Neurosarcoidosis and Neurologic Complications of Sarcoidosis Treatment.

Sarcoidosis is an immune-mediated multisystem granulomatous disorder. Neurosarcoidosis (NS) accounts for 5% to 35% of cases. The diagnostic evaluation of NS can be a clinical challenge. Gadolinium-enhanced magnetic resonance imaging (MRI) is the gold standard to evaluate central nervous system NS. In almost all cases treatment is warranted. Although glucocorticoids remain the first-line therapy in patients with sarcoidosis, in NS timely initiation of second- or third-line treatment is strongly recommended. Of these, tumor necrosis factor-alpha inhibitors are the most promising. However, the treatment itself may be responsible for/associated with developing neurologic symptoms mimicking NS. Thus, it is important to consider the possibility of drug-induced neurologic symptoms in sarcoidosis.

Prognostication of progressive pulmonary fibrosis in connective tissue disease-associated interstitial lung diseases: A cohort study.

Background: Connective tissue diseases-associated interstitial lung disease (CTD-ILD) is a heterogeneous condition that impairs quality of life and is associated with premature death. Progressive pulmonary fibrosis (PPF) has been identified as an important risk factor for poor prognosis. However, different criteria for PPF are used in clinical studies, which may complicate comparison between trials and translation of study findings into clinical practice. Methods: This is a retrospective single center study in patients with CTD-ILD. The prognostic relevance of PPF definitions, including INBUILD, ATS/ERS/JRS/ALAT 2022, and simplified progressive fibrosing (simplified PF) criteria, were examined in this cohort and validated in the other reported Dutch CTD-ILD cohort. Results: A total of 230 patients with CTD-ILD were included and the median follow-up period was six (3-9) years. Mortality risk was independently associated with age (adjusted HR 1.07, p < 0.001), smoking history (adjusted HR 1.90, p = 0.045), extent of fibrosis on high-resolution computed tomography (HRCT) at baseline (adjusted HR 1.05, p = 0.018) and baseline DLCO (adjusted HR 0.97, p = 0.013). Patients with regular pulmonary function tests in the first 2 years (adjusted HR 0.42, p = 0.002) had a better survival. The prognostic relevance for survival was similar between the three PPF criteria in the two cohorts. Conclusion: Higher age, smoking, increased extent of fibrosis and low baseline DLCO were associated with poor prognosis, while regular pulmonary function evaluation was associated with better survival. The INBUILD, ATS/ERS/JRS/ALAT 2022, and simplified PF criteria revealed similar prognostication.

Clinical features and immune-related protein patterns of anti-MDA5 positive clinically amyopathic dermatomyositis Dutch patients.

OBJECTIVES: The presence of melanoma differentiation-associated protein 5 (MDA5) antibodies in patients with DM is associated with the development of a rapidly progressive interstitial lung disease (RPILD), unresponsive to conventional treatment. We characterize patients and provide more insight into potential biomarkers to identify patients with RPILD. METHODS: Patients diagnosed with anti-MDA5 positive DM between December 2015 and November 2017 were included in this study. Clinical data were retrospectively retrieved from medical records. A total of 180 immune-related markers were measured in sera of 16 patients and 15 healthy controls using proximity extension assay-based technology. RESULTS: Twenty patients were included, with a median time from symptoms till diagnosis of 4 months. All patients had clinically amyopathic DM. Interstitial lung disease (ILD) was present at diagnosis in 94% of the patients, 45% presented with RPILD. The mortality rate was 35% within 4 months after diagnosis and respiratory failure was the main cause of death in these patients. Furthermore, unsupervised analysis revealed that patients with RPILD show clearly different inflammatory serum profiles than healthy controls. In addition, in comparison to healthy controls, the IFN, IL1, IL10 and IL18 signalling pathways are different regulated in anti-MDA5 positive patients. CONCLUSION: In this Dutch anti-MDA5 positive clinically amyopathic DM (CADM) cohort, one-third of the patients died due to RPILD soon after diagnosis, which underlines the severity of this disease. In addition, we have found several possible pathways that are differentially regulated in RPILD vs no RPILD DM and healthy controls. These markers await further validation before clinical use.

