Impaired TGF-ß signaling in patients with active systemic lupus erythematosus is associated with an overexpression of IL-22.

The mechanisms leading to the disruption of self-tolerance in systemic lupus erythematosus (SLE) remain elusive. Herein, we aimed to decipher the molecular basis of the impaired response of mononuclear cells to TGF-ß1. The Smad3-pathway was explored on CD3+ lymphocytes in either active or non active SLE patients. An impaired transcription of TGF-ß1 target genes was demonstrated in the CD3+ lymphocytes of active SLE patients confirming that the defect involves T cells and pointing to its extrinsic nature. We further demonstrate that the defect did not result from an impaired TGF-ßRII expression or Smad2/3 phosphorylation suggesting that the mechanism lies downstream Smad2/3 translocation. Interestingly, the TGF-1 signaling defect did not correlate with an increased expression of soluble or membrane-bound IL-15. However, it was associated with an overexpression of IL-22. This suggests that an excessive activation of AhR pathway (through UV radiations, infections, etc.) could lead to the inhibition of immunosuppressive actions of TGF-ß thus disrupting immune homeostasis in SLE. Collectively, our data suggest that the impaired response to TGF-ß in SLE patients is associated with disease activity and provide new insights into the pathogenesis of SLE since it could establish the link between the environmental factors and the aberrancies of the immune system usually described in SLE.

Pulmonary manifestations in antisynthetase syndrome.

INTRODUCTION: Pulmonary manifestations are frequent in patients with antisynthetase syndrome which is a particular form of inflammatory myopathies. AIM: The aim of this study is to describe clinical features and long term outcome of interstitial lung disease in these patients. METHODS: This is a retrospective descriptive study in an internal medicine department. Patients with antisynthetase syndrome hospitalized from 2000 to 2014 were collected. RESULTS: There were nine patients; five women and four men. The mean age at diagnosis was 54.4 ±11.2 years. Interstitial lung disease was observed in all cases and revealed the disease in five cases. The more frequent aspect in high resolution computer thoracic scan was ground-glass opacities (n=8). Traction bronchiectasis and septal thickening were noted each one, in five cases. Honeycombing was observed in one case. Restrictive syndrome was noted in 4/4 cases. All patients received corticosteroids. Two patients were treated with methotrexate for myositis. Intravenous cyclophosphamide was used in five patients (at diagnosis for severe interstitial lung disease in three cases and after pulmonary function worsening in two other cases). Improvement was noted in seven patients. Two patients died after pulmonary symptom worsening and respiratory insufficiency. CONCLUSION: Interstitial lung disease in patients with antisynthetase syndrome may have a poor prognosis and should be treated at time. Altough the optimal therapy was not clearly established, corticosteroids are considered to be the first line therapy. Immunosuppressive agents as cyclophosphamide, azathioprine or methotrexate may be used in some cases.

Erdheim-Chester disease: A multisystem disease case illustration with rare manifestations and treatment challenges.

Erdheim-Chester disease is a rare multisystemic disease. A 50-year-old woman, presented with a recurrent pain and swelling of the left knee. Bone scintigraphy showed increased tracer uptake of peripheral skeleton. The computed tomography showed tissular infiltration in the retroperitoneum, around the vessels. Immunohistochemistry showed CD68 (+) and CD1a (-).

Adult-onset Still's disease after SARS-Cov-2 infection.

Adult-onset Still's disease (AOSD) is an uncommon inflammatory disorder. AOSD and SARS-Cov-2 infection share clinical and laboratory features, including systemic inflammation. A 19-year-old woman had prolonged fever for 3 weeks, joint pain, and biological inflammatory syndrome. Post COVID-19 AOSD was diagnosed. SARS-Cov-2 infection induces many inflammatory diseases including AOSD.

Particularities of infectious complications in systemic lupus erythematosus.

