Long-term efficacy and safety of 2CdA (cladribine) in extra-pulmonary adult-onset Langerhans cell histiocytosis: analysis of 23 cases from the French Histiocytosis Group and systematic literature review.

Langerhans cell histiocytosis (LCH) is a rare protean disease that usually affects children. Few data are available for management of adult-onset cases. A complete picture of the efficacy and safety of 2CdA (2-chlorodeoxyadenosine, cladribine) is lacking. We report a retrospective multicentre study of 23 adult LCH (a-LCH) patients who received single-agent 2CdA and a systematic literature review. All had previously received systemic therapy (vinblastine, n = 19). Response to 2CdA was evaluable in 22 cases. Overall response rate (ORR) was 91%. Complete response (CR) occurred in 11 cases (50%). Nine patients (39%) developed grade 3-4 neutropenia and/or severe infection. A literature review yielded 48 additional cases. A pooled analysis confirmed our findings (ORR: 88%, CR: 49%). CRs were rare with cumulative dose <50 mg/m2 . Disease progression rates were 20% and 30% at two and five years, respectively. Partial response (PR) to 2CdA was predictive of disease progression. Among eight re-treated patients, five went into CR, two in PR, and one died. Single-agent 2CdA is effective in reactivated a-LCH, including at intermediate doses. Toxicity, significant but acceptable, warrants infectious prophylaxis. Complete responders may enter prolonged remission. Further studies are needed to determine 2CdA sequencing with other agents (vinblastine, cytarabine).

Granulomatosis with polyangiitis: endoscopic management of tracheobronchial stenosis: results from a multicentre experience.

OBJECTIVES: Tracheobronchial stenosis (TBS) is noted in 12-23% of patients with granulomatosis with polyangiitis (GPA), and includes subglottic stenosis and bronchial stenosis. We aimed to analyse the endoscopic management of TBS in GPA and to identify factors associated with the efficacy of endoscopic interventions. METHODS: We conducted a French nationwide retrospective study that included 47 patients with GPA-related TBS. RESULTS: Compared with patients without TBS, those with TBS were younger, more frequently female and had less frequent kidney, ocular and gastrointestinal involvement and mononeuritis multiplex. Endoscopic procedures included 137 tracheal and 50 bronchial interventions, mainly endoscopic dilatation, local steroid injection and conservative laser surgery, and less frequently stenting. After the first endoscopic procedure, the cumulative incidence of endoscopic treatment failure was 49% at 1 year, 70% at 2 years and 80% at 5 years. Factors significantly associated with a higher cumulative incidence of treatment failure were a shorter time from GPA diagnosis to endoscopic procedure [hazard ratio (HR) 1.08 (95% CI 1.01, 1.14); P = 0.01] and a bronchial stenosis [HR 1.96 (95% CI 1.28, 3.00); P = 0.002]. A prednisone dose ≥30 mg/day at the time of the procedure was associated with a lower cumulative incidence of treatment failure [HR 0.53 (95% CI 0.31, 0.89); P = 0.02]. CONCLUSION: TBS represents severe and refractory manifestations with a high rate of restenosis. High-dose systemic CSs at the time of the procedure and increased time from GPA diagnosis to bronchoscopic intervention are associated with a better event-free survival. In contrast, bronchial stenoses are associated with a higher rate of restenosis than subglottic stenosis.

Efficacy of vinblastine in central nervous system Langerhans cell histiocytosis: a nationwide retrospective study.

BACKGROUND: Vinblastine (VBL) is the standard treatment for systemic Langerhans cell histiocytosis (LCH), but little is known about its efficacy in central nervous system (CNS) mass lesions. METHODS: A retrospective chart review was conducted. Twenty patients from the French LCH Study Group register met the inclusion criteria. In brief, they had CNS mass lesions, had been treated with VBL, and were evaluable for radiologic response. RESULTS: The median age at diagnosis of LCH was 11.5 years (range: 1-50). Intravenous VBL 6 mg/m2 was given in a 6-week induction treatment, followed by a maintenance treatment. The median total duration was 12 months (range: 3-30). Eleven patients received steroids concomitantly. Fifteen patients achieved an objective response; five had a complete response (CR: 25%), ten had a partial response (PR: 50%), four had stable disease (SD: 20%) and one patient progressed (PD: 5%). Of interest, four out of the six patients who received VBL without concomitant steroids achieved an objective response. With a median follow-up of 6.8 years, the 5-year event-free and overall survival was 61% and 84%, respectively. VBL was well-tolerated and there were no patient withdrawals due to adverse events. CONCLUSION: VBL, with or without steroids, could potentially be a useful therapeutic option in LCH with CNS mass lesions, especially for those with inoperable lesions or multiple lesions. Prospective clinical trials are warranted for the evaluation of VBL in this indication.

