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AIMS: This study aimed to evaluate the effectiveness of somatostatin analogues (SA) for cystoid maculopathy (CM) in retinitis pigmentosa (RP) patients. MATERIALS AND METHODS: In this retrospective case series, clinical and imaging characteristics of 28 RP patients with CM, unresponsive to carbonic anhydrase inhibitors, were collected from medical charts. All patients received SA treatment as an alternative (octreotide long-acting release at 20 mg/month or 30 mg/month, or lanreotide at 90 mg/month or 120 mg/month). Outcome measures were mean reduction in foveal thickness (FT) and foveal volume (FV) and mean increase in best-corrected visual acuity at 3, 6 and 12 months of treatment initiation. Linear mixed models were used to calculate the effectiveness over time. RESULTS: 52 eyes of 28 RP patients were included; 39% were male. The median age at the start of treatment was 39 years (IQR 30-53). Median follow-up was 12 months (range 6-12). From baseline to 12 months, the mean FT decreased from 409±136 µm to 334±119 µm and the mean FV decreased from 0.31±0.10 mm3 to 0.25±0.04 mm3. Linear mixed model analyses showed a significant decrease in log FT and log FV at 3, 6 and 12 months after the start of treatment compared with baseline measurements (p<0.001, p<0.001, p<0.001). Mean best-corrected visual acuity did not increase significantly (0.46±0.35 logMAR to 0.45±0.38 logMAR after 12 months). DISCUSSION: SA may be an effective alternative treatment to reduce CM in RP patients.
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Retinitis Pigmentosa , Somatostatina , Tomografía de Coherencia Óptica , Agudeza Visual , Humanos , Retinitis Pigmentosa/tratamiento farmacológico , Masculino , Femenino , Somatostatina/análogos & derivados , Somatostatina/uso terapéutico , Estudios Retrospectivos , Persona de Mediana Edad , Agudeza Visual/efectos de los fármacos , Adulto , Péptidos Cíclicos/uso terapéutico , Octreótido/uso terapéutico , Octreótido/administración & dosificación , Resultado del Tratamiento , Edema Macular/tratamiento farmacológico , Edema Macular/etiologíaAsunto(s)
Apófisis Odontoides , Fracturas de la Columna Vertebral , Humanos , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/etiología , Apófisis Odontoides/lesiones , Apófisis Odontoides/diagnóstico por imagen , Masculino , Femenino , Tomografía Computarizada por Rayos XAsunto(s)
Síndrome de Liberación de Citoquinas , Linfohistiocitosis Hemofagocítica , Pirazoles , Humanos , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/etiología , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Linfohistiocitosis Hemofagocítica/etiología , Nitrilos , PirimidinasRESUMEN
In this retrospective study, BRAF mutation status did not correlate with disease extent or (event-free) survival in 156 adults with Langerhans cell histiocytosis. BRAFV600E was associated with an increased incidence of second malignancies, often comprising hematological cancers, which may be clonally related.
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Histiocitosis de Células de Langerhans , Neoplasias Primarias Secundarias , Humanos , Adulto , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/genética , Proteínas Proto-Oncogénicas B-raf/genética , Estudios Retrospectivos , Incidencia , Histiocitosis de Células de Langerhans/epidemiología , Histiocitosis de Células de Langerhans/genética , Histiocitosis de Células de Langerhans/patología , MutaciónRESUMEN
PURPOSE: We report the long-term effect of rituximab (RTX) in scleritis and determine the value of B-cell monitoring for the prediction of relapses. METHODS: We retrospectively studied 10 patients with scleritis, who were treated with RTX. Clinical characteristics were collected, and blood B-cell counts were measured before the start of RTX, and at various time points after treatment. RESULTS: Clinical activity of scleritis decreased after RTX treatment in all patients within a median time of 8 weeks (range 3-13), and all reached remission. The median follow-up was 101 months (range 9-138). Relapses occurred in 6 out of 10 patients. All relapses, where B-cell counts were measured (11 out of 19), were heralded by returning B cells. However, B cells also returned in patients with long-term remissions. CONCLUSIONS: RTX is a promising therapeutic option for scleritis. Recurrence of B cells after initial depletion does not always predict relapse of scleritis.