AIM: To describe characteristics of systemic lupus erythematosus (SLE) patients with infectious complications and to determine frequency, clinical and microbiological features and outcomes of reported infections. METHODS: This is a descriptive, retrospective study conducted over an 11-year period at the Internal Medicine Department La Rabta Hospital Tunis, collecting medical records of SLE patients who had experienced infectious complications. RESULTS: Fifty-six patients were included, consisting of 52 females and 4 males (gender ratio M/F= 0.07). The mean age at SLE diagnosis was 35±13.8 years. The mean duration of the disease was 4.8±3.1 years. A total of seventy-eight infections were documented. Infection revealed the disease in 12 patients (21%) and occurred after an average delay of 36 months [1-156 months] of SLE diagnosis. Forty-three patients (74%) were receiving corticosteroid therapy, associated in 37.5% of cases with immunosuppressive treatment. Urinary and pleuro-pulmonary infections were most common infectious sites. An infectious agent was identified in 59 cases (76%). Bacterial infections were the most common (76%), dominated by the enterobacteria pathogen agent. Viral infections (n=12) were mainly caused by varicella-zoster virus and cytomegalovirus. Five patients required intensive care. Twenty patients experienced a lupus flare during the infectious episode. The outcome was favorable in 52 (93%) patients. Three patients died, two due to septic shock caused by pulmonary infection in two cases and cutaneous infection in one patient. One patient died from a probable pulmonary embolism. CONCLUSION: Infectious complications are responsible for significant morbidity and mortality during SLE. Hence the importance of early diagnosis and adequate management.

Unilateral pseudouveitis revealing a pancreatic neuroendocrine carcinoma: A case report.

Neuroendocrine tumors are a heterogeneous group of tumors with a wide range of malignant potential that tend to have a relative prolonged course. These tumors infrequently metastasize to the orbit. To the best of our knowledge, ocular metastases from pancreatic neuroendocrine tumors (PNETs) have never been reported in the literature. We report the case of a 61-year-old man who presented with progressive deterioration of general condition with unilateral recurrent episodes of non-granulomatous panuveitis of the left eye related to a choroidal metastasis. Radiological imaging and histopathological analyses led to the diagnosis of metastatic pancreatic neuroendocrine carcinoma as the primary tumor. Choroidal metastases from neuroendocrine tumors are extremely rare, but compromise patients' well-being because of visual impairment. Uncommonly, these metastases can be the first manifestation of unknown tumors, warranting further investigations to detect the primary cancer.

Resistance to exogenous TGF-ß effects in patients with systemic lupus erythematosus.

BACKGROUND: The mechanisms underlying the loss of self-tolerance in systemic lupus erythematosus (SLE) are incompletely deciphered. TGF-ß plays a key role in self-tolerance demonstrated by the onset of a fatal autoimmune syndrome associated with lupus autoantibodies in mice lacking a functional TGF-ß receptor. The present work aims to define whether resistance to TGF-ß might contribute to the pathogenesis of SLE. METHODS: Twenty-two patients with active SLE, 16 with other connective tissue diseases, and 10 healthy controls were prospectively included in this study. The effects of exogenous TGF-ß1 on IL-2-dependent T-cell proliferation, IFN-γ secretion, and target gene transcription were analyzed on peripheral blood mononuclear cells. RESULTS: Our results showed that 75% of patients with SLE or other connective tissue diseases were totally or partially resistant to the effects of TGF-ß1. The responses to the anti-proliferative and transcriptional effects of TGF-ß were, however, discordant in a high proportion of our patients. Hence, we distinguish three distinct profiles of resistance to TGF-ß1 and suggest that patients may exhibit different defects affecting distinct points of TGF-ß1 signaling pathways. CONCLUSION: Our data demonstrate the presence of an impaired response of peripheral cells to TGF-ß1 in patients with active SLE that may participate to the pathogenesis of the disease. Further studies will be necessary to delineate the mechanisms underlying the lymphocyte resistance to TGF-ß1 in SLE.

Association of systemic beta-defensin-1 and -20G/A DEFB1 gene polymorphism with Behçet's disease.

