High rate of indeterminate results of the QuantiFERON-TB Gold in-tube test, third generation, in patients with systemic vasculitis.

OBJECTIVES: To describe the frequency of QuantiFERON-TB Gold in-tube test® (QFT-GIT) indeterminate results due to no response to phytohaemagglutinin A stimulation in the control tube in vasculitis patients prior to immunosuppressant therapy; and to compare it with other groups of patients. METHODS: This was a single-centre, retrospective study. Patients and controls were included between 1 January 2008 and 31 December 2015. We assessed the rate of indeterminate results of the QFT-GIT in 38 patients with systemic vasculitis prior to any corticosteroid or immunosuppressant therapy, compared with 40 non-vasculitis patients with biological inflammatory syndrome, and 310 non-immunosuppressed patients matched for gender and age. RESULTS: Indeterminate results due to no response to phytohaemagglutinin A were more frequent in vasculitis patients (21.1%) compared with non-vasculitis patients with biological inflammatory syndrome (7.5%) (Fisher's exact test: P = 0.11) and to anonymized controls (7%) (P = 0.009). Responses to phytohaemagglutinin A were significantly lower in vasculitis patients compared with other groups (Kruskal-Wallis test: P < 0.0001) and compared with non-vasculitis patients with biological inflammatory syndrome (P = 0.0015). The multivariable analysis identified as independent predictors of an indeterminate result of the QFT-GIT: the presence of systemic vasculitis (odds ratio 9.64 [1.14-81.3], P = 0.037) and a high neutrophil-to-lymphocyte ratio (odds ratio 1.70 [1.21-2.37], P = 0.002). One patient with an indeterminate result of QFT-GIT developed active tuberculosis after one year of corticosteroid therapy for giant cell arteritis. CONCLUSION: Our results question the reliability of QFT-GIT to rule out latent tuberculosis in vasculitis patients at diagnosis, prior to immunosuppressant therapy.

Immunoglobulin Abnormalities in Gaucher Disease: an Analysis of 278 Patients Included in the French Gaucher Disease Registry.

Gaucher disease (GD) is a rare lysosomal autosomal-recessive disorder due to deficiency of glucocerebrosidase; polyclonal gammopathy (PG) and/or monoclonal gammopathy (MG) can occur in this disease. We aimed to describe these immunoglobulin abnormalities in a large cohort of GD patients and to study the risk factors, clinical significance, and evolution. Data for patients enrolled in the French GD Registry were studied retrospectively. The risk factors of PG and/or MG developing and their association with clinical bone events and severe thrombocytopenia, two markers of GD severity, were assessed with multivariable Cox models and the effect of GD treatment on gammaglobulin levels with linear/logarithmic mixed models. Regression of MG and the occurrence of hematological malignancies were described. The 278 patients included (132 males, 47.5%) were followed up during a mean (SD) of 19 (14) years after GD diagnosis. PG occurred in 112/235 (47.7%) patients at GD diagnosis or during follow-up and MG in 59/187 (31.6%). Multivariable analysis retained age at GD diagnosis as the only independent risk factor for MG (> 30 vs. ≤30 years, HR 4.71, 95%CI [2.40-9.27]; p < 0.001). Risk of bone events or severe thrombocytopenia was not significantly associated with PG or MG. During follow-up, non-Hodgkin lymphoma developed in five patients and multiple myeloma in one. MG was observed in almost one third of patients with GD. Immunoglobulin abnormalities were not associated with the disease severity. However, prolonged surveillance of patients with GD is needed because hematologic malignancies may occur.

A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments.