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BACKGROUND: Despite enormous clinical improvements, due to better management strategies and the availability of biologicals, immune-mediated inflammatory diseases (IMIDs) still have a significant impact on patients' lives. To further reduce disease burden, provider- as well as patient-reported outcomes (PROs) should be taken into account during treatment and follow-up. Web-based collection of these outcomes generates valuable repeated measurements, which could be used (1) in daily clinical practice for patient-centered care, including shared decision-making; (2) for research purposes; and (3) as an essential step toward the implementation of value-based health care (VBHC). Our ultimate goal is that our health care delivery system is completely aligned with the principles of VBHC. For aforementioned reasons, we implemented the IMID registry. OBJECTIVE: The IMID registry is a digital system for routine outcome measurement that mainly includes PROs to improve care for patients with IMIDs. METHODS: The IMID registry is a longitudinal observational prospective cohort study within the departments of rheumatology, gastroenterology, dermatology, immunology, clinical pharmacy, and outpatient pharmacy of the Erasmus MC, the Netherlands. Patients with the following diseases are eligible for inclusion: inflammatory arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, uveitis, Behçet disease, sarcoidosis, and systemic vasculitis. Generic and disease-specific (patient-reported) outcomes, including adherence to medication, side effects, quality of life, work productivity, disease damage, and activity, are collected from patients and providers at fixed intervals before and during outpatient clinic visits. Data are collected and visualized through a data capture system, which is linked directly to the patients' electronic health record, which not only facilitates a more holistic care approach, but also helps with shared decision-making. RESULTS: The IMID registry is an ongoing cohort with no end date. Inclusion started in April 2018. From start until September 2022, a total of 1417 patients have been included from the participating departments. The mean age at inclusion was 46 (SD 16) years, and 56% of the patient population is female. The average percentage of filled out questionnaires at baseline is 84%, which drops to 72% after 1 year of follow-up. This decline may be due to the fact that the outcomes are not always discussed during the outpatient clinic visit or because the questionnaires were sometimes forgotten to set out. The registry is also used for research purposes and 92% of the patients with IMIDs gave informed consent to use their data for that. CONCLUSIONS: The IMID registry is a web-based digital system that collects provider- and PROs. The collected outcomes are used to improve care for the individual patient with an IMID and facilitate shared decision-making, and they are also used for research purposes. The measurement of these outcomes is an essential step toward the implementation of VBHC. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/43230.
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Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal inflammatory clinical condition, in which an exaggerated immune response is ineffectively regulated. Although etoposide-containing regimens are generally recommended for children with HLH, the exact role of etoposide in the adult setting remains unclear. We performed a systematic review of the literature on the use of etoposide in adults with HLH. All articles written in English on the use of etoposide in adults with HLH available from seven databases and published on or before July 2021 were analyzed. Thirteen studies were found to be relevant to the search results. Ten of these studies report a statistical analysis on the effect of etoposide, of which five found etoposide-containing regimens superior to non-etoposide-containing regimens. Seven studies provided sufficient data to be included in the meta-analysis. For these data, the estimated logit relative risk of etoposide on survival was 1.06 (95% confidence interval: 0.92-1.21, standard error: 2.06). The pooled data of the meta-analysis did thus not support a beneficial effect of etoposide. It should be taken into account that the presented results are highly susceptible to bias and that the effect of etoposide differs between HLH-triggers. Although the meta-analysis does not support the effect of etoposide, we do not recommend abandoning etoposide as treatment modality. The limitations of the meta-analysis, together with several individual articles confirming the benefit of etoposide, justify etoposide for select cases in adults with HLH such as refractory or severe disease with (threatening) multiorgan failure.
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Purpose: During the SARS-CoV-2 pandemic, national and international societies have recommended continuing biological agents in patients with immune-mediated inflammatory diseases (IMID) in the absence of SARS-CoV-2 symptoms. However, adherence to biological treatment might decrease, because these recommendations contradict patients' beliefs. Especially an increased concern about side effects could have influenced the adherence to biological treatment during the first lockdown. The primary objective was to investigate the impact of the first SARS-CoV-2 lockdown on adherence to biological treatment in IMID patients. Patients and Methods: In this prospective cohort study, IMID patients who received a biological agent before and during the first SARS-CoV-2 lockdown (March 2020- June 2020) were included. Patients were excluded if they did not complete the medication adherence report scale-5 (MARS-5) questionnaire at ≥1 visit before the lockdown and ≥1 visit during the lockdown. Adherence to biological treatment was measured with the MARS-5 and Medication Possession Ratio (MPR). Results: We included 157 IMID patients. The percentage of adherent patients, defined as MARS-5 score >21, was significantly lower during the lockdown compared to the period before the lockdown (88.5% vs 84.1%, p<0.001). Additionally, the overall percentage of adherent patients during the lockdown based on the MPR ≥90% was significantly lower compared to adherence based upon the MARS-5 (65.1% vs 84.1%, p<0.001). Conclusion: This study showed that the first SARS-CoV-2 lockdown negatively impacts adherence to biological treatment in IMID patients. Therefore, treating physicians should be aware of this problem to minimize the potential harmful effects of non-adherence.