BACKGROUND: Behçet's disease (BD) is a multisystem inflammatory disease of unknown etiology. Beta-defensins are antimicrobial peptides involved in epithelial host defense. To explore whether beta-defensins might be involved in BD pathogenesis, we examined plasma human beta-defensin-1 (hBD-1) and DEFB1 -20G/A polymorphism in BD patients. METHODS: This case-control study included 106 BD patients fulfilling the criteria of the International Study Group for BD and 156 controls. The -20G/A genotypes were determined by PCR-RFLP analysis in all participants, and plasma hBD-1 was assessed by ELISA in 77 BD patients and 44 controls, only. Stepwise multiple regression models were applied to determine independent predictors for plasma hBD-1 in BD patients. RESULTS: Distribution of -20G/A genotypes was different between BD patients and controls. Compared to GG genotype, "GA" genotype [OR (95% CI), 3.12 (1.56-6.16); p = .001] and "AA" genotype [2.57 (1.10-5.96); p = .027)] were associated with increased risk for BD. Plasma hBD-1 concentrations were significantly higher in BD patients than controls (9.81 ±â€¯3.52 ng/mL vs. 5.30 ±â€¯3.02 ng/mL; p < .001), and in BD patients with neurological involvement than those without (11.1 ±â€¯4.12 ng/mL vs. 9.19 ±â€¯3.10 ng/mL; p = .040). No variation was noted according to other clinical features, treatment received or -20G/A genotypes. In multivariate analysis, neurological involvement was the only predictor for plasma hBD-1 (ß, 0.274; p = .029). CONCLUSIONS: Findings suggest that hBD-1 and its encoding gene DEFB1 could modulate the risk for BD, especially for BD neurological involvement. Further work is needed for a better understanding of role of hBD-1 and its genetic variants in the pathogenesis of BD.

TH17 cells expressing CD146 are significantly increased in patients with Systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disorder characterized by vascular damage, excessive fibrosis and abnormal T cells immune-regulation. CD146 is an adhesion molecule essentially expressed in the vascular system, but also on TH17 lymphocytes. In view of the recently described role of CD146 in SSc, we hypothesized an involvement of CD146 positive TH17 cells in this disease. Compared to healthy controls, we showed that both soluble form of CD146 (sCD146), and IL17A levels were increased in patients with SSc with a positive correlation between both factors. A significant increase in TH17 cells attested by an increase of RORγT, IL17A mRNA and CD4+ IL17A+ cell was observed in patients with SSc. Interestingly, the percentage of TH17 cells expressing CD146 was higher in patients with SSc and inversely correlated with pulmonary fibrosis. In vitro experiments showed an augmentation of the percentage of TH17 cells expressing CD146 after cell treatment with sCD146, suggesting that, in patients the increase of this sub-population could be the consequence of the sCD146 increase in serum. In conclusion, TH17 cells expressing CD146 could represent a new component of the adaptive immune response, opening the way for the generation of new tools for the management of SSc.

Tumor necrosis factor gene polymorphisms in Tunisian patients with Behcet's disease.

Behcet's disease (BD) is an inflammatory disorder that is mainly characterized by recurrent oral and genital ulcers, skin lesions, and uveitis. Recent reports focused on the genetic factors of susceptibility to this disease and especially the TNF in view of the major role played by this proinflammatory cytokine in the lesional process of Behcet's disease. In this report, we investigated the possible association between Behcet's disease and the TNF-alpha gene promoter polymorphisms -1031T/C, -308A/G, and the TNF-beta polymorphism +252A/G in Tunisian population. We compared the distribution of these polymorphisms between 89 BD patients and 157 healthy controls using polymerase chain reaction restriction fragment length-polymorphism (PCR-RFLP) analysis. The frequency of the TNF-alpha -1031C allele was significantly higher in Behcet's patients than in healthy controls (p = 0.015; chi(2) = 5.84; OR = 1.65; 95% CI = 1.08-2.54), whereas the frequencies of the TNF-alpha -308G and the TNF-beta +252G alleles were similar in the two compared groups. These results suggest that the variability of the TNF-alpha -1031T/C polymorphism can be associated with the susceptibility to Behcet's disease in our study group. Therefore, the TNF molecule may have an important genetically and/or functionally implication in the pathogenesis of BD in the Tunisian population.

Protracted superficial Wegener granulomatosis in a child.

