Biomarker profiles of endothelial activation and dysfunction in rare systemic autoimmune diseases: implications for cardiovascular risk.

OBJECTIVES: Vasculopathy is an important hallmark of systemic chronic inflammatory connective tissue diseases (CICTD) and is associated with increased cardiovascular risk. We investigated disease-specific biomarker profiles associated with endothelial dysfunction, angiogenic homeostasis and (tissue) inflammation, and their relation to disease activity in rare CICTD. METHODS: A total of 38 serum proteins associated with endothelial (dys)function and inflammation were measured by multiplex-immunoassay in treatment-naive patients with localized scleroderma (LoS, 30), eosinophilic fasciitis (EF, 8) or (juvenile) dermatomyositis (34), 119 (follow-up) samples during treatment, and 65 controls. Data were analysed by unsupervised clustering, Spearman correlations, non-parametric t test and ANOVA. RESULTS: The systemic CICTD, EF and dermatomyositis, had distinct biomarker profiles, with 'signature' markers galectin-9 (dermatomyositis) and CCL4, CCL18, CXCL9, fetuin, fibronectin, galectin-1 and TSP-1 (EF). In LoS, CCL18, CXCL9 and CXCL10 were subtly increased. Furthermore, dermatomyositis and EF shared upregulation of markers related to interferon (CCL2, CXCL10), endothelial activation (VCAM-1), inhibition of angiogenesis (angiopoietin-2, sVEGFR-1) and inflammation/leucocyte chemo-attraction (CCL19, CXCL13, IL-18, YKL-40), as well as disturbance of the Angiopoietin-Tie receptor system and VEGF-VEGFR system. These profiles were related to disease activity, and largely normalized during treatment. However, a subgroup of CICTD patients showed continued elevation of CXCL10, CXCL13, galectin-9, IL-18, TNFR2, VCAM-1, and/or YKL-40 during clinically inactive disease, possibly indicating subclinical interferon-driven inflammation and/or endothelial dysfunction. CONCLUSION: CICTD-specific biomarker profiles revealed an anti-angiogenic, interferon-driven environment during active disease, with incomplete normalization under treatment. This warrants further investigation into monitoring of vascular biomarkers during clinical follow-up, or targeted interventions to minimize cardiovascular risk in the long term.

A Rare Case of Intravascular Fasciitis Misdiagnosed as Deep Venous Thrombosis.

PURPOSE: This case aimed to explore the clinical, histological, and immunohistochemical features of intravascular fasciitis (IVF) that involve a large blood vessel. CASE REPORT: A 27-year-old man presented with swelling and pain of the left lower limb for 5 days. The report of Doppler ultrasonography confirmed deep venous thrombosis (DVT) in the lower left limb (acute phase). However, laboratory value for the presence of D-dimer was negative. Thus, we performed an ascending venography and identified a mass in the common femoral vein. At operation, an incision of the left common femoral vein was made, and the mass was completely resected. CONCLUSIONS: The situation of IVF that grew in a large vein is extremely rare and can easily be misdiagnosed as DVT. The presence of D-dimer is important for a differential diagnosis. Ascending venography can be applied in making an accurate diagnosis.

Unusual presentation of eosinophilic fasciitis (EF) with a raised ALT.

Eosinophilic fasciitis (EF) is a syndrome of unknown aetiology characterised by progressive collagenous thickening of the subcutaneous fascia. Limb oedema can precede the skin thickening and induration classically associated with EF. We describe a case of EF in a 31-year-old woman who presented to her general practitioner with lower limb oedema and stiffness. Blood tests in primary care showed a persistently raised alanine transferase (ALT). No hepatic cause for her raised ALT was found despite investigation. The unusual manner of her presentation led to delay in her referral to the autoimmune connective tissue disease (CTD) clinic. This case illustrates the importance of considering autoimmune CTD such as EF in young patients presenting with limb oedema and raised ALT, as early treatment influences prognosis and functional recovery.