Langerhans' cell histiocytosis of the liver in adults.

Among adults, liver involvement is relatively frequent in Langerhans' cell histiocytosis (LCH), even though it is often overlooked. In fact, the liver involvement may be missed in apparently localized LCH or when it is the sole site of involvement. We present 23 cases of liver involvement in LCH out of a cohort study of 85 adult patients included in the French Histiocytosis Study Group Registry. The most frequent clinical setting was multiorgan involvement (87% of our cases). The main histological pattern in liver LCH was sclerosing cholangitis (56% of the cases). The symptoms included hepatomegaly (48%) and/or liver biochemistry abnormalities (61%, including cholestasis associated with increased transaminases levels in 35% of cases, cholestasis only in 22% and increased transaminases levels only in 4% of the cases). Particularly suggestive of the diagnosis was the observation of biliary tree abnormalities through magnetic resonance imaging (MRI). The natural history of liver LCH fits into two stages: early infiltration by histiocytes and late sclerosis of the biliary tree. We found that liver involvement had a significant impact on survival. Thus we suggest that clinical and biological liver evaluation must be performed regularly onwards to screen every LCH adult patient from the time of the initial diagnosis. MRI and liver biopsy should be considered as soon as the data point to a possible liver localization. If this diagnosis is confirmed, we suggest a treatment with ursodesoxycholic acid, as in other cholestatic diseases, together with treatments specifically directed towards LCH. However, the ideal treatment of liver LCH remains to be found, and in advanced cases transplantation is the sole option.

Severe strongyloidiasis in corticosteroid-treated patients: case series and literature review.

OBJECTIVE: To describe the main features of severe strongyloidiasis in corticosteroid-treated patients METHODS: We report on 3 cases of corticosteroid-treated patients with severe strongyloidiasis and review cases of severe strongyloidiasis in corticosteroid-treated patients reported in the literature. RESULTS: One hundred and fifty-one cases of severe strongyloidiasis complicated a therapy with corticosteroids were evaluated. The mean age of the patients was 48+/-17 years and 71% were men. Corticosteroids were given for hematological malignancies in 34 (23%), systemic lupus erythematosus or vasculitis in 27 (18%), and nephropathy or renal transplantation in 32 (21%). At time of infection, the mean daily dosage of prednisone-equivalent was 52+/-42 mg (median: 40 mg) and 84% of patients had received a cumulative dosage of prednisone-equivalent higher than 1000 mg. The total duration of treatment ranged from 4 days to 20 years (6 months or less: 69%). Non-specific gastro-intestinal symptoms were reported in 91% of these patients associated or not with pulmonary complaints. Low-grade fever was present in 54% of patients. Fifty-nine patients (39%) experienced severe bacterial or yeast infection during the course of severe strongyloidiasis. Peripheral eosinophilia was detected at presentation in 32% of patients. Strongyloidiasis was usually confirmed by repeated stool examinations. Thiabendazole was the treatment the more widely used. Eighty-nine patients (59%) deceased during the course of the disease. CONCLUSIONS: Severe strongyloidiasis is a risk in every corticosteroid-treated patient who has traveled to a soil-infested country, even if the contact was 30 years prior. This diagnosis should be suspected in patients who either experience unusual gastro-intestinal or pulmonary symptoms or suffer from unexplained Gram-negative bacilli sepsis.

Visual loss mimicking a treated temporal arteritis relapse.

We describe a patient who, during tapering of corticosteroids prescribed for temporal arteritis (TA), developed nocardiosis that was mimicking a specific relapse. An isolated choroidal ischemia was thought to be a symptom of TA. Steroid therapy was intensified and, while on aggressive steroid therapy, the patient died of septic shock. Autopsy revealed occult disseminated nocardiosis with septic arteritis and apparently cured TA. Visual loss occurring during TA treatment should lead clinicians to consider a specific relapse as well as an opportunistic infection like nocardiosis.

Celiprolol-induced lupus-like syndrome.

Systemic lupus erythematosus can be idiopathic or drug-induced. Although a number of beta-blockers have been reported to induce a lupus-like syndrome, to the best of our knowledge, no such case has been described following celiprolol therapy. We diagnosed a lupus-like syndrome in a 67-year-old female patient who developed febrile polyarthritis, percarditis, antinuclear and anti-histone antibodies after taking celiprolol for 2 years. Despite drug withdrawal, prolonged corticotherapy was needed to obtain clinical and biological remission.