Wegener granulomatosis is a rare, chronic, multisystemic vasculitis affecting mainly the upper and lower respiratory tracts together with glomerulonephritis, but the disease may involve any other organ. Protracted superficial form is a rare variant of the disease. We report a case of protracted superficial Wegener granulomatosis in a 16-year-old boy in whom the disease started with recurrent digital ulcers at age 7 years. Later, he developed nodules and papules associated with upper airway involvement and ocular keratitis without lung or renal involvement. C-ANCA was positive. The patient was treated with oral prednisone. Similar cutaneous and mucosal lesions developed during two relapses of the disease without renal or respiratory involvement.

Primary Sjögren's syndrome complicated by anti-neutrophil cytoplasmic antibody-mediated crescentic glomerulonephritis.

Ocular and oral dryness are the hallmark of Sjögren's syndrome (SS). However, SS can be associated with a variety of complications, affecting organs such as the liver, kidneys, lungs, muscle, and nervous system. Renal involvement has been usually in the form of tubulointerstitial nephritis. However, glomerulonephritis is rare in primary SS. We report three clinical cases of SS with anti-neutrophil cytoplasmic antibody-mediated crescentic glomerulo-nephritis treated with prednisone and cyclophosphamide, with favorable outcome.

[Ureteral stenosis in Wegener's granulomatosis. Case report]. / Sténose urétérale au cours de la granulomatose de Wegener. Une observation.

INTRODUCTION: Ureteral stenoses in Wegener's granulomatosis are rare. They usually involve the pelvic portion of the ureter and are caused by vasculitic lesions or granulomatous inflammation. CASE: A 38-year-old woman with Wegener's granulomatosis was treated with corticosteroids and monthly intravenous cyclophosphamide pulses. After 4 months, urinary retention developed, accompanied by lumbar pain, associated with protenuria and hematuria, and related to bilateral ureteral stenoses. Treatment by endoscopic dilatation and double J stents led to with clinical and radiological improvement, while the medical treatment continued. CONCLUSION: Hematuria in patients with Wegener's granulomatosis suggests renal involvement, but ureteral stenoses must also be considered when these patients present hematuria or urinary tract infections. Surgery should be reserved for those patients in whom medical treatment is not rapidly effective.

[Shulman syndrome. A report of 4 cases and review of the literature]. / Syndrome de Shulman. A propos de 4 cas avec revue de la litterature.

The goal of this study is to report four cases of Shulman syndrome with a literature review. Shulman syndrome is a rare disorder recently considered a systemic disease. Our first case shows woody induration of the buttock and trunk with features of morphea. The diagnosis of eosinophilic fasciitis, suspected on hypereosinophilia, was confirmed by histological findings of muscle biopsy. In the second and the third case, the induration affected arms and legs. Obiouvs streneous exercise was noted in the third patient. Those patients fullfiled the criteria of eosinopfilic fasciitis. Visceral involvement consisted on restrictive lung function defects on the second case and oesophageal hypokinesia in the third case. In the fourth case, there was a scleroderma-like on the extremitis with extension to abdomen. Erythrocyte sedimentation rate was normal. Histological findings confirm the diagnosis of eosinophilic fasciitis. All patients were treated with general steroids at high doses associated to cimetidine in the second patient. Once therapy ended, relapses occur in escond and third cases.

Central Retinal Vein Occlusion Revealing Coeliac Disease.

INTRODUCTION: Thrombosis has been widely reported in coeliac disease (CD) but central retinal vein occlusion (CRVO) is rarely described. CASE PRESENTATION: A 27-year-old woman presented with acute visual loss and was diagnosed with CRVO. Her protein S and protein C levels were low and CD was diagnosed on the basis of endoscopic, immunological and histological results. A gluten-free diet resulted in favourable evolution. CONCLUSION: CD should be considered in young patients with thrombosis, especially if in an unusual location. Treatment is based on a gluten-free diet. LEARNING POINTS: Coeliac disease (CD) should be considered in young patients with central retinal vein occlusion (CRVO).Several mechanisms can cause thrombosis in CD.CRVO in CD is often reversible with a gluten-free diet.

[Panniculitis in patient undergoing treatment for dermatomyositis with methotrexate]. / Panniculite au cours d'un traitement d'une dermatomyosite par du méthotrexate.

