, whilst dysphagia and myositis were found more frequently in NXP2 LB+/IP+ patients. The 21 LB+ /IP-myositis patients did not show differences in clinical features when compared with the NXP2-myositis patients and more frequently displayed multiple positivity at LB. Risk of developing cancer-associated myositis was similar between NXP2-positive and NXP2-negative myositis patients, either when detected by LB or IP. Protein-IP confirmed NXP2 antibodies in nearly 60% of sera positive for the same specificity with commercial assay. Double-positive cases rarely occurred in myositis patients with a clinical diagnosis other than dermatomyositis. Patients only positive by LB (LB+/IP-) did not display clinical features typical of NXP2. NXP2 positivity by LB should be confirmed by other methods in order to correctly diagnose and characterize patients affected by idiopathic inflammatory myositis.

The clinical phenotype of systemic sclerosis patients with anti-PM/Scl antibodies: results from the EUSTAR cohort.

OBJECTIVE: To evaluate clinical associations of anti-PM/Scl antibodies in patients with SSc in a multicentre international cohort, with particular focus on unresolved issues, including scleroderma renal crisis (RC), malignancies, and functional outcome of interstitial lung disease (ILD). METHODS: (1) Analysis of SSc patients from the EUSTAR database: 144 anti-PM/Scl+ without SSc-specific autoantibodies were compared with 7202 anti-PM/Scl-, and then to 155 anti-Pm/Scl+ with SSc-specific antibodies. (2) Case-control study: additional data were collected for 165 anti-PM/Scl+ SSc patients (85 from the EUSTAR registry) and compared with 257 anti-PM/Scl- SSc controls, matched for sex, cutaneous subset, disease duration and age at SSc onset. RESULTS: Patients with isolated anti-PM/Scl+, as compared with anti-Pm/Scl-, had higher frequency of muscle involvement, ILD, calcinosis and cutaneous signs of DM, but similar frequency of SRC and malignancies (either synchronous with SSc onset or not). The presence of muscle involvement was associated with a more severe disease phenotype. Although very frequent, ILD had a better functional outcome in cases than in controls. In patients with both anti-PM/Scl and SSc-specific antibodies, a higher frequency of typical SSc features than in those with isolated anti-PM/Scl was observed. CONCLUSION: The analysis of the largest series of anti-PM/Scl+ SSc patients so far reported helps to delineate a specific clinical subset with muscle involvement, cutaneous DM, calcinosis and ILD characterized by a good functional outcome. SRC and malignancies do not seem to be part of this syndrome.

Epidemiology of systemic sclerosis: a multi-database population-based study in Tuscany (Italy).

BACKGROUND: Systemic Sclerosis (SSc) is a chronic autoimmune disease with a complex pathogenesis that includes vascular injury, abnormal immune activation, and tissue fibrosis. We provided a complete epidemiological characterization of SSc in the Tuscany region (Italy), considering prevalence and incidence, survival, comorbidities and drug prescriptions, by using a multi-database population-based approach. Cases of SSc diagnosed between 1st January 2003 and 31st December 2017 among residents in Tuscany were collected from the population-based Rare Diseases Registry of Tuscany. All cases were linked to regional health and demographic databases to obtain information about vital statistics, principal causes of hospitalization, complications and comorbidities, and drug prescriptions. RESULTS: The prevalence of SSc in Tuscany population resulted to be 22.2 per 100,000, with the highest prevalence observed for the cases aged ≥ 65 years (33.2 per 100,000, CI 95% 29.6-37.3). In females, SSc was predominant (86.7% on the total) with an overall sex ratio F/M of 6.5. Nevertheless, males presented a more severe disease, with a lower survival and significant differences in respiratory complications and metabolic comorbidities. Complications and comorbidities such as pulmonary involvement (HR = 1.66, CI 95% 1.17-2.35), congestive heart failure (HR = 2.76, CI 95% 1.80-4.25), subarachnoid and intracerebral haemorrhage (HR = 2.33, CI 95% 1.21-4.48) and malignant neoplasms (HR = 1.63, CI 95% 1.06-2.52), were significantly associated to a lower survival, also after adjustment for age, sex and other SSc-related complications. Disease-modifying antirheumatic drugs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors were the drugs with the more increasing prevalence of use in the 2008-2017 period. CONCLUSIONS: The multi-database approach is important in the investigation of rare diseases where it is often difficult to provide accurate epidemiological indicators. A population-based registry can be exploited in synergy with health databases, to provide evidence related to disease outcomes and therapies and to assess the burden of disease, relying on a large cohort of cases. Building an integrated archive of data from multiple databases linking a cohort of patients to their comorbidities, clinical outcomes and survival, is important both in terms of treatment and prevention.

The impact of skin calcinosis on digital ulcers in patients with SSc: clinical and prognostic stratification using the "wound bed score".

