Screening for neurodegeneration in Langerhans cell histiocytosis with neurofilament light in plasma.

Patients with Langerhans cell histiocytosis (LCH) may develop progressive neurodegeneration in the central nervous system (ND-CNS-LCH). Neurofilament light protein (NFL) in cerebrospinal fluid (CSF) is a promising biomarker to detect and monitor ND-CNS-LCH. We compared paired samples of NFL in plasma (p-NFL) and CSF in 10 patients (19 samples). Nine samples had abnormal CSF-NFL (defined as ≥380 ng/l) with corresponding p-NFL ≥ 2 ng/l. Ten samples had CSF-NFL < 380 ng/l; eight (80%) with p-NFL < 2 ng/l (p < 0.001; Fisher's exact test). Thus, our results suggest that p-NFL may be used to screen for ND-CNS-LCH. Further studies are encouraged, including the role of p-NFL for monitoring of ND-CNS-LCH.

Neutralizing Anti-IL-17A Antibody Demonstrates Preclinical Activity Enhanced by Vinblastine in Langerhans Cell Histiocytosis.

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm characterised by the accumulation into granulomas of apoptosis-resistant pathological dendritic cells (LCH-DCs). LCH outcome ranges from self-resolving to fatal. Having previously shown that, (i) monocyte-derived DCs (Mo-DCs) from LCH patients differentiate into abnormal and pro-inflammatory IL-17A-producing DCs, and (ii) recombinant IL-17A induces survival and chemoresistance of healthy Mo-DCs, we investigated the link between IL-17A and resistance to apoptosis of LCH-DCs. In LCH granulomas, we uncovered the strong expression of BCL2A1 (alias BFL1), an anti-apoptotic BCL2 family member. In vitro, intracellular IL-17A expression was correlated with BCL2A1 expression and survival of Mo-DCs from LCH patients. Based on the chemotherapeutic drugs routinely used as first or second line LCH therapy, we treated these cells with vinblastine, or cytarabine and cladribine. Our preclinical results indicate that high doses of these drugs decreased the expression of Mcl-1, the main anti-apoptotic BCL2 family member for myeloid cells, and killed Mo-DCs from LCH patients ex vivo, without affecting BCL2A1 expression. Conversely, neutralizing anti-IL-17A antibodies decreased BCL2A1 expression, the downregulation of which lowered the survival rate of Mo-DCs from LCH patients. Interestingly, the in vitro combination of low-dose vinblastine with neutralizing anti-IL-17A antibodies killed Mo-DCs from LCH patients. In conclusion, we show that BCL2A1 expression induced by IL-17A links the inflammatory environment to the unusual pro-survival gene activation in LCH-DCs. Finally, these preclinical data support that targeting both Mcl-1 and BCL2A1 with low-dose vinblastine and anti-IL-17A biotherapy may represent a synergistic combination for managing recurrent or severe forms of LCH.

High levels of plasma interleukin-17A are associated with severe neurological sequelae in Langerhans cell histiocytosis.

OBJECTIVE: Langerhans cell histiocytosis (LCH) is a granulomatous inflammatory myeloid neoplasia associated with a cytokine storm in both serum and lesions. Increased levels of plasma interleukin-17A (IL-17A) in LCH patients have been reported, but this finding was not confirmed in all studies. Neurodegeneration is a devastating complication of LCH (ND-LCH). We aimed to revisit the issue of plasma IL-17A levels in LCH, by using a larger number of patients, and also to investigate the relationship between IL-17A and LCH sequelae, especially ND-LCH. METHODS: Plasma samples from 68 LCH patients and 127 controls were analyzed for IL-17A levels by two ELISAs with different anti-IL-17A capture antibodies: either polyclonal or neutralizing monoclonal antibodies in 17polyAb-ELISA or 17mAb-ELISA, respectively. RESULTS: Both ELISAs had a similar capacity to specifically detect recombinant or native human IL-17A, as well as plasma IL-17A from LCH patients. We confirmed the finding of higher levels of plasma IL-17A in LCH patients compared to controls (p < 0.0001). The association of IL-17A with LCH was independent of the ELISA used, and of gender, age, disease class activity, and pattern of tissue-organ involvement (single-system versus multi-system). ROC analyses (p < 0.0001) allow to discriminate LCH patients from the control group, supporting the notion that IL-17A may be a potential biomarker for LCH. More interestingly, high IL-17A levels were significantly associated with LCH patients having sequelae, with the highest plasma levels in patients with ND-LCH (p < 0.0001). CONCLUSION: The association between high levels of IL-17A and LCH was confirmed. IL-17A may be associated with ND-LCH development. This might have therapeutic implications, offering a novel target for precision therapy of ND-LCH.

Detection of IL-17A-producing peripheral blood monocytes in Langerhans cell histiocytosis patients.