Predictors for progressive fibrosis in patients with connective tissue disease associated interstitial lung diseases.

BACKGROUND: Connective tissue disease associated interstitial lung disease (CTD-ILD) is associated with decreased quality of life and high mortality risk. Outcome and treatment response is unpredictable. This study aimed to identify clinical predictors for CTD-ILD with poor outcome. METHODS: We performed a retrospective single centre cohort study in outpatients with CTD-ILD seen between 2004 and 2018. Clinical and biochemical data, pulmonary function tests (PFT) and high-resolution computed tomography (HRCT) results were analysed. Overall survival and progressive fibrosing ILD (PF-ILD, defined as a significant deterioration of PFT or HRCT) after two years of follow-up were assessed. RESULTS: In total, 150 patients with CTD-ILD were included. Thirty (20%) deaths occurred during a median follow-up of 40 months (IQR 27.3-60.8), which were attributed to pulmonary infection in six (4%), respiratory failure due to PF-ILD in ten (7%) and due to other causes in fourteen patients. PF-ILD occurred in 76 (50.7%) patients and was associated with poor overall survival (adjusted HR 5.73, 95%CI 1.17-28.11). Age, smoking, C-reactive protein, and steroid-use were independently associated with increased mortality risk as well. Furthermore, patients with diabetes mellitus (adjusted OR 4.52, 95%CI 1.10-18.51), steroid-use (adjusted OR 2.26, 95%CI 1.04-4.93), and a fibrotic HRCT pattern at baseline (adjusted OR 3.11, 95%CI 1.15-8.38) had a higher risk of PF-ILD. CONCLUSION: PF-ILD is associated with increased mortality in patients with CTD-ILD. Patients with a fibrotic HRCT pattern at baseline, diabetes mellitus and steroid-use have a higher risk of developing PF-ILD.

The Burden of Neurosarcoidosis: Essential Approaches to Early Diagnosis and Treatment.

Neurosarcoidosis (NS) is an often severe, destructive manifestation with a likely under-reported prevalence of 5 to 15% of sarcoidosis cases, and in its active phase demands timely treatment intervention. Clinical signs and symptoms of NS are variable and wide-ranging, depending on anatomical involvement. Cranial nerve dysfunction, cerebrospinal parenchymal disease, aseptic meningitis, and leptomeningeal disease are the most commonly recognized manifestations. However, non-organ-specific potentially neurologically driven symptoms, such as fatigue, cognitive dysfunction, and small fiber neuropathy, appear frequently.Heterogeneous clinical presentations and absence of any single conclusive test or biomarker render NS, and sarcoidosis itself, a challenging definitive diagnosis. Clinical suspicion of NS warrants a thorough systemic and neurologic evaluation hopefully resulting in supportive extraneural physical exam and/or tissue findings. Treatment targets the severity of the manifestation, with careful discernment of whether NS reflects active potentially reversible inflammatory granulomatous disease versus inactive postinflammatory damage whereby functional impairment is unlikely to be pharmacologically responsive. Non-organ-specific symptoms are poorly understood, challenging in deciphering reversibility and often identified too late to respond to conventional immunosuppressive/pharmacological treatment. Physical therapy, coping strategies, and stress reduction may benefit patients with all disease activity levels of NS.This publication provides an approach to screening, diagnosis, disease activity discernment, and pharmacological as well as nonpharmacological treatment interventions to reduce disability and protect health-related quality of life in NS.

Quality of Life of Couples Living with Sarcoidosis.

