Clinical spectrum, outcome and management of immune thrombocytopenia associated with myelodysplastic syndromes and chronic myelomonocytic leukemia.

Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are associated with systemic inflammatory or autoimmune diseases in 10-20 % of cases. Among them, immune thrombocytopenia (ITP) has been reported but large studies assessing this association are missing. Whether such patients have a particular phenotype and require particular management is unclear. This study analyzes the clinical spectrum, outcome and therapeutic management of patients with ITP associated with MDS or CMML, in comparison (i) to patients with primary ITP without MDS/CMML and (ii) to patients with MDS/CMML without ITP. Forty-one MDS/CMML-associated ITP patients were included, with chronic ITP in 26 (63%) patients, low-risk myelodysplasia in 30 (73%) patients and CMML in 24 (59%) patients. An associated autoimmune disease was noted in 10 (24%) patients. In comparison to primary ITP patients, MDS/CMML-associated ITP patients had a higher occurrence of severe bleeding despite similar platelet counts at diagnosis. First-line treatment consisted of glucocorticoids (98%) and intravenous immunoglobulin (IVIg) (56%). Response achievement with IVIg was more frequent in primary ITP than in MDS/CMML-associated ITP patients. Response rates to second-line therapies were not statistically different between primary ITP and MDS/CMMLassociated ITP patients. Ten percent (n=4) of patients with MDS/CMML-associated ITP had multirefractory ITP versus none in primary ITP controls. After a median follow-up of 60 months, there was no difference in overall survival between MDS/CMML-associated ITP and primary ITP patients. Leukemia-free-survival was significantly better in MDS/CMMLassociated ITP patients than in MDS/CMML without ITP MDS/CMML-associated ITP have a particular outcome with more severe bleeding and multirefractory profile than primary ITP, similar response profile to primary ITP therapy except for IVIg, and less progression toward acute myeloid leukemia than MDS/CMML without ITP.

Acute and Chronic Sarcoid Arthropathies: Characteristics and Treatments From a Retrospective Nationwide French Study.

Introduction: We aimed to analyze patients with acute and chronic joint involvements in sarcoidosis. Methods: This is a retrospective multicenter analysis of patients with proven sarcoidosis, as defined by clinical, radiological, and histological criteria, with at least one clinical and/or ultrasonographic synovitis. Results: Thirty-nine patients with sarcoid arthropathy were included, and among them 19 had acute sarcoidosis (Lofgren's syndrome). Joint involvement and DAS44-CRP were not significantly different in acute and chronic sarcoid arthropathies. Acute forms were more frequent than chronic sarcoid arthropathy in Caucasians, without any difference of sex or age between these 2 forms. Joint involvement was frequently more symmetrical in acute than chronic forms (100 vs. 70%; p < 0.05), with a more frequent involvement in wrists and ankles in acute forms, whereas the tender and swollen joint counts and the DAS44-CRP were similar between the 2 groups. Skin lesions were significantly more frequent in patients with acute forms [17 (89%) vs. 5 (25%); p < 0.05] and were erythema nodosum in all patients with Löfgren's syndrome and sarcoid skin lesions in those with chronic sarcoidosis. Among 20 patients with chronic sarcoidosis, treatment was used in 17 (85%) cases, and consisted in NSAIDs alone (n = 5; 25%), steroids alone (n = 5; 25%), hydroxychloroquine (n = 2; 20%), methotrexate (n = 3; 15%), and TNF inhibitors (n = 2; 10%). A complete/partial joint response was noted in 14 (70%) cases with a DAS44-CRP reduction of 2.07 [1.85-2.44] (from 3.13 [2.76-3.42] to 1.06 [0.9-1.17]; p < 0.05). Conclusion: Sarcoid arthropathies have different clinical phenotypes in acute and chronic forms and various treatment regimens such as hydroxychloroquine and methotrexate could be used in chronic forms.

Vasculitis associated with myelodysplastic syndrome and chronic myelomonocytic leukemia: French multicenter case-control study.

