Simone Barsotti

Clinical Spectrum Time Course in Anti Jo-1 Positive Antisynthetase Syndrome: Results From an International Retrospective Multicenter Study.

AbstractAnti Jo-1 antibodies are the main markers of the antisynthetase syndrome (ASSD), an autoimmune disease clinically characterized by the occurrence of arthritis, myositis, and interstitial lung disease (ILD). These manifestations usually co-occur (for practical purpose complete forms) in the same patient, but cases with only 1 or 2 of these findings (for practical purpose incomplete forms) have been described. In incomplete forms, the ex novo occurrence of further manifestations is possible, although with frequencies and timing not still defined. The aim of this international, multicenter, retrospective study was to characterize the clinical time course of anti Jo-1 positive ASSD in a large cohort of patients. Included patients should be anti Jo-1 positive and with at least 1 feature between arthritis, myositis, and ILD. We evaluated the differences between complete and incomplete forms, timing of clinical picture appearance and analyzed factors predicting the appearance of further manifestations in incomplete ASSD. Finally, we collected 225 patients (58 males and 167 females) with a median follow-up of 80 months. At the onset, complete ASSD were 44 and incomplete 181. Patients with incomplete ASSD had frequently only 1 of the classic triad findings (110 cases), in particular, isolated arthritis in 54 cases, isolated myositis in 28 cases, and isolated ILD in 28 cases. At the end of follow-up, complete ASSD were 113, incomplete 112. Only 5 patients had an isolated arthritis, only 5 an isolated myositis, and 15 an isolated ILD. During the follow-up, 108 patients with incomplete forms developed further manifestations. Single main feature onset was the main risk factor for the ex novo appearance of further manifestation. ILD was the prevalent ex novo manifestation (74 cases). In conclusion, ASSD is a condition that should be carefully considered in all patients presenting with arthritis, myositis, and ILD, even when isolated. The ex novo appearance of further manifestations in patients with incomplete forms is common, thus indicating the need for an adequate clinical and instrumental follow-up. Furthermore, the study clearly suggested that in ASSD multidisciplinary approach involving Rheumatology, Neurology, Pneumology, and Internal Medicine specialists is mandatory.

Clinical follow-up predictors of disease pattern change in anti-Jo1 positive anti-synthetase syndrome: Results from a multicenter, international and retrospective study

OBJECTIVE Arthritis, myositis and interstitial lung disease (ILD) constitute the classic clinical triad of anti-synthetase syndrome (ASSD). These patients experience other accompanying features, such as Raynauds phenomenon, fever or mechanics hands. Most ASSD patients develop the complete triad during the follow-up. In the present study we aimed to determine whether the subsequent appearance of accompanying features may suggest the development of triad findings lacking at the onset in anti-Jo1 positive ASSD patients. METHODS Anti-Jo1 positive patients presenting with incomplete ASSD (no >2 classic triad features) were assessed. Clinical characteristics and clusters of disease manifestations were retrospectively collected and analyzed in a large international multicenter cohort of ASSD patients. RESULTS 165 patients (123 women) with incomplete ASSD were identified. Ninety-five patients (57.5%) developed new classic triad manifestations after 15months median (IQR 9-51) and 40 (24%) developed new accompanying features after 19months median (IQR 6-56) from disease onset. During the follow-up, the ex-novo occurrence of triad features was observed in 32 out of 40 patients (80%) with new accompanying findings and in 63 out of 125 patients (50.5%) without new accompanying findings (p=0.002). In patients with at least one new accompanying feature the odds ratio for the occurrence of new triad manifestations was 3.94 with respect to patients not developing ex-novo accompanying findings (95% CI 1.68-9.21, p=0.002). CONCLUSION Anti-Jo1 ASSD patients with incomplete forms at disease onset are at high risk for the subsequent occurrence of lacking classic triad findings. Although all ASSD patients should be carefully assessed for the occurrence of new triad features, a closer follow-up should be considered in the subgroup of patients developing ex novo accompanying findings. These patients, indeed, have near four-fold increased risk for new classic triad manifestation occurrence with respect to patients not presenting ex novo accompanying findings.

Thigh magnetic resonance imaging for the evaluation of disease activity in patients with idiopathic inflammatory myopathies followed in a single center.

Introduction: In patients with idiopathic inflammatory myopathies (IIM), magnetic resonance imaging (MRI) has been proposed as a useful tool for diagnosis and follow‐up. It may identify muscle inflammation (edema) and fatty infiltration for evaluation of disease activity and damage. Little information is available on the role of MRI in assessment of large cohorts of adult patients with IIM. Methods: Fifty‐one patients underwent MRI of the thigh muscles, laboratory tests, and clinical evaluation, including Physician Global Assessment (PGA) of myositis activity and the Manual Muscle Test 8 (MMT8). Results: Muscle edema correlated significantly with creatine kinase values (P = 0.017) and PGA (P < 0.001). A significant correlation between edema and MMT8 values (P = 0.025) was observed when patients with muscle fatty infiltration were excluded. With respect to clinical diagnosis, the sensitivity of MRI was 92.3%, and specificity was 83.3%. Conclusions: MRI appears to provide additional information that complements clinical and biochemical examinations. Muscle Nerve 54: 666–672, 2016

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.