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Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder caused by somatic genetic alterations in hematopoietic precursor cells differentiating into CD1a+/CD207+ histiocytes. LCH clinical manifestation is highly heterogeneous. BRAF and MAP2K1 mutations account for â¼80% of genetic driver alterations in neoplastic LCH cells. However, their clinical associations remain incompletely understood. Here, we present an international clinicogenomic study of childhood LCH, investigating 377 patients genotyped for at least BRAFV600E. MAPK pathway gene alterations were detected in 300 (79.6%) patients, including 191 (50.7%) with BRAFV600E, 54 with MAP2K1 mutations, 39 with BRAF exon 12 mutations, 13 with rare BRAF alterations, and 3 with ARAF or KRAS mutations. Our results confirm that BRAFV600E associates with lower age at diagnosis and higher prevalence of multisystem LCH, high-risk disease, and skin involvement. Furthermore, BRAFV600E appeared to correlate with a higher prevalence of central nervous system (CNS)-risk bone lesions. In contrast, MAP2K1 mutations associated with a higher prevalence of single-system (SS)-bone LCH, and BRAF exon 12 deletions seemed to correlate with more lung involvement. Although BRAFV600E correlated with reduced event-free survival in the overall cohort, neither BRAF nor MAP2K1 mutations associated with event-free survival when patients were stratified by disease extent. Thus, the correlation of BRAFV600E with inferior clinical outcome is (primarily) driven by its association with disease extents known for high rates of progression or relapse, including multisystem LCH. These findings advance our understanding of factors underlying the remarkable clinical heterogeneity of LCH but also question the independent prognostic value of lesional BRAFV600E status.
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Histiocitosis de Células de Langerhans , Neoplasias , Humanos , Estudios de Cohortes , Proteínas Proto-Oncogénicas B-raf/genética , Histiocitosis de Células de Langerhans/genética , MutaciónRESUMEN
BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare haematological neoplasm characterized by the accumulation of CD1a+, CD207/Langerin+ histiocytes within inflammatory lesions. LCH can involve any organ, but osteolytic bone lesions are most often encountered. Unifocal bone lesions may regress spontaneously after a thick needle biopsy has been taken. CASE PRESENTATION: In this case report, we describe the initial presentation of a single BRAFV600E mutated osteolytic LCH lesion in the left proximal humerus of a 46-year-old previously healthy woman. Despite multiple surgical interventions, she unexpectedly experienced progressive disease manifestation with significant soft tissue extension to the surrounding musculature, subcutis and epidermis. Because the disease manifestation remained loco-regional, radiotherapy (RT) (total dose of 20 Gy in 10 fractions) was initiated. CONCLUSION: The patient achieved a complete remission without any side effects. This case highlights that RT is a rational and relative mild local treatment option for patients with aggressive LCH affecting the bone and surrounding soft tissue.