INTRODUCTION: Our objective was to evaluate characteristics, treatment and outcome of vasculitis associated with myelodysplastic syndrome (MDS) and chronic myelomonicytic leukemia (CMML) PATIENTS AND METHODS: Retrospective descriptive analysis of MDS/CMML-related vasculitis and comparison with MDS/CMML patients without dysimmune features. RESULTS: Seventy patients with vasculitis and MDS/CMML were included, with median age of 71.5 [21-90] years and male/female ratio of 2.3. Vasculitis was diagnosed prior to MDS/CMML in 31 patients (44%), and after in 20 patients. In comparison with MDS/CMML without autoimmune/inflammatory features, vasculitis with MDS/MPN showed no difference in MDS/CMML subtypes distribution nor International Prognostic Scoring System and CMML-specific prognostic (IPSS/CPSS) scores. Vasculitis subtypes included Giant cell arteritis in 24 patients (34%), Behçet's-like syndrome in 11 patients (20%) and polyarteritis nodosa in 6 patients (9%). Glucocorticoids (GCs) were used as first-line therapy for MDS/CMML vasculitis in 64/70 patients (91%) and 41 (59%) received combined immunosuppressive therapies during the follow-up. After a median follow-up of 33.2 months [1-162], 31 patients (44%) achieved sustained remission. At least one relapse occurred in 43 patients (61%). Relapse rates were higher in patients treated with conventional Disease Modifying Anti-Rheumatic Drug (DMARDs) (odds ratio 4.86 [95% CI 1.38 - 17.10]), but did not differ for biologics (odds ratio 0.59 [95% CI 0.11-3.20]) and azacytidine (odds ratio 1.44 [95% CI 0.21-9.76]) than under glucocorticoids. Overall survival in MDS/CMML vasculitis was not significantly different from MDS/CMML patients without autoimmune/inflammatory features (p = 0.5), but acute leukemia progression rates were decreased (log rank <0.05). CONCLUSION: This study shows no correlation of vasculitis diagnoses with subtypes and severity of MDS/CMML, and no significant impact of vasculitis on overall survival. Whereas conventional DMARDs seem to be less effective, biologics or azacytidine therapy could be considered for even low-risk MDS/CMML vasculitis.

Giant-cell arteritis associated with myelodysplastic syndrome: French multicenter case control study and literature review.

INTRODUCTION: Myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasms (MDS/MPN) can be associated with giant cell arteritis (GCA). In this nationwide study by the "French Network of dysimmune disorders associated with hemopathies" (MINHEMON) the objective was to evaluate characteristics, treatment and outcome of GCA MDS-MDS/MPN. PATIENTS AND METHODS: Retrospective analysis of patients that presented a MDS or MDS/MPN associated with GCA. Treatment efficiency, relapse-free and overall survival of GCA MDS-MDS/MPN were compared to GCA alone. RESULTS: Twenty-one patients with GCA MDS-MDS/MPN were included with median age 76 [42-92], M/F ratio 2.5, 8 MDS with multilineage dysplasia (38%), 4 chronic myelomonocytic leukemia (19%), at low or intermediate risk according to IPPS and IPSS-R. The prevalence of headaches, jaw claudication and anterior ischemic optic neuropathy was significantly lower in patients with GCA MDS-MDS/MPN compared to idiopathic GCA (14.3%, 0% and 0% versus 30%, 25%, and 25%, respectively; p < .05). Other clinical and histology findings were similar. All GCA patients received steroid therapy as first-line treatment. Complete or partial response was observed in 14 GCA MDS-MDS/MPN patients (66.7%), of whom 6 (28.6%) received combined immunosuppressive therapies (versus 10% of idiopathic GCA; p = .07). Relapse incidence was similar in the two groups. Steroid dependence was more frequent among GCA MDS-MDS/MPN patients (12 (57%) versus 18 (22.5%); p < .05). Relapse-free and steroid-free survivals were significantly decreased in GCA MDS-MDS/MPN patients (log rank 0.002 and 0.049 respectively), but not overall survival. CONCLUSION: Characteristics of GCA MDS-MDS/MPN seem different than idiopathic GCA, with a distinct clinical phenotype and poorer outcome with a higher risk of steroid dependence and relapse.