Gaucher disease (GD, ORPHA355) is a rare, autosomal recessive genetic disorder. It is caused by a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of its substrate, glucosylceramide, in macrophages. In the general population, its incidence is approximately 1/40,000 to 1/60,000 births, rising to 1/800 in Ashkenazi Jews. The main cause of the cytopenia, splenomegaly, hepatomegaly, and bone lesions associated with the disease is considered to be the infiltration of the bone marrow, spleen, and liver by Gaucher cells. Type-1 Gaucher disease, which affects the majority of patients (90% in Europe and USA, but less in other regions), is characterized by effects on the viscera, whereas types 2 and 3 are also associated with neurological impairment, either severe in type 2 or variable in type 3. A diagnosis of GD can be confirmed by demonstrating the deficiency of acid glucocerebrosidase activity in leukocytes. Mutations in the GBA1 gene should be identified as they may be of prognostic value in some cases. Patients with type-1 GD-but also carriers of GBA1 mutation-have been found to be predisposed to developing Parkinson's disease, and the risk of neoplasia associated with the disease is still subject to discussion. Disease-specific treatment consists of intravenous enzyme replacement therapy (ERT) using one of the currently available molecules (imiglucerase, velaglucerase, or taliglucerase). Orally administered inhibitors of glucosylceramide biosynthesis can also be used (miglustat or eliglustat).

Monogenic neurological disorders of sphingolipid metabolism.

Sphingolipids comprise a wide variety of molecules containing a sphingoid long-chain base that can be N-acylated. These lipids are particularly abundant in the central nervous system, being membrane components of neurons as well as non-neuronal cells. Direct evidence that these brain lipids play critical functions in brain physiology is illustrated by the dramatic consequences of genetic disturbances of their metabolism. Inherited defects of both synthesis and catabolism of sphingolipids are now identified in humans. These monogenic disorders are due to mutations in the genes encoding for the enzymes that catalyze either the formation or degradation of simple sphingolipids such as ceramides, or complex sphingolipids like glycolipids. They cause varying degrees of central nervous system dysfunction, quite similarly to the neurological disorders induced in mice by gene disruption of the corresponding enzymes. Herein, the enzyme deficiencies and metabolic alterations that underlie these diseases are reviewed. Their possible pathophysiological mechanisms and the functions played by sphingolipids one can deduce from these conditions are discussed. This article is part of a Special Issue entitled Brain Lipids.

Human genetic disorders of sphingolipid biosynthesis.

Monogenic defects of sphingolipid biosynthesis have been recently identified in human patients. These enzyme deficiencies affect the synthesis of sphingolipid precursors, ceramides or complex glycosphingolipids. They are transmitted as autosomal recessive or dominant traits, and their resulting phenotypes often replicate the abnormalities seen in murine models deficient for the corresponding enzymes. In quite good agreement with the known critical roles of sphingolipids in cells from the nervous system and the epidermis, these genetic defects clinically manifest as neurological disorders, including paraplegia, epilepsy or peripheral neuropathies, or present with ichthyosis. The present review summarizes the genetic alterations, biochemical changes and clinical symptoms of this new group of inherited metabolic disorders. Hypotheses regarding the molecular pathophysiology and potential treatments of these diseases are also discussed.

Biologics in relapsing polychondritis: a case series.

OBJECTIVES: To describe the effects of biologics in an unbiased series of relapsing polychondritis cases. METHODS: We extracted all the cases encoded 'polychondritis' from the computerized medical files of our department. The relapsing polychondritis diagnosis was confirmed using Damiani's criteria. Patients treated with biologics were evaluated for efficacy and adverse drugs reactions until October 2012. RESULTS: Nine patients were exposed to 22 biologics as corticosteroid-sparing drugs. Biologics were used at the same doses as in rheumatoid arthritis. Mean duration of exposure to biologics was 28 months. A TNF-antagonist was most frequently used as first-line biologic therapy (7/9), leading to partial or complete efficacy in six cases (85.7%). Loss of efficacy occurred in 5 cases. Abatacept (n=3) and tocilizumab (n=2) were effective as second-line biologic therapy while anakinra (n=2) and certolizumab (n=1) were not. Seven serious adverse drug reactions occurred, including 5 infections. CONCLUSIONS: TNF-α antagonists may be proposed earlier in relapsing polychondritis to spare corticosteroids. Switching to another biologic can be proposed in case of loss of efficacy. Tocilizumab or abatacept can be proposed as third-line therapy. The benefit-to-risk ratio of biologics in relapsing polychondritis should be evaluated prospectively.