Digital ulcers (DUs) represent one of the major burdens for patients with systemic sclerosis (SSc), especially when associated with skin calcinosis (SC). The aim of this work is to evaluate the impact of SC in DUs of patients with SSc for clinical characteristics and prognosis assessed by the wound bed score (WBS). We prospectively enrolled 55 patients with DUs and SSc followed in our dedicated wound care clinic. For all the patients we collected clinical and anthropometric data and characteristics of the DU, and we calculated the WBS for each DU. Ninety-nine DUs were evaluated (24 with SC). SC was prevalent in limited cutaneous SSc (75%) and in patients with longer disease duration (P = 0.02). SC-DUs were prevalent at the fingertip (P = 0.04). The healing time was significantly higher in patients with SC (10.4 ± 7.9 weeks) compared with non-SC (7.0 ± 5.7 weeks) P = 0.03. The WBS negatively correlated with the time to achieve complete healing (r = -0.237 P = 0.023) and the correlation was maintained in the non-SC (r = -0.46, P = 0.033). DUs in SSc patients with SC are common and difficult to heal. When DUs are treated in dedicated centres, the prognosis is good. The WBS is fast and easy and maybe commonly applied in clinical practice.

Risk factors for relapse and long-term outcome of idiopathic retroperitoneal fibrosis.

BACKGROUND: Retroperitoneal fibrosis (RF) is a rare disease of unclear etiology characterized by the presence of fibroinflammatory tissue in the retroperitoneal space, which can entrap and obstruct retroperitoneal structures, notably the ureters. The disease responds well to steroid therapy, but tends to recur even after years. The aim of our study was to evaluate the long-term renal outcome of patients affected by idiopathic retroperitoneal fibrosis looking for predictive risk factors for recurrence of the disease and progression to end-stage renal disease. METHODS: Retrospective observational study of patients with idiopathic RF diagnosed from 2004 to 2017 and follow-up of at least 1 year after the end of first course therapy with steroid, with or without tamoxifen (TMX) and with urological procedures when applicable. RESULTS: Forty-three patients were included in the study. The follow-up was 93 ± 52 months. All the patients obtained remission after therapy that was maintained until the last observation in 26 of them. In 17 patients, there was at least one recurrence. Risk factors associated with relapse were identified and resulted in smoking habit, onset with acute kidney injury (AKI), low back pain and antinuclear antibodies (ANA) positivity. Renal function remained fairly stable during the long-term follow-up. The renal end-point (doubling of serum creatinine or ESRD) occurred in 8% of the patients; however, eGFR in patients with relapse was similar to that of non-recurrent at the diagnoses, but it decreased over time more in the relapsing than in non-relapsing patients (p group = 0.20; p time = 0.001; p time × group interactions = 0.04). Based on these 4 predictor conditions, patients were divided into "low risk" (with 0-1 risk factor), and "high risk" (3-4 risk factors). The renal end-point occurred in 40% of high-risk patients, while none of the low-risk patients reached it (p = 0.02). CONCLUSIONS: Smoking habit, AKI at diagnosis, ANA positivity and lumbar pain were associated with relapse of RF after initial remission due to steroid and/or TMX therapy; the combination of these conditions was also predictive of worse renal function outcome. Identification of risk factors for relapse can be useful not only to modulate the choice, the dosage of first-line treatment and the duration of maintenance therapy but also for preventing a progressive loss of kidney function, as well.

Cardiometabolic risk and subclinical vascular damage assessment in idiopathic inflammatory myopathies: a challenge for the clinician.

OBJECTIVES: A high prevalence of cardiovascular disease (CVD), not fully explained by the prevalence of traditional risk factors only, is reported in patients with idiopathic inflammatory myopathies (IIMs). Thus, we investigated if novel markers of CVD risk, like carotid diameter and advanced glycated end products, can better predict increased CVD risk in IIM patients. METHODS: We studied 43 consecutive patients diagnosed with IIM. All the patients underwent a clinical and laboratory evaluation of cardiovascular risk factors and characterisation of myositis disease activity. Non-invasive instrumental examinations performed included the measurement of carotid parameters (intima-media thickness, IMT and mean arterial diameter, mAD) by ultrasonic techniques, advanced glycation end-product accumulation in the skin by autofluorescence (AF) and body composition by bioelectrical impedance analysis. The parameters were compared to those measured in 29 controls, with similar mean age, BMI, blood pressure and smoking habits. RESULTS: IIM patients showed normal carotid IMT and distensibility, but higher carotid mAD (p=0.012), higher skin AF (p<0.001), lower fat free mass (p=0.036) and increased waist circumference compared to controls. A significant correlation was observed among AF and mAD (rho=0.317 p<0.05), carotid distension (rho=0.391 p=0.036) and IMT (rho=0.627 p<0.001). CONCLUSIONS: Abnormalities of the studied parameters suggest a higher risk of CV disease in IIM patients independent of disease activity. In this population, a thorough assessment of CV risk is recommended also in absence of overt CV disease during the clinical evaluation.

Myositis an evolving spectrum of disease.

