Circulating immune profile in granulomatosis with polyangiitis reveals distinct patterns related to disease activity.

Granulomatosis with polyangiitis (GPA) is an autoimmune disorder characterized by recurrent relapses that can cause severe tissue damage and life-threatening organ dysfunction. Multiple immune cells and cytokines/chemokines are involved in the different stages of the disease. Immune profiling of patients may be useful for tracking disease activity, however, reliable immune signatures for GPA activity are lacking. In this study, we examined circulating immune profiles in GPA patients during active and remission disease states to identify potential immune patterns associated with disease activity. The distribution and phenotypic characteristics of major circulating immune cells, and the profiles of circulating cytokines/chemokines, were studied on cryopreserved peripheral blood mononuclear cells from GPA patients (active, n = 20; remission, n = 20) and healthy controls (n = 20) leveraging a 40-color optimized multicolor immunofluorescence panel (OMIP-69) and in serum using a 46-plex Luminex multiplex assay, respectively. Deep phenotyping uncovered a distinct composition of major circulating immune cells in active GPA and GPA in remission, with the most significant findings emerging within the monocyte compartment. Our detailed analysis revealed circulating monocyte diversity beyond the conventional monocyte subsets. We identified eight classical monocyte populations, two intermediate monocyte populations, and one non-classical monocyte population. Notably, active GPA had a higher frequency of CD45RA+CCR5+CCR6-CCR7+/lowCD127-HLA-DR+CD2- classical monocytes and a lower frequency of CD45RA-CCR5-/lowCCR6-CCR7-CD127-HLA-DR+CD2+/- classical monocytes, which both strongly correlated with disease activity. Furthermore, serum levels of CXCL1, CXCL2, and CCL20, all linked to monocyte biology, were elevated in active GPA and correlated strongly with disease activity. These findings shed light on the circulating immune profile of GPA and may lead to immune signature profiles for assessing disease activity. Monocytes in particular may be studied further as potential markers for monitoring GPA.

[Salivary gland disorder: consider IgG4-related disease]. / Speekselklierafwijking: denk aan IgG4-gerelateerde ziekte.

A 73-year-old man was presented with painless, bilateral swelling of the submandibular salivary glands and unilateral swelling of the parotid gland on the right side, and complaints of dry mouth. A parotid biopsy was taken and a serologic exam was carried out, resulting in the diagnosis of IgG4-related disease. IgG4-related disease is a rare systemic disorder that can cause symptoms in the head and neck region. Usually there are complaints of bilateral, painless swelling of the submandibular, parotid and/or lacrimal glands, with or without complaints of dryness of the mouth and eyes.

Immune checkpoint inhibitor-associated myocarditis : Case reports and a review of the literature.

Immune checkpoint inhibitors (ICIs) are increasingly recognised to effectuate long-lasting therapeutic responses in solid tumours. However, ICI therapy can also result in various immune-related adverse events, such as ICI-associated myocarditis, a rare but serious complication. The clinical spectrum is wide and includes asymptomatic patients and patients with fulminant heart failure, making it challenging to diagnose this condition. Furthermore, the optimal diagnostic algorithm and treatment of ICI-associated myocarditis is unknown. In this review, we describe two cases on both ends of the spectrum and discuss the challenges in recognising, diagnosing and treating ICI-associated myocarditis.

The Nasal Microbiome in ANCA-Associated Vasculitis: Picking the Nose for Clues on Disease Pathogenesis.

PURPOSE OF REVIEW: The onset and progression of small vessel vasculitis associated with anti-neutrophil cytoplasmic antibodies has been linked to microbial infections. Here, we provide a brief overview of the association of nasal colonization of Staphylococcus aureus with ANCA-associated vasculitis (AAV) and discuss several recent studies mapping the nasal microbiome in AAV patients in particular. RECENT FINDINGS: Nasal microbiome studies revealed dysbiosis as a common trait in active AAV which tends to normalize upon immunosuppressive treatment and quiescent disease. However, due to differences in study design, patient selection, and methodology, the reported microbiome profiles differ considerably precluding conclusions on causal relationships. The microbiome is an emerging area of research in AAV warranting further investigation. Ideally, such studies should be combined with mechanistic studies to unravel key elements related to host-microbe interactions and their relevance for AAV pathogenesis.