BACKGROUND: Consequences of sarcoidosis are wide ranging, and the symptom burden has a great impact on patients' quality of life (QoL). However, the QoL of couples living with sarcoidosis has not yet been studied. OBJECTIVES: Our aim was to assess the QoL of couples living with sarcoidosis and to evaluate whether living with a partner with sarcoidosis influences the partner's QoL. Furthermore, we aimed to assess whether nonspecific symptoms (fatigue, cognitive failure, small fiber neuropathy (SFN)-related symptoms, depressive symptoms, and state/trait anxiety) predict QoL of partners as well as sarcoidosis patients. METHOD: Sarcoidosis outpatients, recruited at Maastricht University Medical Centre (n = 443), and their partners (n = 208) completed several questionnaires, including the World Health Organization QoL - BREF, Fatigue Assessment Scale, SFN screening list, and cognitive failure questionnaire. RESULTS: QoL of the partners as well as the sarcoidosis patients was reduced compared with healthy controls, especially regarding the physical health domain. All nonspecific symptoms studied, as well as perceived social support, predicted one or more QoL domains in the sarcoidosis patients, but these factors did not predict the QoL of their partners. CONCLUSIONS: The QoL of partners of sarcoidosis patients was reduced, although to a lesser extent than that of the patients. Although the nonspecific symptoms and perceived social support were related to the patients' QoL, this was not the case for the partners. In the management of sarcoidosis, it is important to focus not only on the patients but also on their partners.

Management of neurosarcoidosis: a clinical challenge.

PURPOSE OF REVIEW: Sarcoidosis is a complex disease with many faces, and the clinical manifestation and course of neurosarcoidosis are particularly variable. Although neurosarcoidosis occurs in up to 10% of sarcoidosis patients, it can lead to significant morbidity and some mortality. RECENT FINDINGS: Three criteria are usually required for a diagnosis of (neuro)sarcoidosis: clinical and radiologic manifestations, noncaseating granulomas, and no evidence of alternative disease. Recent guidelines have helped to clarify criteria for diagnosing neurosarcoidosis. No firm guidelines exist on whether, when, and how treatment should be started. Treatment depends on the presentation and distribution, extensiveness, and severity of neurosarcoidosis. As regards evidence-based treatment, only a few randomized controlled trials have been done. Hence, several aspects of (neuro)sarcoidosis management are not fully addressed by the current literature. SUMMARY: Significant advances have been made in the potential and accuracy of diagnostics for neurosarcoidosis. Treatment should be approached within the context of the patient's anticipated clinical course, avoidance of adverse drug effects, and, if necessary, from the perspective of the comprehensive management of a chronic disease. A multidisciplinary approach to the management of sarcoidosis is strongly recommended.

Everyday cognitive failure in patients suffering from neurosarcoidosis.

BACKGROUND: Cognitive failure is associated with memory and concentration problems. Previously, a prevalence of one third was found in a general sarcoidosis population. The aim of this study was to assess if neurosarcoidosis patients are at higher risk for developing everyday cognitive failure using the Cognitive Failure Questionnaire (CFQ) and to determine what factors were associated with cognitive failure. METHODS: A cross-sectional web-based survey was conducted from April to May 2017 in a national sample of neurosarcoidosis patients. The survey asked about complaints and included 3 questionnaires (Fatigue Assessment Scale [FAS], Small Fiber Neuropathy Screening List [SFNSL] and CFQ. Data were compared to a general sarcoidosis population. RESULTS: Of the 152 patients who completed the survey, 131 had neurosarcoidosis. The mean CFQ score was significantly higher in the neurosarcoidosis (45.6±20.7) compared to the general sarcoidosis population (36.2±15.9; p< 0.0001). High CFQ scores (≥43) were found in 55.7% and 33.9%, respectively (p<0.0001). The FAS score (OR 21.4) and SFNSL score (OR 4.3) were the strongest positive predictors of a high CFQ score. CONCLUSION: Cognitive failure is a significant problem in neurosarcoidosis. More than half of the patients reported cognitive deficits, compared to one third of a general sarcoidosis population. Fatigue and small fiber neuropathy play a role in cognitive failure.

Determination of the smallest detectable change (SDC) and the minimal important difference (MID) for the Small Fiber Neuropathy Screening List (SFNSL) in sarcoidosis.