Association between Takayasu arteritis and ischemic heart disease: a cohort study.

PURPOSE OF THE STUDY: Takayasu arteritis (TA) is an idiopathic large vessel vasculitis, which involves the aorta and its major branches. Our aim was to examine the association between TA and the development of ischemic heart disease (IHD) and its impact on survival. STUDY DESIGN: Using data from Clalit Health Services (CHS), the largest Health Maintenance Organization (HMO) in Israel, the proportion of IHD was compared between patients diagnosed with TA and age- and gender-matched controls. Chi-square and t-tests were used for univariate analysis, and a logistic regression model was employed for multivariate analysis. Survival analysis was performed using Kaplan-Meier plots and cox regression. RESULTS: The study included 155 TA patients and 755 age- and gender-frequency matched controls. The proportion of IHD in TA patients was increased in comparison with controls (32.3% and 8.9%, p<0.001). In multivariate analysis, IHD was associated with TA (OR=6.576, 95% CI: 4.09-10.64) and male gender (OR=2.29, 95% CI: 1.43-4.26). Survival analysis over 15 years of follow-up showed a higher proportion of all-causes mortality in the TA group. In a multivariate analysis, TA (HR=2.58, 95%CI: 1.64-4.06) and IHD (HR=1.64, 95%CI: 1.05-2.55) were found to be associated with reduced survival. CONCLUSIONS: TA patients present an increased proportion of IHD, and a reduced 15-years survival rate compared to controls.

The long-term prognostic significance of sarcoidosis-associated pulmonary hypertension - A cohort study.

BACKGROUND: Sarcoidosis is a multisystem, chronic, progressive, granulomatous disease. Sarcoidosis-associated pulmonary hypertension is a well described, but not common, complication of sarcoidosis. In small scale studies, it has been previously described as manifestation of advanced disease and was found to be associated increased morbidity and mortality. This study sought to assess the long-term prognostic significance of sarcoidosis-associated pulmonary hypertension (SAPH) by using data obtained from a large population-based registry which contains longitudinal follow-up data. METHODS: Utilizing the records of the largest healthcare provider in Israel, we extracted a cohort consisting of sarcoidosis patients and age-and-sex matched controls. Dates of sarcoidosis registration, pulmonary hypertension and death, as well as anthropometric information and medical comorbidities, were extracted from the database. A multivariate logistic regression model was used to find variables associated with pulmonary hypertension. Cox proportional hazards method and log-rank test were used for survival analysis. RESULTS: The cohort included 3993 sarcoidosis patients and 19,856 controls. Pulmonary hypertension was observed among 269 sarcoidosis patients (6.74%) vs. 400 controls (2.01%). Sarcoidosis was found as independently associated with pulmonary hypertension (OR 3.17). After a mean follow-up of 7.49 years (median 7.24, maximum 17.88 years), 710 (17.8%) of the sarcoidosis patients and 2121 (10.7%) of the controls had died. Both sarcoidosis and pulmonary hypertension were found to be significantly associated with an increased risk of all-cause mortality (HR 1.82 and HR 2.31, respectively). CONCLUSIONS: SAPH is associated with a poor prognosis. Proper screening methods may assess whether early identification and treatment improve life expectancy.

Thyroid Autoimmunity and Antiphospholipid Syndrome: Not Such a Trivial Association.

Antiphospholipid syndrome (APS) is an autoimmune disease that manifests as recurrent venous or arterial thrombosis and/or pregnancy-related complications in the presence of persistent antiphospholipid (aPL) antibodies measured at least 3 months apart. APS occurs either as a primary condition or as a part of an underlying disorder, usually systemic lupus erythematosus (SLE). Otherwise, APS may be frequently associated with autoimmune disorders. Little is known about the association of APS and aPL antibodies with thyroid autoimmune diseases or thyroid autoantibodies. This is even more interesting that thyroid autoantibodies and aPL are both recognized causes of repeated miscarriages. Therefore, their combination is of particular importance in women of childbearing age. Several studies have pointed out an association between APS and thyroid autoimmunity, some of them suggesting common pathophysiologic processes and genetic background. A literature review was conducted on existing data on aPL/APS and thyroid autoimmune disorders, paying particular attention to the possible role of this association in obstetrical complications.