Diagnostic criteria, severity classification and guidelines of eosinophilic fasciitis.

We established diagnostic criteria and severity classification of eosinophilic fasciitis because there is no established diagnostic criteria or widely accepted severity classification of the disease. Also, there has been no clinical guideline for eosinophilic fasciitis, so we established its clinical guideline ahead of all over the world. In particular, the clinical guideline was established by clinical questions based on evidence-based medicine according to the New Minds Clinical Practice Guideline Creation Manual (version 1.0). We aimed to make the guideline easy to use and reliable based on the newest evidence, and to present guidance as specific as possible for various clinical problems in treatment of eosinophilic fasciitis.

Juvenile eosinophilic fasciitis: three case reports with review of the literature.

OBJECTIVES: Eosinophilic fasciitis is an uncommon scleroderma-like disorder characterised by induration and thickening of skin and soft tissue, usually associated with peripheral eosinophilia, poorly characterised in childhood. METHODS: We report 3 paediatric cases of eosinophilic fasciitis showing unusual clinical and histopathological features with a review of the literature. RESULTS: All cases presented progressive motility impairment started from upper limbs with no skin abnormalities. All cases showed systemic inflammatory involvement and 2 patients had acute complications. Two patients developed disabling outcomes despite appropriate treatments. CONCLUSIONS: Eosinophilic fasciitis may present unusual clinical and histopathological features during childhood and requires early recognition in order to prevent acute complications and disabling outcomes.

Aluminum adjuvants of vaccines injected into the muscle: Normal fate, pathology and associated disease.

Aluminum oxyhydroxide (Alhydrogel(®)) is a nano-crystalline compound forming aggregates that has been introduced in vaccine for its immunologic adjuvant effect in 1926. It is the most commonly used adjuvant in human and veterinary vaccines but mechanisms by which it stimulates immune responses remain ill-defined. Although generally well tolerated on the short term, it has been suspected to occasionally cause delayed neurologic problems in susceptible individuals. In particular, the long-term persistence of aluminic granuloma also termed macrophagic myofasciitis is associated with chronic arthromyalgias and fatigue and cognitive dysfunction. Safety concerns largely depend on the long biopersistence time inherent to this adjuvant, which may be related to its quick withdrawal from the interstitial fluid by avid cellular uptake; and the capacity of adjuvant particles to migrate and slowly accumulate in lymphoid organs and the brain, a phenomenon documented in animal models and resulting from MCP1/CCL2-dependant translocation of adjuvant-loaded monocyte-lineage cells (Trojan horse phenomenon). These novel insights strongly suggest that serious re-evaluation of long-term aluminum adjuvant phamacokinetics and safety should be carried out.

The use of an elevated aldolase in diagnosing and managing eosinophilic fasciitis.

Eosinophilic fasciitis (EF) is a rare localized fibrosing disorder of the fascia whose diagnosis is often suspected based on clinical findings and laboratory values. These lab abnormalities can be transient in early disease and may not always be present. We have reviewed a case series of patients to assess the utility of the various laboratory abnormalities in diagnosing EF. We performed a retrospective review of EF patients seen at Georgetown University Hospital in the Division of Rheumatology during 2009 and 2013. This review included 15 adult patients with EF with a mean age at diagnosis of 45 years (range 18 to 77 years). The majority of patients 13/15 had classic skin thickening documented on all four extremities Only eight patients had peripheral eosinophilia ranging between 8 and 38 %. In these patients, the peripheral eosinophilia was an early but transient finding. Inflammatory markers including the erythrocyte sedimentation rate (ESR) was elevated in 5/14 and C-reactive Protein (CRP) was elevated in 7/11. At disease presentation, only one of eleven patients checked had an elevated creatine phosphokinase (CPK). Aldolase levels were available for 12 of the 15 patients, and they were increased in 11 out of 12 patients. We have found that in this case series, aldolase was more likely to be abnormal than peripheral eosinophilia, hypergammaglobulinemia, and ESR particularly after starting treatment. Aldolase should be measured in all patients suspected of having EF, and may also play a useful role in following disease activity.