Drugs in induction and treatment of idiopathic inflammatory myopathies

Idiopathic inflammatory myopathies (IIM) are a rare disease; so far standardized therapy has not been adequately defined by national or international guidelines or recommendations. Corticosteroids are the mainstay of treatment, but these drugs are burdened by several side effects. Thus, additional treatment based on immunosuppressive agents, especially azathioprine, methotrexate, mycophenolate mofetil and cyclosporine, is often needed. This combinate approach both improves the disease response and allows reduction of the dosage of corticosteroids, decreasing the risk of steroid-related long-term complications. Biological agents, particularly B cell depleting agent, are emergent therapeutic tools for refractory cases. Notably, drugs currently used for the therapy of IIM or other rheumatologic and non-rheumatologic conditions can induce myopathy. Drug-induced myopathies represent a considerable part of the complex topic of muscular disorders and should be always considered in the usual diagnostic work-up of a subject with muscle disease. Several mechanisms have been advocated to explain muscular damage induced by a number of drugs and, although a recovery after drug removal is usually observed, severe or persistent myopathy may be observed following the administration of some drugs, particularly in subjects with genetic predisposition. In this review the traditional and novel therapeutic approaches for patients with IIM, particularly biologics, will be discussed and an overview on drug-induced myopathies will also be provided.

Post-occlusive reactive hyperaemia (POHR) in systemic sclerosis: very early disease (VEDOSS) represents a separate entity compared to established disease

Objectives: Vascular involvement is a key feature of systemic sclerosis (SSc). Vascular changes are central to the pathogenesis of the disease and the assessment of vascular involvement has a prognostic value. This assessment therefore has a pivotal role in the management of SSc patients. The aim of our study was to evaluate post-occlusive reactive hyperaemia (PORH) in consecutive SSc patients and to test whether a PORH test might be a useful tool for the early diagnosis of SSc. Method: Between April 2011 and April 2015, 60 consecutive SSc patients (mean age 56 ± 15 years, females:males = 18:1) were enrolled in the study. The patients were divided into those with full-blown SSc (n = 50) and those with very early diagnosis of SSc (VEDOSS) (n = 10) according to the literature. Laser speckle contrast analysis (LASCA) was used to assess PORH. Results: A statistically significant difference was detected in the post-ischaemic hyperaemic peak flow between VEDOSS and established SSc (424% vs. 137%, p = 0.0011). PORH peak flow decreased according to the capillaroscopic pattern (early = 419%, active = 163%, late = 145%, p = 0.0027). Moreover, a correlation between capillary density and peak flow was revealed (rho = 0.33, p < 0.01). Conclusions: These data show a different pattern of vascular involvement in VEDOSS compared to established disease that mirrors capillaroscopic changes. Functional features of very early and established disease seem to be the physiological counterpart of abnormalities detected by capillaroscopy. The POHR test might be a useful aid for further characterization of vascular involvement in SSc. In particular, blunted POHR might prove a tool to separate pre-clinical from full-blown SSc.

Systemic sclerosis chronic ulcers: preliminary results of treatment with allogenic skin grafting in a cohort of Italian patients