Primary immunodeficiencies in the Netherlands: national patient data demonstrate the increased risk of malignancy.

PURPOSE: To analyze the data of the national registry of all Dutch primary immune deficiency (PID) patients, according to the European Society for Immunodeficiencies (ESID) definitions. RESULTS: In the Netherlands, 745 patients had been registered between 2009 and 2012. An overall prevalence of 4.0 per 100,000 inhabitants was calculated. The most prevalent PID was 'predominantly antibody disorder (PAD)' (60.4%). In total, 118 transplantations were reported, mostly hematopoietic stem cell transplantations (HSCT). Almost 10% of the PID patients suffered from a malignancy, in particular 'lymphoma' and 'skin cancer'. Compared to the general Dutch population, the relative risk of developing any malignancy was 2.3-fold increased, with a >10-fold increase for some solid tumors (thymus, endocrine organs) and hematological disease (lymphoma, leukemia), varying per disease category. CONCLUSIONS: The incidence rate and characteristics of PID in the Netherlands are similar to those in other European countries. Compared to the general population, PID patients carry an increased risk to develop a malignancy.

Health care in patients 1 year post-stroke in general practice: research on the utilisation of the Dutch Transmural Protocol transient ischaemic attack/cerebrovascular accident.

This study evaluates the kind of aftercare that ischaemic stroke patients receive and the extent that aftercare fulfils the criteria of the 'Dutch Transmural Protocol transient ischaemic attack/cerebrovascular accident'. Fifty-seven patients were interviewed 1 year post-stroke about secondary prevention and aftercare. Forty general practitioners (GPs) completed a questionnaire about guidance and secondary prevention (concerning medication and lifestyle advice). Most patients would like to see their GP more regularly. More aftercare was required than was planned. The use of aspirin remained the same, fewer patients used statins and more used antihypertensives. Of the 40 GPs who participated, 12% did not apply prevention. Blood pressure, glucose and cholesterol were measured in 84%, 28% and 40% of patients. All of these measures were often elevated, but treatment was not given. Lifestyle advice was offered to one-quarter of patients. Considering all of the advice given in the Dutch Protocol, several aspects can be improved in relation to secondary prevention. Too little attention is paid to giving lifestyle advice, stricter medical checkups by GPs are necessary and there is a decrease in use of preventive medication, partly because GPs monitors use of medication inadequately. The use of the Dutch Protocol in aftercare can be improved by a more detailed description of advice.

Self-Reported Visual Complaints in People with Parkinson's Disease: A Systematic Review.

BACKGROUND: Scientific research increasingly focuses on visual symptoms of people with Parkinson's disease (PD). However, this mostly involves functional measures, whereas self-reported data are equally important for guiding clinical care. OBJECTIVE: This review provides an overview of the nature and prevalence of self-reported visual complaints by people with PD, compared to healthy controls. METHODS: A systematic literature search was performed. Studies from three databases (PubMed, PsycInfo, and Web of Science) were screened for eligibility. Only studies that reported results of visual self-reports in people with idiopathic PD were included. RESULTS: One hundred and thirty-nine eligible articles were analyzed. Visual complaints ranged from function-related complaints (e.g., blurred vision, double vision, increased sensitivity to light or changes in contrast sensitivity) to activity-related complaints (e.g., difficulty reading, reaching, or driving). Visual complaints were more prevalent in people with PD compared to healthy controls. The presence of visual complaints leads to a reduced quality of life (QoL). Increased prevalence and severity of visual complaints in people with PD are related to longer disease duration, higher disease severity, and off-state. CONCLUSION: A large proportion of people with PD have visual complaints, which negatively affect QoL. Complaints are diverse in nature, and specific and active questioning by clinicians is advised to foster timely recognition, acknowledgement, and management of these complaints.