Serum levels of matrix metalloproteinase-13 in patients with eosinophilic fasciitis.

Matrix metalloproteinase-13 (MMP-13), a member of the collagenase family, has been implicated in the pathogenesis of connective tissue diseases characterized by extracellular matrix remodeling. Since serum MMP-13 levels reflect disease severity of systemic sclerosis and localized scleroderma, we evaluated the clinical significance of serum MMP-13 levels in eosinophilic fasciitis (EF). All the EF patients had serum MMP-13 levels lower than the mean - 2SD of healthy controls. Serum MMP-13 levels were also significantly decreased in EF patients compared with diffuse cutaneous systemic sclerosis, limited cutaneous systemic sclerosis, and generalized morphea patients. Although serum MMP-13 levels did not reflect any clinical and serological features of EF, these results indicate that MMP-13 may be involved in the development of this disease.

Selective elevation of circulating CCL2/MCP1 levels in patients with longstanding post-vaccinal macrophagic myofasciitis and ASIA.

Several medical conditions sharing similar signs and symptoms may be related to immune adjuvants. These conditions described as ASIA (Autoimmune/inflammatory Syndrome Induced by Adjuvants), include a condition characterized by macrophagic myofasciitis (MMF) assessing long-term persistence of vaccine derived-alum adjuvants into macrophages at sites of previous immunization. Despite increasing data describing clinical manifestations of ASIA have been reported, biological markers are particularly lacking for their characterization and follow up. We report an extensive cytokine screening performed in serum from 44 MMF patients compared both to sex and age matched healthy controls and to patients with various types of inflammatory neuromuscular diseases. Thirty cytokines were quantified using combination of Luminex® technology and ELISA. There was significant mean increase of serum levels of the monocytechemoattractant protein 1 (CCL2/MCP-1) in MMF patients compared to healthy subjects. MMF patients showed no elevation of other cytokines. This contrasted with inflammatory patients in whom CCL2/MCP-1 serum levels were unchanged, whereas several other inflammatory cytokines were elevated (IL1ß, IL5 and CCL3/MIP1α). These results suggest that CCL2 may represent a biological marker relevant to the pathophysiology of MMF rather than a non specific inflammatory marker and that it should be checked in the other syndromes constitutive of ASIA.

Tumor necrosis factor receptor 1-associated periodic syndrome without fever: cytokine profile before and during etanercept treatment.

The objectives of this study are autoinflammatory syndromes which are usually characterized by repeated attacks of fever, especially in children. The presentation of these diseases, however, varies between entities and between patients of a particular syndrome. We report a 16-year-old female patient, who suffered from periodic erythema and myositis/fasciitis. She experienced at least nine attacks of dermatitis and myositis, while no fever episodes were noted over a 3-year period. A delay of puberty with amenorrhea and a short stature were also present. Laboratory investigations consistently showed markedly increased inflammatory parameters (especially a high serum amyloid A) and dysproteinemia. Because the patient's mother complained about chronic and periodic abdominal pain with also persistently elevated inflammatory parameters, the differential diagnosis included hereditary disorders resulting in chronic inflammation. The diagnosis of an inherited tumor necrosis factor receptor (TNFR) 1-associated periodic syndrome (TRAPS) was confirmed by genetic analyses. Long-term anti-inflammatory treatment with etanercept resulted in a significant clinical improvement and reduction of the inflammatory parameters ESR, CRP, interleukin-6, TNF-α, and soluble TNF-α receptor 1, but not of interleukin-12. Monitoring of the cytokine profile suggested partial effectiveness of etanercept in the treatment of TRAPS. Hereditary fever syndromes have to be considered in case of chronic unexplained inflammation even if fever is no presenting symptom.

[Fasciitis eosinophilica: personal observations and a review of the literature]. / Eozynofilowe zapalenie powiezi: opis 5 przypadków i przeglad literatury.