[Langerhans cell histiocytosis in an adult patient associated with sclerosing cholangitis and cerebellar atrophy]. / Histiocytose langerhansienne de l'adulte avec cholangite sclérosante et atrophie cérébelleuse.

Langerhans' cell histiocytosis is a disorder in children or young adults, characterized by clonal proliferation of histiocytic cells, staining for CD1a, with uni or multifocal organ involvement. It's a rare condition in adults. We report a case of Langerhans' cell histiocytosis in an adult with sclerosing cholangitis which rapidly progressed to fatal liver failure and progressive cerebellar atrophy. Langerhans cell histiocytosis is a rare cause of sclerosing cholangititis in adults.

Cardiovascular involvement, an overlooked feature of Erdheim-Chester disease: report of 6 new cases and a literature review.

Erdheim-Chester disease (ECD) is a rare, non-Langerhans form of histiocytosis of unknown origin. It is characterized by xanthomatous or xanthogranulomatous infiltration of tissues by spumous ("foamy") histiocytes. As of this writing, 178 cases have been reported. ECD is characterized by heterogeneous systemic manifestations. Bone pain is the most frequent symptom. About half of all patients have extraskeletal manifestations. Cardiovascular manifestations of ECD remain underestimated. We report 6 new cases of ECD associated with periaortic fibrosis. In 4 of these cases, the whole aorta had a "coated" aspect. A literature review revealed 66 cases of ECD with cardiovascular involvement. We therefore analyzed 72 ECD patients with cardiovascular involvement: 40 (55.6%) had periaortic "fibrosis," 32 (44.4%) had pericardial involvement, and 22 (30.6%) had myocardial involvement. Six had a right atrial tumor. Symptomatic valvular heart disease (3 aortic and 3 mitral regurgitations) was found in 6 patients. Nineteen patients (26.4%) had heart failure, leading to death in 8 cases. Six patients had renovascular hypertension related to perirenal artery stenosis. Data concerning follow-up were available for 58 (80.6%) patients. Of these, 35 (60.3%) patients died, confirming the severe prognosis of ECD. Cardiovascular complications were responsible for the death of 11 of the 35 patients (31.4%).

[Physiopathological data of Horton's syndrome]. / Données physiopathologiques de la maladie de Horton.

GREAT PROGRESS: The understanding of the physiopathology of Horton's syndrome has been made in view of the prevalence of the disease, the access to affected tissue and new molecular biology techniques. And it is now possible to specify the intricacy between the genetic, immunological and vascular components. HORTON'S SYNDROME, A GENETIC DISEASE: The preferential association of the disease with some alleles pf the HLA DR4 group has helped to emphasize the fundamental role of a few amino acids of the second hypervariable area of the HLA-DR molecule. An immunogenetic predisposition appears favourable, or even necessary, for the development of the disease. HORTON'S SYNDROME, AN IMMUNOLOGICAL DISEASE: The temporal arteries of patients presenting with Horton's syndrome are infiltrated by polymorphous inflammatory cells, fundamentally including CD4 T-cell lymphocytes, macrophages, and a few giant cells. Some CD4 lymphocytes have undergone clonal proliferation and show signs of recent antigenic recognition. A fraction of them secrete interferon gamma, which plays a crucial role in the onset, maintenance and orientation of the immunological response. The macrophages play multiple roles notably in maintaining the inflammatory reaction, but also in the destruction of certain structures of the arterial wall. HORTON'S SYNDROME, A VASCULAR DISEASE: The destruction of the arterial wall at the acute stage of the disease appears responsible, sometimes later on, for aneurismal dilatations observed on the aorta of certain patients. Moreover, intimal hyperplasia (mediated by the PDGF (platelet derived growth factor) A and B) and thrombosis (related to the inflammation) join up in reducing the arterial flow and enhancing the risk of ischemic complications during the acute stage. PATHOGENESIS, HYPOTHESES: Various candidate-antigens have been incriminated in the onset of the inflammatory reaction during Horton's syndrome. Some epidemiological and molecular studies are in favour of an exogenous antigen, possibly infectious, but no evidence has been demonstrated in the studies published. A parietal, endogenous antigen might also be at the origin of the cascade of events described during this disease.

Endocrine involvement in pediatric-onset Langerhans' cell histiocytosis: a population-based study.