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Histiocitosis de Células de Langerhans , Femenino , Histiocitosis de Células de Langerhans/patología , Histiocitosis de Células de Langerhans/radioterapia , Histiocitosis de Células de Langerhans/cirugía , Humanos , Persona de Mediana EdadRESUMEN
Autosomal recessive mutations in RAB27A are associated with Griscelli syndrome type 2 (GS2), characterized by hypopigmentation and development of early-onset, potentially fatal hemophagocytic lymphohistiocytosis (HLH). We describe a 35-year old male who presented with recurrent fever, was diagnosed with Epstein-Barr virus-driven chronic lymphoproliferation, fulfilled clinical HLH criteria, and who carried a novel homozygous RAB27A c.551G > A p.(R184Q) variant. We aimed to evaluate the contribution of the identified RAB27A variant in regard to the clinical phenotype as well as cellular and biochemical function. The patient displayed normal pigmentation as well as RAB27A expression in blood-derived cells. However, patient NK and CD8+ T cell exocytosis was low. Ectopic expression of the RAB27A p.R184Q variant rescued melanosome distribution in mouse Rab27a-deficient melanocytes, but failed to increase exocytosis upon reconstitution of human RAB27A-deficient CD8+ T cells. Mechanistically, the RAB27A p.R184Q variant displayed reduced binding to SLP2A but augmented binding to MUNC13-4, two key effector proteins in immune cells. MUNC13-4 binding was particularly strong to an inactive RAB27A p.T23N/p.R184Q double mutant. RAB27A p.R184Q was expressed and could facilitate melanosome trafficking, but did not support lymphocyte exocytosis. The HLH-associated RAB27A variant increased Munc13-4 binding, potentially representing a novel mode of impairing RAB27A function selectively in hematopoietic cells.
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Infecciones por Virus de Epstein-Barr , Linfohistiocitosis Hemofagocítica , Adulto , Humanos , Masculino , Linfocitos T CD8-positivos , Herpesvirus Humano 4 , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/genética , Unión Proteica , Proteínas de Unión al GTP rab/genética , Proteínas de Unión al GTP rab/química , Proteínas de Unión al GTP rab/metabolismo , Proteínas rab27 de Unión a GTP/genética , Proteínas rab27 de Unión a GTP/metabolismoRESUMEN
OBJECTIVES: The aim of this study is to investigate the cumulative incidence and the severity of COVID-19 infections in patients with Behçet's disease. METHODS: A retrospective cohort study of patients with Behçet's disease was conducted. We obtained the data systematically from electronic patient files and through telephone interviews between February 2020 and May 1, 2021. Main outcomes were COVID-19 infection, disease duration, hospitalisation, intensive care admission and mortality. Secondary outcome was adherence to quarantine measures as recommended by the government. RESULTS: 185 Behçet's disease patients were included (mean age 42.2 years, 54% female); 58% of the patients were receiving colchicine, 30% anti-TNFα, 16% azathioprine and 8% systemic steroids. 30 patients (16.2%) were positive for COVID-19. Within our cohort, the cumulative incidence of COVID-19 was therefore 16.2% (95% CI 11.2-22.3%), which is significantly increased when compared to the general Dutch population (8.7% (95% CI 8.72-8.73%)) (p < 0.001). Four out of 30 (13%) patients were admitted to the hospital. There was no COVID-19 related mortality observed. Patients adhered to government measures; except in the period between the 1st of June and the 28th of September, this cohort received more visitors than in period 1 and 3. CONCLUSIONS: In this cohort, Behçet's disease patients have a higher risk for COVID-19 infection, without an increase of virus-related mortality. The course of COVID-19 disease in this cohort is relatively mild, with a lower admission rate than expected of patients using immunosuppressive medication.
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Síndrome de Behçet , COVID-19 , Adulto , Azatioprina/uso terapéutico , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/tratamiento farmacológico , Síndrome de Behçet/epidemiología , COVID-19/epidemiología , Femenino , Humanos , Masculino , Países Bajos/epidemiología , Estudios RetrospectivosRESUMEN
Interpretation of biopsies taken on suspicion of immunoglobulin (Ig)G4-related disease (IgG4-RD) may be hampered by uninterpretable immunohistochemical stains for IgG because of strong background signals. This study aims to determine the significance of tissue IgG2 positive plasma cell counts in IgG4-RD in comparison with non-IgG4-related inflammatory disorders. Descriptive, retrospective case-control study of 16 patients with IgG4-related orbital disease (IgG4-ROD) and 24 with extraorbital IgG4-RD. Histopathology and serology of this group was compared with 16 patients with orbital non-IgG4-related disorders and 22 patients with extraorbital non-IgG4-related disorders. The mean tissue IgG2/IgG4 ratio was 0.16 in IgG4-ROD and 0.27 in extraorbital IgG4-RD and far below 1 in 98% of patients. This was significantly lower compared with the non-IgG4-related disorders that showed a mean tissue IgG2/IgG4 ratio of 1.98 in the orbital and 2.20 in the extraorbital group (range: 0.20 to 10, P <0.05). In 74% of tissue samples an IgG2/IgG4 ratio >1 was seen. The tissue IgG2/IgG ratio was significantly lower in IgG4-RD compared with non-IgG4-related inflammatory disorders. Serum IgG2 concentration was not abnormal in patients with IgG4-RD. A significantly lower tissue IgG2/IgG4 and IgG2/IgG ratio was observed in IgG4-RD, compared with non-IgG4-related inflammatory disorders. Additional immunohistochemical staining for IgG2 positive plasma cells can be helpful in the diagnosis of IgG4-RD. Especially in cases with uninterpretable IgG staining, a well-recognized problem that may give rise to a failed interpretation of the biopsy.