Eosinophilic fasciitis is a rare disease that is classified by some authors to scleroderma-like syndromes. Symmetrical induration of skin and subcutaneous tissue associated by eosinophilia in peripheral blood are characteristic features of the disease. Internal organ involvement is uncommon. It is often difficult to diagnose eosinophilic fasciitis and its course may be variable. Glucocorticosteroids are most commonly used in the treatment but in many cases they are ineffective. Then other immunosuppressive therapy must be considered. Prognosis is rather favorable. The remission is not always achieved and sometimes flares of the disease are observed as evidenced by the described cases. It should be emphasized that a majority of our patients were females. In four out of five patients anti-thyreoglobulin antibodies and/or anti-thyroid peroxidase antibodies were present suggesting their involvement in the pathogenesis of eosinophilic fasciitis. Neither indicators of inflammation nor peripheral blood eosinophilia were pathognomonic. Results of glucocorticosteroid treatment were satisfactory in three patients, but two patients required combined immunosuppressive treatment.

Eosinophilic fasciitis: report of two cases and a systematic review of the literature dealing with clinical variables that predict outcome.

We reported two patients with refractory eosinophilic fasciitis (EF) and provided a systematic review of the literature to determine the clinical variables associated with prognosis of EF. We enrolled 88 cases, whose clinical characteristics were analyzed by separating the patients into two or three groups based on outcome. The incidence of certain clinical and pathological features differed among the groups. In particular, the incidence of morphea-like skin lesions in patients with refractory fibrosis was significantly higher than in patients without refractory fibrosis (p = 0.003). Patients with morphea-like skin lesions were 1.9 times more likely to develop persistent fibrosis than patients without these lesions (95% confidence intervals, 1.5-2.5). A younger age (under 12 years) at onset was associated with a 1.6 times greater risk of residual fibrosis (95% confidence interval, 1.1-2.2). Trunk involvement was associated with a 1.4 times greater risk of residual fibrosis (95% confidence interval, 1.0-2.0). Histopathologically, the presence of dermal fibrosclerosis was associated with a 1.4 times greater risk of refractory fibrosis (95% confidence interval, 1.0-2.1). We consider these clinical characteristics, notably the presence of morphea-like skin lesions may be an important risk factor for developing residual fibrosis in EF patients.

Blood oxidative stress status in patients with macrophagic myofasciitis.

The study aimed at determining the presence of an oxidative stress in patients with macrophagic myofasciitis (MMF), a new inflammatory myopathy with suspected toxic etiology related to aluminium hydroxide-containing vaccines. A total of 30 MMF patients (nine males, 21 females; aged 42+/-14 years), whose diagnosis was confirmed by deltoid biopsy, have been included and compared to 38 sex- and age-matched healthy control subjects (10 males, 28 females; aged 43+/-8 years). The blood oxidative stress status has been evaluated by assaying six parameters: plasma lipid peroxidation products (thiobarbituric acid-reactive substances: TBARS) and antioxidant defense systems: plasma vitamin E and glutathione peroxidase (GSH-Px) activity, erythrocyte GSH-Px and Cu,Zn-superoxide dismutase (SOD) activities. Plasma selenium was also determined as a trace element essential to the activity of GSH-Px. Statistical significance was evaluated by the Mann-Whitney test. Plasma GSH-Px activity, selenium and vitamin E concentration were significantly lower in MMF group than in controls (P=0.004, P=0.003 and P=0.009, respectively), with a positive correlation in MMF patients between plasma GSH-Px activity and selenium concentration (rho=0.0001). The other parameters of oxidative stress did not significantly differ between both groups. A macrophage activation could occur in MMF, consequently to chronic stimulation by aluminium-containing vaccines, and could participate to the lower values of selenium and vitamin E observed in comparison with controls. Nevertheless, since no deficiency in these elements has been observed, no supplementation is to be considered.