Potential Role of Sphingolipidoses-Associated Lysosphingolipids in Cancer.

Sphingolipids play a key structural role in cellular membranes and/or act as signaling molecules. Inherited defects of their catabolism lead to lysosomal storage diseases called sphingolipidoses. Although progress has been made toward a better understanding of their pathophysiology, several issues still remain unsolved. In particular, whether lysosphingolipids, the deacylated form of sphingolipids, both of which accumulate in these diseases, are simple biomarkers or play an instrumental role is unclear. In the meanwhile, evidence has been provided for a high risk of developing malignancies in patients affected with Gaucher disease, the most common sphingolipidosis. This article aims at analyzing the potential involvement of lysosphingolipids in cancer. Knowledge about lysosphingolipids in the context of lysosomal storage diseases is summarized. Available data on the nature and prevalence of cancers in patients affected with sphingolipidoses are also reviewed. Then, studies investigating the biological effects of lysosphingolipids toward pro or antitumor pathways are discussed. Finally, original findings exploring the role of glucosylsphingosine in the development of melanoma are presented. While this lysosphingolipid may behave like a protumorigenic agent, further investigations in appropriate models are needed to elucidate the role of these peculiar lipids, not only in sphingolipidoses but also in malignant diseases in general.

Clinical impact and prognosis of cryoglobulinemia and cryofibrinogenemia in systemic sclerosis.

INTRODUCTION: An association of systemic sclerosis (SSc) with cryoglobulin and/or cryofibrinogenemia has been described. However, clinical, biological, morphological and prognostic implications are unknown. The objective of this study was to describe the phenotype and evaluate the prognosis of cryoglobulinemia and/or cryofibrinogenemia in the progression of SSc. MATERIALS AND METHODS: Patients were included from the Systemic Scleroderma Toulouse Cohort (SSTC), between June 1, 2005 and May 31, 2018, and underwent a measurement of a cryoglobulin and/or cryofibrinogen in immunology laboratory at the Toulouse University Hospital Center. Patients with and without cryoglobulinemia >50 mg/l and patients with and without cryofibrinogenemia were compared to identified the impact of cryoprcipitate on the phenotype. Mortality based on cryoprecipitate was explored. RESULTS: 166 patients were included in the study. 43.3% and 46.6% had a cryoglobulinemia >50 mg/l and cryofibrinogenemia, respectively. Cryoglobulin >50 mg was not associated with microvascular damage. Cryoglobulin does not influence the phenotype. 5-and 10-years survival were 97.6% and 88.8% respectively in patients with cryoglobulinemia >50 mg/l versus 91.9% and 78.4% in patients without cryoglobulin>50 mg/l. 10-years survival was better for patients with cryoglobulinemia >50 mg/l (log-rank 0.0363). Cryofibrinogenemia was not associated with neoplasia, any clinical (in particular ischemic damage), biological or morphological features. Cryofibrinogenemia had no influence on the mortality of these patients. CONCLUSION: Cryoglobulinemia and cryofibrinogenemia are frequent in SSc. The presence of cryoprecipitate (cryoglobulin or cryofibrinogen) not influence the phenotype and has not associated with a poor survival.

Diagnostic Value of 18F-FDG PET/CT vs. Chest-Abdomen-Pelvis CT Scan in Management of Patients with Fever of Unknown Origin, Inflammation of Unknown Origin or Episodic Fever of Unknown Origin: A Comparative Multicentre Prospective Study.