Biologics in myelodysplastic syndrome-related systemic inflammatory and autoimmune diseases: French multicenter retrospective study of 29 patients.

BACKGROUND: Systemic inflammatory and autoimmune diseases (SIADs) associated with myelodysplastic syndromes are often difficult to treat. Corticosteroids are efficient but only usually at high doses. The use of biologics needs to be specified. METHODS: In a French multicenter retrospective study, we analyzed the efficacy and safety of biologics (tumor necrosis factor-α [TNF-α] antagonists, tocilizumab, rituximab and anakinra) for SIADs associated with myelodysplastic syndromes (MDSs). Clinical, biological and overall treatment responses were evaluated. When several lines of treatment were used, data were analyzed before and at the end of each treatment line and were pooled to compare overall response among steroids, disease-modifying anti-rheumatic drugs (DMARDs) and biologics. RESULTS: We included 29 patients (median age 67years [interquartile range 62-76], 83% males) with MDS-related SIADs treated with at least one biologic. The MDSs were predominantly refractory anemia with excess blasts 1 (38%) and refractory cytopenia with multilineage dysplasia (21%). The SIADs were mainly arthritis (n=6; 20%), relapsing polychondritis (n=8; 30%) and vasculitis (n=10; 34%). During a 3-year median follow-up (IQR 1.3-4.5), a total of 114 lines of treatments were used for all patients: steroids alone (22%), DMARDs (23%), TNF-α antagonists (14%), anakinra (10%), rituximab (10%), tocilizumab (7%) and azacytidine (9%). Considering all 114 lines, overall response (complete and partial) was shown in 54% cases. Overall response was more frequent with steroids (78%) and rituximab (66%) than DMARDs (45%) and other biologics (33%) (p<0.05). Rituximab had better response in vasculitis and TNF-α antagonists in arthritis. During follow-up, 20 patients (71%) presented at least one severe infection. CONCLUSION: This nationwide study demonstrates the efficacy of steroids for SIAD-associated MDSs but a high frequency of steroid dependence. The response to biologics seems low, but rituximab and azacytidine seem promising.

Smoking and obesity in systemic lupus erythematosus: a cross-sectional study.

BACKGROUND: Both smoking and obesity have been demonstrated as risk factors in several autoimmune diseases. Little is known about the relationship between systemic lupus erythematosus (SLE) and both smoking and obesity. OBJECTIVES: To investigate the association between SLE, tobacco consumption and body mass index (BMI). MATERIALS AND METHODS: Using data from the largest Health Maintenance Organization (HMO) in Israel, the Clalit Health Services, we searched for an association between SLE, smoking and obesity. Chi-square and t-test were used for univariate analysis, and a logistic regression model was used for multivariate analysis. Data available from Clalit Health Services database included age, sex, BMI, smoking status, socioeconomic status (SES) and diagnoses of chronic diseases. RESULTS: The study included 5018 patients with SLE and 25 090 age- and sex-matched controls. In multivariate analysis, we found a significant association between smoking and SLE (OR = 1·91). Conversely, there was no association between BMI and SLE. CONCLUSION: In this study, we have shown that smoking is independently associated with SLE, whereas BMI scores were not.

Smoke and autoimmunity: The fire behind the disease.