Severe mesenteric ischemia with multiple organ failure in a patient previously treated with a humanized monoclonal antibody against programmed death receptor-1 (pembrolizumab), a case of pembrolizumab associated catastrophic antiphospholipid syndrome?

Immune checkpoint inhibitors are used in the treatment of different types of tumors including melanoma and non-small cell lung carcinoma. The use of these inhibitors is associated with a broad spectrum of immune-related adverse effects. Here we report a case of a patient admitted to the intensive care unit with multiple organ failure due to catastrophic antiphospholipid syndrome following treatment with pembrolizumab, an immune checkpoint inhibitor, because of metastatic melanoma. The presented patient had multiple organ failure of lung, gastro-intestinal, renal, and the liver. Vascular thrombosis was confirmed by both imaging (pulmonary embolism on computed tomography-thorax) and histopathological examination of the intestines. In combination with the presence of IgA anti-cardiolipin antibodies and initially IgM anti-cardiolipin antibodies, catastrophic antiphospholipid syndrome was suspected. Despite treatment with plasmapheresis and corticosteroids, the patient died due to multiple organ failure. Catastrophic antiphospholipid syndrome is difficult to recognize and has high mortality rates despite supportive treatment. In this case report, discussion is provided regarding the possible immunological mechanism behind catastrophic antiphospholipid syndrome during or after treatment with immune checkpoint inhibitors. It is important to realize that in modern intensive care unit, more patients with immune-related adverse effects of the treatment with immune checkpoint inhibitors will be admitted, because of an increase in the number of patients treated with these checkpoint inhibitors. When these patients are admitted on the intensive care unit, multi-disciplinary consultation is important because of the difficulty of early recognition and optimal treatment of these possible lethal side effects.

A Dutch consensus statement on the diagnosis and treatment of ANCA-associated vasculitis.

INTRODUCTION: Despite the availability of several guidelines on the diagnosis and treatment of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), clinical routine practice will only improve when an implementation strategy is in place to support clinical decision making and adequate implementation of guidelines. We describe here an initiative to establish national and multidisciplinary consensus on broad aspects of the diagnosis and treatment of AAV relevant to daily clinical practice in the Netherlands. METHODS: A multidisciplinary working group of physicians in the Netherlands with expertise on AAV addressed the broad spectrum of diagnosis, terminology, and immunosuppressive and non-immunosuppressive treatment, including an algorithm for AAV patients. Based on recommendations from (inter)national guidelines, national consensus was established using a Delphi-based method during a conference in conjunction with a nationally distributed online consensus survey. Cut-off for consensus was 70% (dis)agreement. RESULTS: Ninety-eight professionals were involved in the Delphi procedure to assess consensus on 50 statements regarding diagnosis, treatment, and organisation of care for AAV patients. Consensus was achieved for 37/50 statements (74%) in different domains of diagnosis and treatment of AAV including consensus on the treatment algorithm for AAV. CONCLUSION: We present a national, multidisciplinary consensus on a diagnostic strategy and treatment algorithm for AAV patients as part of the implementation of (inter)national guideline-derived recommendations in the Netherlands. Future studies will focus on evaluating local implementation of treatment protocols for AAV, and assessments of current and future clinical practice variation in the care for AAV patients in the Netherlands.

Learning from Parkinson's patients: Usability of the Cyclops dry powder inhaler.

Effective inhaler therapy requires correct handling of the inhaler, including being able to prepare the inhaler for use. Motor function impairment and cognitive disabilities, may impose problems on patients with Parkinson's disease when they have to prepare medication, such as inhalers, for use. The aim of the present study was to examine whether Parkinson's patients are able to correctly prepare the Cyclops inhaler for use. At first, 12 patients, 6 in an off state and 6 in an on state, were asked to open 5 inhalers with ascending peel resistance of the cover foil. It was investigated up to which peel resistance they were able to successfully pull the foil from the inhaler. For the second part of the study, 48 participants, 24 on and 24 off, were asked to open 2 pouches and the 2 inhalers selected in part 1. For pouch 1, 70.8% of the patients in an on state and 58.3% in an off state were able to open the pouch correctly. For pouch 2, this was 79.2% and 75.0%, respectively. Both Cyclops inhalers were opened correctly by 95.8% of the participants in the on state and 91.7% of the participants in the off state.