Fluorodesoxyglucose Positron Emission Tomography (PET/CT) has never been compared to Chest-Abdomen-Pelvis CT (CAPCT) in patients with a fever of unknown origin (FUO), inflammation of unknown origin (IUO) and episodic fever of unknown origin (EFUO) through a prospective and multicentre study. In this study, we investigated the diagnostic value of PET/CT compared to CAPCT in these patients. The trial was performed between 1 May 2008 through 28 February 2013 with 7 French University Hospital centres. Patients who fulfilled the FUO, IUO or EFUO criteria were included. Diagnostic orientation (DO), diagnostic contribution (DC) and time for diagnosis of both imaging resources were evaluated. One hundred and three patients were included with 35 FUO, 35 IUO and 33 EFUO patients. PET/CT showed both a higher DO (28.2% vs. 7.8%, p < 0.001) and DC (19.4% vs. 5.8%, p < 0.001) than CAPCT and reduced the time for diagnosis in patients (3.8 vs. 17.6 months, p = 0.02). Arthralgia (OR 4.90, p = 0.0012), DO of PET/CT (OR 4.09, p = 0.016), CRP > 30 mg/L (OR 3.70, p = 0.033), and chills (OR 3.06, p = 0.0248) were associated with the achievement of a diagnosis (Se: 89.1%, Sp: 56.8%). PET/CT both orients and contributes to diagnoses at a higher rate than CAPCT, especially in patients with FUO and IUO, and reduces the time for diagnosis.

Abdominal infectious aortitis caused by Streptococcus pneumoniae: a case report and literature review.

We report a case of a 75-year-old man who had been complaining of fever and pelvic pain for 3 weeks. First angio-computed tomography (CT) characteristics and blood culture led to suspicion of a pneumococcal-infected aortic aneurysm, which however was not confirmed by the surgeon. The abdominal infectious aortitis caused by Streptococcus pneumoniae was affirmed by a second angio-CT performed 7 days later. Without further delay, the patient underwent surgery for resection of mycotic aneurysm and in situ reconstruction with aortobiiliac homograft, in association with antibiotics. He died 10 days after the surgery as a result of severe sepsis in a polyvalent intensive care unit. This case report highlights the severity of this pathology. We reviewed the relevant literature related to Streptococcal pneumoniae mycotic aneurysm located in the abdominal aorta, including 29 more cases. Various microorganisms have already been associated with mycotic aneurysms, including S pneumoniae. Infectious aortitis remains a rare disease. It is extremely important to establish an early diagnosis but it may be delayed because clinical manifestations are usually nonspecific. However, if left untreated it is always lethal. Antibiotic in combination with complete surgical excision of the infected aorta is the treatment of reference. This therapeutic association dramatically improved patient survival.

Sine scleroderma, limited cutaneous, and diffused cutaneous systemic sclerosis survival and predictors of mortality.

BACKGROUND: Systemic sclerosis (SSc) is associated with a variability of mortality rates in the literature. OBJECTIVE: To determine the mortality and its predictors in a long-term follow-up of a bi-centric cohort of SSc patients. METHODS: A retrospective observational study by systematically analyzing the medical records of patients diagnosed with SSc in Toulouse University Hospital and Ducuing Hospital. Standardized Mortality Ratio (SMR), mortality at 1, 3, 5, 10, and 15 years of disease and causes of death were described. Predictors of mortality using Cox regression were assessed. RESULTS: Three hundred seventy-five patients were included: 63 with diffuse cutaneous SSc, 279 with limited cutaneous SSc, and 33 with sine scleroderma. The SMR ratio was 1.88 (95% CI 1.46-1.97). The overall survival rates were 97.6% at 1 year, 93.4% at 3 years, 87.1% at 5 years, 77.9% at 10 years, and 61.3% at 15 years. Sixty-nine deaths were recorded. 46.4% were SSc related deaths secondary to interstitial lung disease (ILD) (34.4%), pulmonary hypertension (31.2%), and digestive tract involvement (18.8%). 53.6% were non-related to SSc: cardiovascular disorders (37.8%) and various infections (35.1%) largely distanced those from cancer (13.5%). Four significant independent predictive factors were identified: carbon monoxide diffusing capacity (DLCO) < 70% (HR=3.01; p=0.0053), C-reactive protein (CRP) >5 mg/l (HR=2.13; p=0.0174), cardiac involvement (HR=2.86; p=0.0012), and the fact of being male (HR=3.25; p=0.0004). CONCLUSION: Long-term data confirmed high mortality of SSc. Male sex, DLCO <70%, cardiac involvement, and CRP> 5mg/l were identified as independent predictors of mortality.