The association between smoke habit and autoimmunity has been hypothesized a long time ago. Smoke has been found to play a pathogenic role in certain autoimmune disease as it may trigger the development of autoantibodies and act on pathogenic mechanism possibly related with an imbalance of the immune system. Indeed, both epidemiological studies and animal models have showed the potential deleterious effect caused by smoke. For instance, smoke, by provoking oxidative stress, may contribute to lupus disease by dysregulating DNA demethylation, upregulating immune genes, thereby leading to autoreactivity. Moreover, it can alter the lung microenvironment, facilitating infections, which, in turn, may trigger the development of an autoimmune condition. This, in turn, may result in a dysregulation of immune system leading to autoimmune phenomena. Not only cigarette smoke but also air pollution has been reported as being responsible for the development of autoimmunity. Large epidemiological studies are needed to further explore the accountability of smoking effect in the pathogenesis of autoimmune diseases.

[Of worms and men--Administration of helminth products as an innovative approach to treatment of autoimmune diseases].

In areas where helminth infections are common, there is a low prevalence of autoimmune diseases. This observation gave rise to the hygiene hypothesis, claiming that certain organisms which were abundant in the human microenvironment hold an immunoregulatory and immunosuppressive effect, therefore, their eradication led to an increase in immune mediated diseases. This hypothesis laid the foundation for several directions of research which demonstrated an immunosuppressive and immunoregulatory effect of helminths on both the acquired and the innate immune systems. These studies led to the examination of the therapeutic potential of helminths and their components in treating different autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus. The administration of helminth products in murine models of these diseases exhibited a positive effect on disease expression, morbidity and mortality, as well as the ability to prevent the onset of disease to some extent (when given in a preventive protocol). Recently, a synthetic molecule composed of phosphorylcholine (a product of the nematode a. vitae) combined with the protein tuftsin, which is produced by human splenocytes, was shown to exert the aforementioned positive effects on a murine model of systemic lupus erythematosus (SLE). These discoveries point to a new direction in research for developing helminth-based therapies for autoimmune diseases.

Successful modulation of murine lupus nephritis with tuftsin-phosphorylcholine.

In areas where helminths infections are common, autoimmune diseases are rare. Treatment with helminths and ova from helminths, improved clinical findings of inflammatory bowel disease, multiple-sclerosis and rheumatoid-arthritis. The immunomodulatory functions of some helminths were attributed to the phosphorylcholine (PC) moiety. We aimed to decipher the tolerogenic potential of Tuftsin-PC (TPC) compound in mice genetically prone to develop lupus. Lupus prone NZBXW/F1 mice received subcutaneously TPC (5 µg/1 ml), 3 times a week starting at 14 weeks age. Autoantibodies were tested by ELISA, T-regulatory-cells by FACS, cytokines profile by RT-PCR and cytokines protein levels by DuoSet ELISA. Glomerulonephritis was addressed by detection of proteinuria, and immunoglobulin complex deposition in the mesangium of the kidneys of the mice by immunofluorescence. Our results show that TPC attenuated the development of glomerulonephritis in lupus prone mice, in particular, it ameliorated proteinuria (p < 0.02), and reduced immunoglobulin deposition in the kidney mesangium. TPC also enhanced the expression of TGFß and IL-10 (p < 0.001), and inhibited the production of IFNγ and IL-17 (p < 0.03). TPC Significantly enhanced the expansion of CD4+CD25+FOXP3+ T-regulatory cells (Tregs) phenotype in the treated mice. These data indicate that TPC hampered lupus development in genetically lupus prone mice which was exemplified by moderate glomerulonephritis, attenuation of pro-inflammatory cytokines and enhancement of anti-inflammatory cytokines expression, as well as Tregs expansion. Our results propose harnessing novel natural therapy for lupus patients.

Unraveling the Hygiene Hypothesis of helminthes and autoimmunity: origins, pathophysiology, and clinical applications.