Transient thyrotoxicosis during nivolumab treatment.

Two patients presented with transient thyrotoxicosis within 2-4 weeks after starting treatment with nivolumab. This thyrotoxicosis turned into hypothyroidism within 6-8 weeks. Temporary treatment with a beta blocker may be sufficient.

Chronic stimulation of the subthalamic nucleus increases daily on-time without dyskinesia in advanced Parkinson's disease.

We assessed the efficacy of chronic stimulation of the subthalamic nucleus (STN-DBS) in 20 patients with Parkinson's disease (PD) by means of clinical assessments and patient diaries 12 months after surgery. STN-DBS reduced the UPDRS part III off-medication score by 33%, and successively improved complete daily on-time without dyskinesia at 12 months significantly. In conclusion, our study demonstrates the efficacy of chronic STN-DBS on motor features in a selected population of advanced PD patients. In addition to clinical assessments, patients' diaries serve as an essential tool to evaluate the functional motor status after STN-DBS.

Effect of Rectal Levodopa Administration: A Case Report.

OBJECTIVE: The aim of this report is to discuss whether or not rectal levodopa administration is useful in some situations. BACKGROUND: In situations where oral intake of levodopa formulations is not possible, the treatment options of Parkinson's disease patients are limited. The literature describes no or low rectal absorption of levodopa. CASE DESCRIPTION: A patient with an ileus was unable to take oral medication. After consulting the neurologist and pharmacist, the surgeon decided to describe a rectal formulation of levodopa/carbidopa (100/25 mg) once daily. On day 3 of the therapy, 1 h after administration of the rectal formulation of levodopa/carbidopa, a blood sample was drawn. The patient was unable to take his other Parkinson medication; therefore the dose of the rectal levodopa/carbidopa was increased to 5 times a day. RESULTS: Full control of the symptoms was not achieved, but alleviation of the most severe tremor and rigidity was seen, which was confirmed by the neurologist, nurses and patient. The levodopa concentration detected was 17 nmol/l. Compared to levodopa concentrations described in the literature (1,400-12,000 nmol/l), the concentration is very low. There are some possible explanations for the low concentration detected. The presence of a specific amino acid transport system in the rectum is not known, which could lead to no or reduced absorption. The poor rectal absorption of carbidopa leads to a higher conversion of levodopa to dopamine peripherally. CONCLUSIONS: In situations where patients are unable to take oral medication, rectal administration of levodopa/carbidopa is worth considering.

Can Patients with Parkinson's Disease Use Dry Powder Inhalers during Off Periods?

Because of its rapid onset of action, pulmonary administration of levodopa is an interesting alternative to oral administration for the rescue treatment of Parkinson's disease patients in an off period. We studied the ability of Parkinson's disease patients to operate a dry powder inhaler (DPI) correctly during an off period. We used an instrumented test inhaler with three different resistances to air flow to record flow curves and computed various inhalation parameters. We observed that all (13) patients were able to generate pressure drops > 2 kPa over the highest resistance and 10 out of 13 patients achieved at least 4 kPa. Inhaled volumes (all resistances) varied from 1.2 L to 3.5 L. Total inhalation time and the time to peak inspiratory flow rate both decreased with decreasing inhaler resistance. Twelve out of thirteen patients could hold their breath for at least five seconds after inhalation and nine could extend this time to ten seconds. The data from this study indicate that patients with Parkinson's disease will indeed be able to use a dry powder inhaler during an off period and they provide an adequate starting point for the development of a levodopa powder inhaler to treat this particular patient group.

Tracing of dopamine receptors in hemiparkinsonism with positron emission tomography (PET).