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Enfermedad Relacionada con Inmunoglobulina G4 , Enfermedades Orbitales , Estudios de Casos y Controles , Humanos , Inmunoglobulina G , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Enfermedad Relacionada con Inmunoglobulina G4/patología , Células Plasmáticas , Estudios RetrospectivosRESUMEN
PURPOSE: To evaluate the effectiveness and reasons for discontinuation including the side effect profiles of adalimumab in a real-world setting. DESIGN: Retrospective clinical cohort study. METHODS: A medical chart review of clinical practice in 2 tertiary eye care services in Rotterdam, the Netherlands, was performed Data were collected from May 1, 2004, through September 1, 2020. Patients with noninfectious uveitis treated with adalimumab (n = 341; 633 affected eyes) were included. The primary outcome was the effectiveness of adalimumab, measured by the number of patients achieving inactive disease, remission, and relapse-free survival. The secondary outcomes were the reasons for discontinuation, including side effects, and the number of patients who developed antibodies. RESULTS: In total, 341 patients were treated with adalimumab between May 2004 and September 2020. The uveitis recurrence-free survival interval was 3.4 years (range, 0-13 years). Adalimumab had an acceptable side effect profile. A total of 178 patients achieved inactive disease while continuing adalimumab, and 51 patients maintained remission after discontinuing adalimumab. Reasons for discontinuation of adalimumab were no response, relapse, or reasons unrelated to the effectiveness of treatment. Adalimumab antibodies were present in 40 of 115 patients (35%). Antibodies were associated with lower adalimumab levels, and antibodies were observed more often in patients on adalimumab monotherapy (P < .01). CONCLUSIONS: Adalimumab is effective for patients with noninfectious uveitis, with an acceptable side effect profile. Although relapses can occur, the majority of the patients achieved inactive disease or remission after cessation of adalimumab, without other systemic immunosuppressive medication.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Uveítis , Adalimumab/efectos adversos , Estudios de Cohortes , Estudios de Seguimiento , Humanos , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Resultado del Tratamiento , Uveítis/inducido químicamente , Uveítis/diagnóstico , Uveítis/tratamiento farmacológicoRESUMEN
BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a fibro-inflammatory disorder and manifestation in de paranasal and sphenoid sinus is well recognized. In this patient, IgG4-RD presented in an unusual manner with vision loss due to mucocele formation in the sphenoid sinus. CASE DESCRIPTION: A 19-year-old man, with an unremarkable medical history, was referred with decreased vision in the left eye, headaches, and a sharp pain in the left orbit and ear. Compression of the left optic nerve due to a large mucocele caused papillary edema and emergency endoscopic marsupialization of the mucocele was performed. When the vision decreased again, a more extensive decompressing sphenoidotomy was performed. Histopathology showed IgG4-RD. Despite dexamethasone, the lesion expanded to the anterior skull base and the patient required repeat endoscopic surgery. After 3 months, a decrease in smell and vision warranted for a fourth extensive endoscopic decompressing surgery, complicated by a cerebrospinal fluid leak. Prednisone and later rituximab were commenced. Unfortunately, the patient reported a complete loss of vision after 4 months of rituximab due to increased mass effect on the optic nerve. An extensive combined craniofacial-endoscopic surgery was performed to remove the entire mucocele and to prevent further contralateral and intracranial progression. Methylprednisolone monthly was commenced to prevent further complications. DISCUSSION: This case illustrates that in therapy-resistant sino-orbital IgG4-RD, extensive surgery might be necessary at an earlier stage. It may even be the only option to prevent irreversible damage to the surrounding tissues. A multidisciplinary approach in the management of sino-orbital IgG4-RD is therefore warranted.