BACKGROUND: The Hygiene Hypothesis (HH) attributes the dramatic increase in autoimmune and allergic diseases observed in recent decades in Western countries to the reduced exposure to diverse immunoregulatory infectious agents. This theory has since largely been supported by strong epidemiological and experimental evidence. DISCUSSION: The analysis of these data along with the evolution of the Western world's microbiome enable us to obtain greater insight into microorganisms involved in the HH, as well as their regulatory mechanisms on the immune system. Helminthes and their derivatives were shown to have a protective role. Helminthes' broad immunomodulatory properties have already begun to be exploited in clinical trials of autoimmune diseases, including inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and type-1 diabetes. SUMMARY: In this review, we will dissect the microbial actors thought to be involved in the HH as well as their immunomodulatory mechanisms as emphasized by experimental studies, with a particular attention on parasites. Thereafter, we will review the early clinical trials using helminthes' derivatives focusing on autoimmune diseases.

Treating prolactinoma can prevent autoimmune diseases.

Prolactin (PRL) is a pleiotropic hormone; in addition to a wide variety of endocrine effects, PRL also exhibits immunostimulating effects. Therefore, there is increasing evidence linking PRL with a large number of systemic and organ specific autoimmune diseases. Herein, we report the case of an adolescent girl diagnosed with multiple sclerosis (MS) occurring in the context of untreated prolactinoma evolving since childhood. This raises the exciting question of the involvement of PRL in the pathogenesis of MS. It is likely that early treatment of hyperprolactinemia in this case would have significantly reduced the risk of developing MS or even prevented its occurrence.

Obesity in autoimmune diseases: not a passive bystander.

In the last decades, autoimmune diseases have experienced a dramatic increase in Western countries. The involvement of environmental factors is strongly suspected to explain this rise. Particularly, over the same period, obesity has followed the same outbreak. Since the exciting discovery of the secretory properties of adipose tissue, the relationship between obesity and autoimmunity and the understanding of the underlying mechanisms have become of major interest. Indeed, the fat tissue has been found to produce a wide variety of "adipokines", involved in the regulation of numerous physiological functions, including the immune response. By conducting a systematic literature review, we extracted 329 articles regarding clinical, experimental and pathophysiological data on the relationship between obesity, adipokines - namely leptin, adiponectin, resistin, visfatin - and various immune-mediated conditions, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), multiple sclerosis (MS), type-1 diabetes (T1D), psoriasis and psoriatic arthritis (PsA), and thyroid autoimmunity (TAI), especially Hashimoto thyroiditis (HT). The strongest levels of evidence support an increased risk of RA (OR=1.2-3.4), MS (OR=2), psoriasis and PsA (OR=1.48-6.46) in obese subjects. A higher risk of IBD, T1D and TAI is also suggested. Moreover, obesity worsens the course of RA, SLE, IBD, psoriasis and PsA, and impairs the treatment response of RA, IBD, psoriasis and PsA. Extensive clinical data and experimental models demonstrate the involvement of adipokines in the pathogenesis of these autoimmune diseases. Obesity appears to be a major environmental factor contributing to the onset and progression of autoimmune diseases.

[Erdheim-Chester disease: radiological findings]. / Maladie d'Erdheim-Chester: apport de l'imagerie.

CONTEXT: Erdheim-Chester disease is a rare non-Langerhans form of histiocytosis. For the past years, the disease has been reported with an increasing frequency, linked to a better knowledge of it's radiological pattern. Indead, it shows specific imaging appearances, that should be recognized. METHODS: We report four cases illustrating those typical imaging findings. RESULTS: Common X-rays films show bilateral and symmetric heterogeneous osteosclerosis of the metaphysis and the diaphysis in the lower limbs long bones, with paget's disease-like pattern. Magnetic resonance imaging depicts a replacement of the normal fatty bone marrow by a heterogeneous high intensity signal infiltrate on T1 fat-suppressed weighted imaging with intravenous injection of gadolinium and T2 fat-suppressed weighted sequences, sparing the subchondral bone. Bone scintigraphy reveals a pathognomonic bilateral and symmetric increased uptake affecting both diaphysis and metaphysis of the femur and the tibiae. Tomodensitometry enable to disclose visceral and vascular involvement, showing typical "hairy kidney" appearance and perivascular infiltration. CONCLUSION: Erdheim-Chester disease may be a life-threatening disease. A good knowledge of it specific imaging features seems to be crucial for early management and improved prognosis.