Are Glucosylceramide-Related Sphingolipids Involved in the Increased Risk for Cancer in Gaucher Disease Patients? Review and Hypotheses.

The roles of ceramide and its catabolites, i.e., sphingosine and sphingosine 1-phosphate, in the development of malignancies and the response to anticancer regimens have been extensively described. Moreover, an abundant literature points to the effects of glucosylceramide synthase, the mammalian enzyme that converts ceramide to ß-glucosylceramide, in protecting tumor cells from chemotherapy. Much less is known about the contribution of ß-glucosylceramide and its breakdown products in cancer progression. In this chapter, we first review published and personal clinical observations that report on the increased risk of developing cancers in patients affected with Gaucher disease, an inborn disorder characterized by defective lysosomal degradation of ß-glucosylceramide. The previously described mechanistic links between lysosomal ß-glucosylceramidase, ß-glucosylceramide and/or ß-glucosylphingosine, and various hallmarks of cancer are reviewed. We further show that melanoma tumor growth is facilitated in a Gaucher disease mouse model. Finally, the potential roles of the ß-glucosylceramidase protein and its lipidic substrates and/or downstream products are discussed.

Pulmonary mucormycosis following autologous hematopoietic stem cell transplantation for rapidly progressive diffuse cutaneous systemic sclerosis: A case report.

RATIONALE: The use of autologous hematopoietic stem cell transplantation (AHSCT) for autoimmune diseases has become the first indication for transplant in nonmalignant disease. Mucormycosis is a rare invasive infection with increasing incidence in patients treated with AHSCT. We report the first case of pulmonary mucormycosis following AHSCT for systemic sclerosis (SSc). PATIENT CONCERNS: A 24-year-old woman with rapidly progressive diffuse cutaneous SSc presented with an acute respiratory distress syndrome 6 days after AHSCT. DIAGNOSES: The results of clinical and computed tomography scan were consistent with pulmonary mucormycosis and the diagnosis was confirmed by a positive Mucorales Polymerase Chain Reaction on a peripheral blood sample. INTERVENTIONS AND OUTCOMES: Early antifungal therapy by intravenous amphotericin B provided rapid improvement within 4 days and sustained recovery after 2 years of follow-up. LESSONS: With the progressively increasing use of AHSCT and other stem cell therapy for treatment of severe SSc and other autoimmune diseases, the potential onset of rare post-transplant fungal infections, such as mucormycosis, requires careful patient monitoring and better awareness of early initiation of adequate therapy.

A Cross-Sectional Retrospective Study of Non-Splenectomized and Never-Treated Patients with Type 1 Gaucher Disease.