In 13 hemiparkinson patients possible changes in dopamine receptors were investigated in vivo with PET, using [11C]methylspiperone as the receptor labeling ligand. Though in individual patients the specific binding of the tracer differed between both striata, no consistent difference was found. However, the specific binding in the striatum of patients with longterm dopaminergic medication was significantly higher than in non-medicated patients, and close to normal. No correlation with the predominantly unilateral clinical pathology was found. Since the postsynaptic receptor changes in hemiparkinson patients appear not to be uniform, these results suggest that the clinical asymmetry is not only caused by a dysfunction of nigral dopaminergic cells, but by pathology in other cells and probably in other neurotransmitter systems as well. The observed bilateral increase in receptor binding during dopaminergic therapy most likely results from a symmetrical change in local pharmacokinetics or from alteration of the receptor binding. Further studies with PET are needed to determine the exact nature of this change.

The role of myeloperoxidase in the pathogenesis of systemic vasculitis.

Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and idiopathic pauci-immune necrotizing crescentic glomerulonephritis are strongly associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). These ANCA-associated vasculitides can serologically be separated into myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA positive patients. The unique properties of the antigen targeted by the anti-MPO antibodies could help to explain the specific characteristics of MPO-ANCA associated disease. Recently, an animal model has been developed that proves that anti-mouse MPO immunoglobulins alone are capable of causing disease similar to that in humans. Also, the in vitro pathologic effects of binding of MPO-ANCA to MPO are better understood. MPO-ANCA can activate (primed) neutrophils directly causing extensive reactive oxygen species formation and degranulation of neutrophil constituents, including MPO, resulting in a destructive inflammatory response towards the vessel wall. MPO-ANCA can prevent the clearing and inactivation of MPO by ceruloplasmin as well, resulting in increased myeloperoxidase activity. Myeloperoxidase produces not only the strong oxidant bleach (hypochlorous acid) out of hydrogen peroxide and chloride ions but also oxidizes LDL into a macrophage high-uptake form, inactivates protease inhibitors, and consumes nitric oxide. These may contribute to endothelial dysfunction and add to the chronic renal lesions observed in patients with MPO-ANCA. MPO levels are influenced by genetic factors including two, MPO463 and MPO129, single nucleotide polymorphisms. The MPO 463 polymorphism has been associated with an increased risk of development of MPO-ANCA associated disease.

Acute effects of thalamotomy and pallidotomy on regional cerebral metabolism, evaluated by PET.

The subacute effect of thalamotomy and pallidotomy on regional cerebral metabolism was studied by means of Positron Emission Tomography (PET). In this way we aimed to identify the pattern of functional deafferentiation following a specific lesion in the basal ganglia. The cerebral distribution of 2-[18F]fluoro 2-deoxy-D-glucose (FDG) uptake at 1-2 weeks after operation was compared with the uptake before operation. Analysis of the changes was done by statistical parametric mapping (SPM). Thalamotomy resulted in a reduction of FDG uptake in predominantly the lateral prefrontal- and the parietal cortex, whereas pallidotomy affected only uptake in the (pre)frontal cortex. The absence of change in the primary sensory-motor cortex after either surgical procedure may suggest that, in man, the motor portions of the thalamus exert a predominantly indirect influence on the human motor cortex.

Selection of specific phage from display libraries: monoclonal antibody against VCS M13 helper phage coat protein III (gIIIp).

Screening of specific phage is often hampered by nonspecific binding either of the VCS M13 helper phage to the solid phase absorbent or to the polyclonal antibodies used for selection. The former is improved by increasing the stringency for selection. However, the available polyclonal anti-VCS M13 antibodies often react with immobilized antigen nonspecifically, making it difficult to distinguish between positive and negative clones. To improve this selection process, a monoclonal antibody (MAb) was produced which recognizes ligand-coat protein three (gIIIp) on the helper phage VCS M13. This MAb is highly sensitive and specific, and it is useful for selecting relevant clones. This reagent should find widespread application in identifying interactive clones from a variety of phage display libraries.