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Enfermedad Relacionada con Inmunoglobulina G4 , Mucocele , Enfermedades de los Senos Paranasales , Adulto , Humanos , Masculino , Rituximab , Base del Cráneo , Seno Esfenoidal , Tomografía Computarizada por Rayos X , Trastornos de la Visión , Adulto JovenRESUMEN
Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a chronic, clinically heterogenous fibroinflammatory condition, characterised by an accumulation of IgG4 secreting plasma cells in affected tissues and associated with increased serum IgG4 concentrations. Despite a growing recognition of the disease among clinicians from different specialties worldwide, its indolent nature, lack of a single diagnostic test and ability to mimic other malignant, infective and inflammatory conditions, makes the diagnosis challenging. As treatment options evolve, biomarkers correlating with disease activity, predicting prognosis and response to treatment are deemed required. A multidisciplinary panel of experts from the European Reference Network for Rare and Complex Connective tissue diseases (ERN ReCONNET) and affiliated international partners have performed a narrative literature search and reviewed the current evidence of biomarkers in IgG4-RD, including immunoglobulins, cytokines, chemokines and other soluble immune mediators, and cellular components of the immune system. The aim of this paper is to provide useful information for clinicians as to the utility of biomarkers for diagnosing and monitoring IgG4-RD in clinical routine and sets out recommendations for clinical decision making.
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Enfermedades Autoinmunes , Enfermedad Relacionada con Inmunoglobulina G4 , Enfermedades Autoinmunes/diagnóstico , Biomarcadores , Quimiocinas , Humanos , Inmunoglobulina G , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Células Plasmáticas/patologíaRESUMEN
OBJECTIVE: Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome that often requires critical care support and remains difficult to diagnose. These guidelines are meant to aid in the early recognition, diagnosis, supportive care, and treatment of patients with hemophagocytic lymphohistiocytosis in ICUs. DATA SOURCES: The literature searches were performed with PubMed (MEDLINE). STUDY SELECTION: Keywords and medical subject headings terms for literature search included "macrophage activation syndrome," hemophagocytic lymphohistiocytosis," and "hemophagocytic syndrome." DATA EXTRACTION: The Histiocyte Society developed these consensus recommendations on the basis of published reports and expert opinions with level of evidence provided for each recommendation. They were endorsed by the Society of Critical Care Medicine. DATA SYNTHESIS: Testing for hemophagocytic lymphohistiocytosis should be initiated promptly in all patients admitted to ICUs with an unexplained or disproportionate inflammatory response, especially those with rapid clinical deterioration. Meeting five or more of eight hemophagocytic lymphohistiocytosis 2004 diagnostic criteria serves as a valuable diagnostic tool for hemophagocytic lymphohistiocytosis. Early aggressive critical care interventions are often required to manage the multisystem organ failure associated with hemophagocytic lymphohistiocytosis. Thorough investigation of the underlying triggers of hemophagocytic lymphohistiocytosis, including infections, malignancies, and autoimmune/autoinflammatory diseases, is essential. Early steroid treatment is indicated for patients with familial hemophagocytic lymphohistiocytosis and is often valuable in patients with acquired hemophagocytic lymphohistiocytosis (i.e., secondary hemophagocytic lymphohistiocytosis) without previous therapy, including macrophage activation syndrome (hemophagocytic lymphohistiocytosis secondary to autoimmune/autoinflammatory disease) without persistent or relapsing disease. Steroid treatment should not be delayed, particularly if organ dysfunction is present. In patients with macrophage activation syndrome, whose disease does not sufficiently respond, interleukin-1 inhibition and/or cyclosporine A is recommended. In familial hemophagocytic lymphohistiocytosis and severe, persistent, or relapsing secondary macrophage activation syndrome, the addition of prompt individualized, age-adjusted etoposide treatment is recommended. CONCLUSIONS: Further studies are needed to determine optimal treatment for patients with hemophagocytic lymphohistiocytosis in ICUs, including the use of novel and adjunct therapies.
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Linfohistiocitosis Hemofagocítica , Síndrome de Activación Macrofágica , Adulto , Niño , Consenso , Enfermedad Crítica/terapia , Humanos , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/terapia , Síndrome de Activación Macrofágica/diagnóstico , Síndrome de Activación Macrofágica/etiología , Síndrome de Activación Macrofágica/terapia , Recurrencia Local de Neoplasia/complicaciones , EsteroidesRESUMEN
ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.