Background: Previous studies found that 40-60% of the sarcoidosis patients suffer from small fiber neuropathy (SFN), substantially affecting quality of life. SFN is difficult to diagnose, as a gold standard is still lacking. The need for an easily administered screening instrument to identify sarcoidosis-associated SFN symptoms led to the development of the SFN Screening List (SFNSL). The usefulness of any questionnaire in clinical management and research trials depends on its interpretability. Obtaining a clinically relevant change score on a questionnaire requires that the smallest detectable change (SDC) and minimal important difference (MID) are known. Objectives: The aim of this study was to determine the SDC and MID for the SFNSL in patients with sarcoidosis. Methods: Patients with neurosarcoidosis and/or sarcoidosis-associated SFN symptoms (N=138) included in the online Dutch Neurosarcoidosis Registry participated in a prospective, longitudinal study. Anchor-based and distribution-based methods were used to estimate the MID and SDC, respectively. Results: The SFNSL was completed both at baseline and at 6-months' follow-up by 89/138 patients. A marginal ROC curve (0.6) indicated cut-off values of 3.5 points, with 73% sensitivity and 49% specificity for change. The SDC was 11.8 points. Conclusions: The MID on the SFNSL is 3.5 points for a clinically relevant change over a 6-month period. The MID can be used in the follow-up and management of SFN-associated symptoms in patients with sarcoidosis, though with some caution as the SDC was found to be higher. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 333-341).

Small fiber neuropathy: a disabling and underrecognized syndrome.

PURPOSE OF REVIEW: To discuss cause, clinical manifestations, diagnostics, and treatment of small fiber neuropathy (SFN). The diagnosis is difficult and can be easily missed. RECENT FINDINGS: SFN causes high morbidity with disabling symptoms and impact on quality of life. Patients may benefit from being diagnosed with SFN, even if no underlying cause is identified and no specific treatment is yet available. Recently, genetic mutations as a possible cause of SFN were identified. Clinical diagnostic criteria have been proposed, but no gold standard exists, and each test has its limitations. The diagnosis requires a combination of typical symptoms, abnormal neurologic findings, and absence of large fiber involvement. Clinicians should be aware of overlapping symptoms of SFN and fibromyalgia. Treatment is often difficult, even when the underlying cause is identified and appropriately treated. Usually, only symptomatic relief of complaints is available. SUMMARY: Awareness of SFN and related symptoms is of great clinical relevance. Guidelines for appropriate diagnostic workup using a stepwise approach involving a combination of tests are warranted. Even if no treatment is available, patients may benefit from timely recognition of SFN.

Many faces of neurosarcoidosis: from chronic meningitis to myelopathy.

PURPOSE OF REVIEW: Neurosarcoidosis occurs in 5% of patients with sarcoidosis and can be difficult to diagnose. In this review we discuss the most recent advances in our understanding of the disease, describing clinical characteristics, diagnostic process, treatment, and prognosis. RECENT FINDINGS: Clinical presentation is heterogeneous with most patients presenting with cranial nerve palsy, headache, or sensory abnormalities. Patients are classified according to probability of the diagnosis with the Zajicek criteria. In these criteria, histopathological confirmation of noncaseating granulomas in affected tissue outside the nervous system is key. Radiological abnormalities on neuroimaging are nonspecific. No biomarkers have been described that adequately identify patients with sarcoidosis. However, soluble interleukin-2 receptor is a relatively novel biomarker that may be useful. In addition to HRCT scan, F-FDG PET-CT scanning can identify occult locations of disease activity and aid in obtaining pathological confirmation. Despite the use of new therapies, still a third of patients remains stable, deteriorate, or die. SUMMARY: Diagnosing and treating patients with neurosarcoidosis remains a challenge. Long-term prospective studies evaluating patients suspected of neurosarcoidosis are needed to assess sensitivity and specificity of ancillary investigations and diagnostic criteria. Furthermore, future studies are needed to evaluate the prognosis and the optimal treatment strategy.