Patients with type 1 Gaucher disease (GD1) present thrombocytopenia, anemia, organomegaly, and bone complications. Most experts consider that the less aggressive forms do not require specific treatment. However, little is known about the disease course of these forms. The objective of this cross-sectional retrospective study was to compare the clinical, radiological, and laboratory characteristics of patients with less severe GD1 at diagnosis and at the last evaluation to identify features that might lead to potential complications. Non-splenectomized and never-treated patients (19 women and 17 men) were identified in the French Gaucher Disease Registry (FGDR). Their median age was 36.6 years (2.4-75.1), and their median follow-up was 7.8 years (0.4-32.4). Moreover, 38.7% were heterozygous for the GBA1 N370S variant, and 22.6% for the GBA1 L444P variant. From diagnosis to the last evaluation, GD1 did not worsen in 75% of these patients. Some parameters improved (fatigue and hemoglobin concentration), whereas platelet count and chitotriosidase level remained stable. In one patient (2.7%), Lewy body dementia was diagnosed at 46 years of age. Bone lesion onset was late and usually a single event in most patients. This analysis highlights the genotypic heterogeneity of this subgroup, in which disease could remain stable and even improve spontaneously. It also draws attention to the possible risk of Lewy body disease and late onset of bone complications, even if isolated, to be confirmed in larger series and with longer follow-up.

Pregnancy outcome in Refsum disease: Affected fetuses and children born to an affected mother.

We describe the case of a young woman, from a consanguineous family, affected by adult Refsum disease (ARD, OMIM#266500). ARD is a rare peroxisomal autosomal recessive disease due to deficient alpha-oxidation of phytanic acid (PA), a branched-chain fatty acid. The accumulation of PA in organs is thought to be responsible for disease symptoms. The patient presented only bilateral shortening of metatarsals and has been treated with a low-PA diet. She is homoallelic for the c.135-2A > G mutation of PHYH, and she married her first cousin carrying the same mutation. She was pregnant seven times and had two homozygous girls. Due to a potential exacerbation of the disease during the third trimester of pregnancy, her weight and plasma PA levels were monitored. No specific events were noticed for the mother during the pregnancies and postpartum periods. This case also raised the question of potential exposure to PA (and its subsequent toxicity) of a homozygous fetus in a homozygous mother. Despite modestly elevated plasma concentrations of PA at birth (<30 µmol/L), the two affected girls did not present any specific sign of ARD and have so far developed normally. As only a few determinations of plasma PA levels in the mother could be performed during pregnancies, showing mild elevations (<350 µmol/L), it remains difficult to conclude as to a possible transplacental crossing of PA.

Clinical Characteristics and Outcomes of Ocular Cicatricial Pemphigoid: A Cohort Study and Literature Review.

PURPOSE: Ocular cicatricial pemphigoid (OCP) is a rare systemic autoimmune disease and a potentially blinding subepithelial blistering disorder. The purpose of this study was to describe the clinical spectrum of the disease and to assess the efficacy and safety of immunosuppressive agents in a cohort of patients with OCP. METHODS: We conducted a monocentric retrospective cross-sectional cohort study of all unselected consecutive patients diagnosed with progressive OCP. Ocular and extra ophthalmological involvement as well as histological findings were gathered. Other outcomes were exposures to immunosuppressive agents defined by the use of a particular treatment. For each exposure, success in controlling ocular inflammation was graded as a complete response, response, or failure. Relapses and adverse events (AE) were also recorded. RESULTS: Seventeen patients (34 affected eyes), 35% of whom were women, were included, with an age at diagnosis of 75 ± 11 years. Corneal involvement was diagnosed in 30 of 34 eyes, and 22 of 34 eyes had progressive fibrosing conjunctival involvement. Sixty-two exposures to immunosuppressive agents or biologics were recorded: dapsone, n = 26; mycophenolate mofetil, n = 6; azathioprine, n = 4; cyclophosphamide, n = 10; rituximab, n = 14; and intravenous immunoglobulin, n = 2. Rates of response and of complete response achievement during the first 3 months were 84% and 45%, respectively. Response rates were 100%, 100%, 86%, 85%, and 80% for intravenous immunoglobulin, mycophenolate mofetil, rituximab, dapsone, and cyclophosphamide, respectively. Thirteen percent of those drugs were discontinued because of an adverse event in 4 patients. CONCLUSIONS: This study describes the efficacy of immunosuppressants or biologics with an acceptable safety profile for OCP.