Panniculitis is a rare cutaneous manifestation of dermatomyositis (DM). The appearance of panniculitis during treatment with methotrexate (MTX) is exceptional and has only been described in 3 cases. We report a case of a 50-year-old woman suffering from DM since 1997 who was treated with corticosteroids showing favorable clinical and biological evolution. When a relapse occurred 2 years later, she was treated with higher-dose of corticosteroids in combination with a 7,5 mg weekly dose of methotrexate. The evolution was rapidly favorable. Eighteen months later, the patient had multiple subcutaneous nodules on limbs and buttocks. Anatomopathological examination showed panniculitis. There was no evidence supporting progression in DM. Prednisone dose was increased to 0.5 mg/kg/day, always in combination with MTX, without any clear signs of improvement. MTX treatment was stopped and the cutaneous lesions completely disappeared in 2 months without any relapse. This objective response lasted for 42 months. Our observation is particular given the occurrence of panniculitis in a patient undergoing treatment for dermatomyositis with methotrexate and illustrates the difficulties in the diagnosis. This entity must be known despite its exceptional nature since cutting off MTX treatment generally induces the disappearance of subcutaneous nodules.

Pleural myelomatous involvement in multiple myeloma: five cases.

Pleural myelomatous involvement in multiple myeloma (MM) is rare, occurring in less than 1% of cases. We retrospectively studied five cases of patients with MM who developed myelomatous pleural effusions. Three men and 2 women with a mean age of 61 years presented with myelomatous pleural effusion. The pleural fluid electrophoresis revealed a peak of IgG in three cases, of IgA in one case, and of lambda light chains in one case, which were identical to that in the sera of the patients. Detection of typical plasma cells in pleural fluid cytology was contributive, and histologic confirmation by pleural biopsy was positive in four cases. Treatment consisted of chemotherapy. The clinical outcome was initially good, but relapses occurred in all cases early and were complicated by fatal infections. Myelomatous pleural effusion is a rare affection. It is usually a late complication associated with poor prognosis.

Esophageal involvement in Behcet's disease.

Esophageal involvement in Behcet's disease is very rare, and normally is observed as aphtosis and esophagitis, but serious complications such as erosions, perforations, and stenosis may occur. We carried out this prospective study to evaluate the prevalence of esophageal involvement in Behcet's disease and to establish if routine endoscopy and/or manometry are necessary. Twenty-three patients who fulfilled the diagnostic criteria of the international study group for Behcet's disease were enrolled. None were taking drugs or had disease that might produce esophageal abnormalities or alter any existing changes due to the Behcet's disease itself. Twenty- three patients underwent esophagogastroduodenoscopy by a single observer. Esophageal biopsies were performed in thirteen patients and esophageal manometry in twenty. At the beginning of the study, the disease activity was defined by the presence of more than one symptom related to Behcet's disease, and upon the classification of Behcet's disease. Of the twenty three patients enrolled two were excluded from final analysis because of the presence of hiatus hernia. Thus, 13 men and 8 women, ranging in age from 20 to 63 years with a mean age of 36.2 years were included. Ten patients (47.6%) had active disease and four (19%) complained of upper gastrointestinal symptoms at the time of the study. Fourteen patients had endoscopic, manometric and/or microscopic abnormalities. Esophageal manometry was performed in twenty patients and was abnormal in 7 cases (35%). Esophageal biopsies were done in 13 patients and revealed histopathological abnormalities in 5 cases. Microscopic findings showed vasculities in one case, and non-specific inflammatory infiltration mainly consisting of neutrophils in 4 cases. Our results suggest that the prevalence of esophageal involvement in Behcet's disease is rather high and occur even in asymptomatic patients, but that this usually does not result in specific abnormalities.

Heparin use during pregnancy.

The use of anticoagulants in pregnancy is problematic. In this focus, the authors reviewed the problems associated with the use of vitamin K antagonist during pregnancy. Then, they presented the general considerations on the use of unfractioned heparin and low molecular weight heparin during pregnancy. Finally they established the therapeutic recommendations for anticoagulation during pregnancy including treatment and prophylaxis of venous thromboembolism, anticoagulation of pregnant women with mechanical heart valves and the management of pregnant women with antiphospholipid antibodies and multiple pregnancy losses.