OBJECTIVE: To document the frequency and outcome of endocrine involvement in pediatric-onset Langerhans' cell histiocytosis (LCH), and the association with other types of organ involvement. STUDY DESIGN: This retrospective nationwide multicenter study involved 589 patients with pediatric-onset LCH, 148 of whom had endocrine dysfunction. Median follow-up was 11.6 years. RESULTS: Pituitary dysfunction was present in 145 patients, and 141 had diabetes insipidus (DI). The estimated 10-year risks of pituitary involvement were 24.2% +/- 1.8%. GH deficiency occurred in 61 patients. Median age at onset was 2.8 years for LCH, 3.9 years for DI, and 7.7 years for GH deficiency. The risk of cranial involvement; ear, nose, and throat involvement; pneumothorax; and cholangitis was significantly higher in patients with endocrinopathy. The chronology of episodes did not support a causal link between pituitary involvement and involvement of other organs. Systemic treatment of LCH did not prevent pituitary involvement. The most severe complication was a neurodegenerative syndrome, which affected 4.3% and 10.8% of patients, respectively, 5 and 15 years after initial diagnosis, and appeared to be linked to pituitary involvement. CONCLUSION: Patients who develop endocrine LCH disorders are at a high risk of neurodegenerative LCH and require long-term follow-up.

[Non-selective and selective non-steroidal anti-inflammatory drugs, administration in pregnancy and breast feeding]. / Anti-inflammatoires non stéroïdiens sélectifs et non sélectifs, utilisation au cours de la grossesse et de l'allaitement.

THE FACTS: Non steroidal anti-inflammatory drugs (NSAI), except aspirin, are classically contraindicated during pregnancy. Nevertheless, they are widely used, in particular by the obstetricians. During pregnancy, the potential toxicity of these drugs is double, maternal and fetal. The maternal toxicity is comparable to that, already known in adults, with however, some particularities at the time of labor and delivery. The fetal toxicity is mainly renal and cardiovascular, with the NSAI responsible for oligoamniosis and premature closure of the arterial canal of the fetus. On the other hand, the use of these molecules during breast-feeding does not seem source of adverse events, notably in the newborn. THE VARIOUS MOLECULES: Among the family of non-selective non-steroidal anti-inflammatories, indications and adverse events of the various molecules differ considerably. Moreover, whereas the majority of these molecules are non-selective, i.e. inhibiting the two isoforms of cyclooxygenase, new therapeutics, specifically inhibiting cyclooxygenase-2, are now available. Few studies have been published concerning their prescription during pregnancy and breast-feeding and their maternal and fetal side effects remain ignored by most of the practitioners.

[Scleroderma and pregnancy]. / Sclérodermie et grossesse.

PURPOSE: - The frequency of concurrent scleroderma and pregnancy is low because scleroderma is a rare connective-tissue disease and the mean age of symptom onset is in the early 40s. The reciprocal influence of pregnancy and scleroderma and management of pregnancy are the purpose of this review. Current knowledge and key points. - There is no increase in infertility in women with scleroderma. The effect of pregnancy on scleroderma is a greater risk of renal crisis, especially when scleroderma is evolutive, diffuse and recent. Conversely, pregnancy is characterized by prematurity and small full-term infants because scleroderma induce placentar vascular abnormalities. There is no increase in miscarriages and spontaneous abortions. The pregnant scleroderma patient is a potential anaesthetic challenge because of physical difficulties and visceral involvement. Future and projects. - Planning of pregnancy and follow-up by a multidisciplinary experienced team in high risk pregnancies are guarantees for successful pregnancies. Future research will try to determine the role of microchimerism in scleroderma physiopathology and specify placental findings in order to ameliorate the obstetrical prognosis.

Pharmacokinetics of teicoplanin during plasma exchange.

OBJECTIVE: To study the elimination of teicoplanin during plasma exchange, a procedure currently used to treat a variety of disorders involving immune complexes. Teicoplanin is a glycopeptide antibiotic that exhibits a long terminal half-life (100-150 h) and is highly bound to plasma proteins (unbound fraction (fu)=0.2). METHODS: Twelve adults with systemic polyarteritis nodosa, cryoglobulinemia-induced vasculitis or dysglobulinemic neuropathy undergoing plasma exchange were studied. Each patient received intravenous teicoplanin, 6 mg/kg body weight, immediately before plasma exchange. Plasma was assayed for teicoplanin by high pressure liquid chromatography. RESULTS: A high level of protein binding of teicoplanin was measured within this patient population (98%). The mean quantity of teicoplanin eliminated (+/-SD) was 74.6+/-34.6 mg. The mean drug fraction eliminated by plasma exchange (+/-SD) was 19.5+/-5.6%. Mean fu value as determined by ultrafiltration (+/-SD) was 2.2+/-1.7%. CONCLUSIONS: These results show that plasma exchange influences teicoplanin pharmacokinetics, with a clinically significant quantity being eliminated. If trough teicoplanin concentrations of around 10 mg/L are desired, it is recommended that teicoplanin dosage be supplemented or given after plasma exchange.