The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of disorders characterized, as common feature, by inflammation of skeletal muscle and muscle weakness. Traditionally, IIMs have been subclassified in into polymyositis, dermatomyositis and inclusion body myositis, but this subclassification has several limitations, because clinical features as well as treatment response vary within the three IIM subgroups. In the last years several novel autoantibodies in patients with IIMs have been identified. These autoantibodies can be myositis-specific autoantibodies (MSAs) or myositis-associated autoantibodies (MAAs) and they may lead to a new approach to the classification of IIMs. This novel approach could help to subdivide patients in more homogeneous groups because, it is very rare that a patient has more than one MSAs positivity and each autoantibody is frequently associated with specific clinical features. Moreover, MSAs can help to identify subsets of IIMs also without muscular symptoms, like patients in which skin manifestations, arthritis or interstitial lung disease represent the main clinical feature. Additionally, as some autoantibodies may be associated to markedly severe manifestations, such as cancer or rapidly progressive interstitial lung disease, they can also provide a prognostic stratification of the patients.

Idiopathic inflammatory myopathies: state of the art on clinical practice guidelines [corrected].

Idiopathic inflammatory myopathies (IIMs) encompass a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and inflammation, but in antisynthetase syndrome arthritis and interstitial lung disease are more frequent and often inaugurate the disease. Clinical practice guidelines (CPGs) have been proposed for IIMs, but they are sparse and heterogeneous. This work aimed at identifying: i) current available CPGs for IIMs, ii) patients ' and clinicians' unmet needs not covered by CPGs. It has been performed in the framework of the European Reference Network on rare and complex connective tissue and musculoskeletal diseases (ReCONNET), a network of centre of expertise and patients funded by the European Union's Health Programme. Fourteen original CPGs were identified, notably recommending that: i) extra-muscular involvements should be assessed; ii) corticosteroids and methotrexate or azathioprine are first-line therapies of IIMs. ii) IVIG is a treatment of resistant-DM that may be also used in other resistant-IIMs; iii) physical therapy and sun protection (in DM patients) are part of the treatment; v) tumour screening for patients with DM include imaging of chest, abdomen, pelvis and breast (in woman) along with colonoscopy (in patients over 50 years); vi) disease activity and damages should be monitor using standardised and validated tools. Yet, only half of these CPGs were evidence-based. Crucial unmet needs were identified both by patients and clinicians. In particular, there was a lack of large multidisciplinary working group and of patients ' preferences. The following fields were not or inappropriately targeted: diagnosis; management of extra-muscular involvements other than skin; co-morbidities and severe manifestations.

Muscular vasculitis confined to lower limbs: description of two case reports and a review of the literature.

Muscular involvement is common during systemic vasculitides, such as polyarteritis nodosa. However, in rare cases, muscular involvement can be the only clinically evident feature of the disease. The clinical pattern of isolated muscular vasculitis may mimic several other inflammatory muscle disorders, such as idiopathic inflammatory myositis, and may represent a challenge in differential diagnosis. Herewith, we present two clinical cases as examples of peculiar clinical and histopathological characteristics of isolated muscular vasculitis. Our patients were successfully treated with steroids and immunosuppressive agents. Moreover, we provide a review of the recent existing medical literature. Our cases suggest the importance of performing muscle biopsy in patients with muscular symptoms to guide the diagnosis and the treatment.

One year in review 2017: systemic sclerosis.

Systemic sclerosis is a rare acquired systemic disease characterised by heterogeneous evolution and outcome. Each year novel insights into the pathogenesis, diagnosis and treatment of this severe disease have been published. We herewith provide our overview of the most significant literature contributions published over the last year.

Clinically amyopathic dermatomyositis: analysis of a monocentric cohort.

OBJECTIVE: Clinically amyopathic dermatomyositis (CADM) is characterized by the presence of specific cutaneous manifestations of dermatomyositis (DM) without clinical signs of muscular involvement. The aim of this study was to examine the prevalence, clinical characteristics, and outcome of patients with CADM followed at our Rheumatology Unit. METHODS: Clinical charts of patients diagnosed as DM were retrospectively examined. Epidemiological, clinical, laboratory, instrumental, and histological features of the patients at the time of diagnosis were collected. CADM was diagnosed in the presence of DM-like rash without muscular involvement. RESULTS: A total of 103 DM patients were identified, of these, 8 were diagnosed with CADM. Six of patients with CADM had subclinical muscle involvement, and were therefore classifiable as hypomyopathic DM. CONCLUSIONS: In our case series, CADM represents 7.7% of the total DM. However, if investigated with instrumental methods, most patients with CADM result to have subclinical muscular involvement.

Cancer-associated myositis: a 35-year retrospective study of a monocentric cohort.

This study is aimed at retrospectively studying cancer-associated inflammatory myopathies (CAM) in a cohort of patients with inflammatory myopathies. CAM were diagnosed if the tumor was diagnosed 2 years before or after disease onset. One hundred and sixty-two patients were included, 27 (17 %) had CAM. A significant association was observed between CAM and dermatomyositis (DM), older age and dysphagia at disease onset. CAM have lower creatine kinase (CK) levels at onset and a low prevalence of autoantibodies. In conclusion, the association of male sex, older age, DM, dysphagia at onset, lower CK, and autoantibodies negativity carries a high suspicion of CAM.