Langerhans cell histiocytosis (LCH) is a rare disease of unknown cause with manifestations ranging from isolated granulomatous lesions to life-threatening multi-system organ involvement. This disorder is further characterized by infiltration of immune cells in affected tissues and an association with interleukin (IL)-17A has been reported. Here, we investigated the presence of IL-17A-producing cells among peripheral blood mononuclear cells isolated from LCH patients and observed a high percentage of IL-17A(+) monocytes in peripheral blood of LCH patients compared to controls. The IL-17A(+) monocytes were also positive for the transcription factor retinoic acid orphan receptor (ROR) γt and showed increased mRNA levels for both IL-17A and RORγt. Notably, IL-17A was produced by all monocyte subsets and the expression level was positively associated with LCH disease activity. These data support a role for monocytes in the pathogenesis of LCH. Future therapeutic approaches may consider identification of patients who may benefit from IL-17A-targeted interventions.

Langerhans cell histiocytosis in children born 1982-2005 after in vitro fertilization.

AIM: In a recent Swedish study, comparing data from the Swedish Cancer Register with the Medical Birth Register including data on IVF, an increased risk of Langerhans cell histiocytosis (LCH) was found in children born 1982-2005 after IVF. Here, we aimed to verify the LCH diagnoses and examine whether any special forms of the disease were overrepresented in this population. METHODS: Medical records for all children with LCH conceived by IVF were acquired and the diagnosis confirmed or discarded. Disease characteristics were compared with data from children diagnosed with LCH 1992-2001 in the Stockholm County. RESULTS: We verified LCH in seven children born after IVF, all born prior to 2002. These children did not have milder disease forms. The odds ratio (OR) to develop LCH for the whole group born after IVF was 3.2 [95% confidence interval (CI), 1.4-7.3] and for children born before 2002, 5.2 [95% CI, 2.3-11.9], compared with children in Stockholm County 1992-2001. CONCLUSION: LCH was overrepresented in children born after IVF prior to 2002. Affected children did not have milder disease forms. These findings may be valuable to understand LCH aetiology. Additional studies on a putative correlation between IVF and LCH in the offspring are encouraged.

Incidence and pattern of radiological central nervous system Langerhans cell histiocytosis in children: a population based study.

BACKGROUND: Patients with Langerhans cell histiocytosis (LCH) may develop neurodegeneration and other central nervous system (CNS) dysfunctions revealed by brain magnetic resonance imaging (MRI). We estimated the incidence and pattern of pathological brain MRI findings in a well-defined, population-based cohort of children with LCH. METHODS: Among children under 15 years of age diagnosed with LCH in the Stockholm County during 1992-2001, brain MRI was performed at a single center in children with clinical and/or laboratory signs of CNS involvement, including endocrine dysfunction. RESULTS: Out of the 29 children (16 males, 13 females) diagnosed with LCH, brain MRI was performed based on clinical indications in 16 children (55%) with either abnormal endocrine findings (n = 6), such as diabetes insipidus (n = 5), low IGF-1 (n = 1), or panhypopituitarism (n = 1), or clinical CNS symptoms (n = 10). CNS MRI abnormalities were demonstrated in eight children (28%), at a median time of 3.5 years after LCH diagnosis (range 1-11.4 years). Altogether 7 of the 29 children (24%) had MRI findings associated with neurodegeneration, corresponding to a minimal incidence of 2.1/10(6) children per year. Neurodegenerative abnormalities tended to be more frequent in patients with craniofacial involvement (P = 0.12). CONCLUSIONS: The minimal annual incidence rate of neurodegenerative associated radiographic findings in LCH is estimated at 2.1/10(6) children (24% of all children with LCH). An important question is whether all patients with LCH, or certain forms of LCH, should be recommended for a late follow-up examination including MRI. In patients with CNS-LCH, neurological, neuropsychological, neurophysiological, neurochemical and neuroradiological follow-up assessment is suggested.

Fifteen years of treatment with intravenous immunoglobulin in central nervous system Langerhans cell histiocytosis.

AIM: There is currently no well-accepted therapy for central nervous system Langerhans cell histiocytosis (CNS-LCH), a neuroinflammatory disease clinically characterized by often progressive, neurological symptoms including ataxia, dysarthria, dysphagia, hypertonicity, intellectual impairment and behavioural abnormalities. We applied immunomodulative/anti-inflammatory treatment on a patient with progressive CNS-LCH disease. METHOD: Intravenous immunoglobulin (IVIG) was administered monthly for 15 years to a patient with severe, image-verified neurodegenerative CNS-LCH. RESULTS: During the IVIG treatment, the neurological deterioration initially appeared to be haltered, but over time there was still some deterioration. CONCLUSIONS: IVIG may be beneficial in partly haltering CNS-LCH neurodegeneration, but further studies are needed.

Biomarkers in the cerebrospinal fluid and neurodegeneration in Langerhans cell histiocytosis.