Dear Editors, Systemic sclerosis (SSc) represents a heterogeneous group of rare diseases characterised by small vessel vasculopathy, production of autoantibodies and fibroblast dysfunction leading to increased deposition of extracellular matrix (1). Skin ulcers are a common manifestation of SSc. Patients often present painful and hard-to-heal lesions that markedly reduce the quality of life (2,3). The prevalence of non-digital ulcers in Ssc patients is estimated at 4% (4); these ulcers have a multifactorial pathogenesis, and some authors have hypothesised a role for large vessel venous and arterial disease in the pathogenesis (5). An innovative approach for the management of chronic ulcers is reconstructive surgery using skin substitutes, particularly for large and deep ulcers (6,7). Allograft using preserved cadaver skin can be used in the same way as a skin substitute (these kinds of grafts are not vascularised and finally the skin is desiccated and avascular necrosis occurs) and has been proved to be effective in both burns and chronic leg wounds. Some authors defined allograft as the ‘gold standard’ for temporary wound coverage (8), which provides a quick pain reduction and a barrier function, reduces bacterial contamination and promotes angiogenesis in the wound bed (8). The aim of this study was to retrospectively evaluate the effect of skin allograft in a cohort of consecutive SSc patients with painful chronic ulcers that were not responsive to modern advanced wound dressing. From January 2006 to December 2012, consecutive SSc subjects affected by chronic ulcer referred to our vascular surgery department for allogenic skin grafting were enrolled. Data were retrospectively retrieved from the clinical charts. The diagnosis of SSc was established using the American College of Rheumatology (ACR) criteria (9). The primary outcome was to assess the effectiveness in terms of pain reduction, which was evaluated using a visual analogue scale (VAS), complications and rate of infections. A total of 43 SSc patients (5 males and 38 females) were treated using allogenic skin grafting. The mean age at the time of intervention was 60.8 years (range 39–83 years). The ulcers were localised in the following areas: 34 lower extremities (10 digital), 8 upper extremities (3 digital) and 1 both upper and lower digital ulcers. The mean ulcer duration was 27 months (range 2–140 months). Patients, in addition to SSc, presented the following additional risk factors for ulcer development: venous insufficiency (13 patients), systemic arterial hypertension (17 patients), diabetes mellitus (3 patients), hypercholesterolaemia (5 patients) and obesity (1 patient). The most relevant result was a rapid reduction of ulcer-related pain. The VAS for pain at baseline was 7.55 cm (range 4–10 cm), and immediately after the procedure, it was significantly reduced by 84%, reaching a mean value of 1.18 cm (range 0–5 cm) (P< 0.001). All patients healed completely in less than 3 months, but 37% had an ulcer recurrence in the same location during the subsequent year. No serious side effects were recorded after the procedure. No patients presented an infection in the grafting area in the first 4 weeks after the surgery. Our study is the first describing the effectiveness of allogenic skin grafting in chronic ulcers in Ssc patients. The use of allogenic skin grafting was found to be a safe and effective treatment for SSc chronic ulcers in serious refractory situations. This procedure seems to favour wound healing and significantly reduces pain as compared with conservative dressing. The major limitations of our study were the retrospective collection of data with some missing values and the lack of a control group. Although the procedure is quite expensive, it may be considered in selected cases with poor outcome despite traditional therapy. Further studies and randomised controlled trials are needed to identify the prognostic factors of response to allografts and to help the selection of patients most suitable for the procedure.

Histopathology of the muscle in rheumatic diseases

The presence of muscular symptoms is common in rheumatological clinical practice, but often the differential diagnosis between muscular involvement in connective tissue diseases, vasculitis and drug-induced myopathy may be difficult. In addition to clinical assessment, laboratory analysis and instrumental examinations, muscle biopsy may help to clarify the diagnosis in patients with muscular involvement. The purpose of this review is to provide a critical analysis of the current medical literature on muscular histopathology, to help clinicians to identify when to perform muscular biopsy and to provide a practical guide to a better understanding of the pathology report. Moreover, we provide an overview of the muscular involvement and the most common histopathological findings in rheumatic diseases.

The use of rituximab in idiopathic inflammatory myopathies: description of a monocentric cohort and review of the literature

Rituximab (RTX), a chimeric monoclonal antibody targeted against CD20, has been used to treat refractory inflammatory myopathies (IIM). The primary objective of this study was to retrospectively assess the efficacy of RTX in reducing disease activity in patients with IIM refractory to conventional therapy. Secondary aim was the evaluation of adverse events (AE) during the treatment period. We examined 26 patients with a diagnosis of IIM, referred to our Rheumatology Unit and treated with RTX for active refractory disease. Patients were treated with RTX 1000 mg i.v., twice, with a 2-week interval. RTX treatment was associated with a significant reduction of creatine kinase (p=0.001) after six months compared to the baseline, an improved muscular strength measured with MMT8 (p<0.001) and a reduction of the extramuscular activity of the disease measured with MYOACT (p<0.001). In particular, RTX improved DM skin rash, arthritis and pulmonary manifestations. Autoantibody positivity (in particular antisynthetase, anti- SRP and antiRo/SSA), and a disease duration <36 months at the moment of the treatment are associated with a better response rate. Treatment with RTX was also associated with a reduction of the mean daily dose of steroids needed to control disease activity (p=0.002). Our results have confirmed that RTX is efficacious in the treatment of refractory IIM. Ad hoc controlled trials are needed to better clarify the specific subset of patients who may better respond to the treatment and the optimal therapeutic schedule.

Current Treatment for Myositis

Purpose of reviewThe purpose of this review was to give an update on treatment modalities for patients with idiopathic inflammatory myopathies, or shortly myositis, excluding the subgroup inclusion body myositis, based on a literature survey on therapies used in myositis. Few controlled trials have been performed in patients with myositis; therefore, we also included a summary of open-label trials, case series, and case reports.Recent findingsGlucocorticoid (GC) in high doses is still the first-line treatment of patients with myositis. There is a general recommendation to combine GCs with another immunosuppressive agent in the early phase of disease to better control disease activity and possibly to reduce the risk for GC-related side effects. Furthermore, combining pharmacological treatment with individualized and supervised exercise can be recommended based on evidence. There is some evidence for the effect of rituximab in patients with certain myositis-specific autoantibodies, whereas other biologic agents are currently being tested in clinical trials.SummaryImmunosuppressive treatment in combination with exercise is recommended for patients with myositis to reduce disease activity and improve muscle performance. Subgrouping of patients into clinical and serological subtypes may be a way to identify biomarkers for response to specific immunosuppressive and biological agents and should be considered in future trials.