BACKGROUND: Progressive neurodegeneration may result in potentially severe cognitive and motor dysfunctions as a complication of Langerhans cell histiocytosis (LCH), a suggested IL-17A-associated inflammatory condition. To detect this complication (CNS-LCH) early and to evaluate the potential efficacy of therapeutic interventions, biomarkers detecting and measuring ongoing neurodegeneration would be valuable. We evaluated cerebrospinal fluid (CSF) biomarkers of ongoing neurodegeneration in CNS-LCH patients. PROCEDURE: Nine patients with endocrine, neuromotor, cognitive or/and behavioral abnormalities as well as neuroradiological evidence of CNS-LCH were evaluated 4-12 years after LCH diagnosis for CSF levels of neurofilament protein light chain (NF-L), glial fibrillary acid protein (GFAp), and total tau protein (TAU). Two patients were analyzed longitudinally. One hundred ten children with newly diagnosed acute lymphoblastic leukemia (ALL) served as controls. RESULTS: NF-L, TAU, and GFAp levels were elevated in four, six, and eight of nine patients studied, respectively. NF-L (P < 0.001) and GFAp (P < 0.001) were higher in patients than in controls (TAU not analyzed in controls). The patient with most severe clinical and neuroradiological CNS-LCH displayed the highest levels of NF-L and GFAp whereas three patients without signs of systemic disease had low TAU levels and normal/slightly elevated NF-L. NF-L tended to be higher at radiological progression of neurodegeneration than at status quo (P = 0.07). Notably, we experienced frequent lumbar puncture complications in these patients. CONCLUSIONS: CSF levels of NF-L, TAU, and GFAp appear to be elevated in CNS-LCH. It would be valuable if these markers were validated in order to serve as markers for early CNS-LCH, to monitor disease progression and to evaluate various treatment attempts for CNS-LCH.

Neuropsychological sequelae in patients with neurodegenerative Langerhans cell histiocytosis.

BACKGROUND: Patients with Langerhans cell histiocytosis (LCH) may develop neurodegeneration and significant CNS sequelae, affecting a significant proportion of the patients. We here aimed to investigate the neuropsychological consequences in more detail. METHODS: Using an extensive neuropsychological test battery, we evaluated nine LCH patients, 6-20 years old, with radiological signs indicative of neurodegeneration. RESULTS: Altogether 3/9 patients performed below 1 SD of normal for age on full IQ. Detailed analysis revealed that 4/9 had deficient performance IQ, whereas 1/9 had subnormal verbal IQ (defined as below 1 SD). Furthermore, 3/8 patients showed slow speed of performance for age. Notably, 8/9 (89%) had deficient verbal working memory and 7/8 (88%) performed below normal on visual-spatial working memory. CONCLUSIONS: The results indicate a specific, uneven neuropsychological profile in patients affected by CNS-LCH, with a decline particularly on perceptual tasks whereas the verbal performance was not as negatively influenced. Furthermore, verbal and visual-spatial working memory functions were below normal for age in all but one patient studied. LCH may easily be misdiagnosed, but it is important that individuals affected by CNS-LCH are diagnosed to provide advice and support. It remains a challenge to find a treatment reducing this unfortunate neurodegeneration.

Incidence of Langerhans cell histiocytosis in children: a population-based study.

BACKGROUND: Langerhans cell histiocytosis is a rare disease of unknown etiology. We wanted to assess the population-based incidence of LCH in a well-defined cohort of children. METHODS: We identified all children <15-years old treated with LCH during the 10 years period 1992-2001 at the Department of Pediatrics, Karolinska University Hospital in Stockholm, the referral center for children with LCH in Stockholm County. We also contacted the Departments of Dermatology, Orthopedics, and Neurosurgery for possible additional patients. RESULTS: Twenty-nine children (16 males) with LCH were identified, with a median age at diagnosis of 3.8 years (2 months-13.7 years). All children but one had a definitive diagnosis of LCH. The minimum incidence of LCH is estimated to 8.9/10(6) children per year. At diagnosis, 20 children (69%) had single system (SS) and 9 (31%) multisystem (MS) manifestations. Five of the 20 children with SS eventually developed MS disease, thus 14 (48%) had MS involvement at the maximal extent of disease (4.3/10(6) children per year). Interestingly, 22 children (76%) were diagnosed during the fall (September-November, n = 12) and winter (December-February, n = 10) seasons, as compared to seven children during the spring (March-May = 1) and summer (June-August = 6) seasons (P = 0.005, Chi-square). CONCLUSIONS: The incidence of childhood LCH in our study is higher than previously reported. In our patient cohort, LCH was more commonly diagnosed during the fall and winter season as compared to the spring and summer season. Whether this seasonal variation can be confirmed in larger studies and whether it has relevance for LCH pathophysiology remains to be elucidated.