Jan A. M. van Laar

Utility of contrast-enhanced ultrasound for the assessment of the carotid artery wall in patients with Takayasu or giant cell arteritis

AIMS Carotid contrast-enhanced ultrasound (CEUS) was recently proposed for the evaluation of large-vessel vasculitides (LVV), particularly to assess vascularization within the vessel wall. The aim of this pilot study was to evaluate the potential of carotid colour Doppler ultrasound (CDUS) and CEUS in patients with LVV. METHODS AND RESULTS This prospective study included seven patients (mean age 48 ± 14 years, all females) with established LVV (Takayasu arteritis or giant cell arteritis). All patients underwent CDUS and CEUS (14 carotid arteries). Intima-media thickness, lumen diameter, Doppler velocities, vessel wall thickening, and lesion thickness were assessed. CEUS was used to improve visualization of the lumen-to-vessel wall border, and to visualize carotid wall vascularization. Four (57%) patients [7 (50%) carotid arteries] exhibited lesions, and the average lesion thickness was 2.0 ± 0.5 mm. According to the Doppler peak systolic velocity, 5 (35%) carotid arteries had a <50% stenosis, 1 (7%) had a 50-70% stenosis, and 1 (7%) had a ≥70% stenosis. The contrast agent improved the image quality and the definition of the lumen-to-vascular wall border. Carotid wall vascularization was observed in 5 (71%) patients [9 (64%) carotid arteries]. Five (36%) carotid arteries had mild-to-moderate vascularization, and 4 (29%) had severe wall vascularization. CONCLUSION Carotid CDUS allows the assessment of anatomical features of LVV, including vessel wall thickening and degree of stenosis. Carotid CEUS improves the visualization of the lumen border, and allows dynamic assessment of carotid wall vascularization, which is a potential marker of disease activity in patients with LVV.

Successful long-term triple disease control by ustekinumab in a patient with Behçet's disease, psoriasis and hidradenitis suppurativa

Behcets disease (BD) is an auto-inflammatory disorder, characterised by recurrent oral aphtosis, genital ulcers, uveitis and pustular skin lesions.1 Associated cutaneous diseases include Sweets syndrome,2 erythema nodosum and pyoderma gangrenosum.3 Next to BD, both psoriasis and hidradenitis suppurativa (HS) are clear neutrophilic and interleukin (IL)-17-based diseases, suggesting a pathomechanistic overlap.4–7 However, these diseases rarely co-occur.4 Ustekinumab (anti-p40 mAb), an effective biological treatment for psoriasis, might be effective in BD by interfering with the IL-17 signalling via IL-23 blockage. We present a 39-year-old Caucasian woman in whom the combination of BD, psoriasis and HS was successfully treated with ustekinumab. At the age of 5, the …

Genome-wide association study in an admixed case series reveals IL12A as a new candidate in Behçet disease.

Introduction The etiology of Behçet’s disease (BD) is unknown, but widely considered an excessive T-cell mediated inflammatory response in a genetically susceptible host. Recent genome-wide association studies (GWAS) have shown limited number of novel loci-associations. The rarity and unequal distribution of the disease prevalence amongst different ethnic backgrounds have hampered the use of GWAS in cohorts of mixed ethnicity and sufficient sample size. However, novel statistical approaches have now enabled GWAS in admixed cohorts. Methods We ran a GWAS on 336 BD cases and 5,843 controls. The cases consisted of Western Europeans, Middle Eastern and Turkish individuals. Participants from the Generation R study, a multiethnic birth cohort in Rotterdam, The Netherlands were used as controls. All samples were genotyped and data was combined. Linear regression models were corrected for population stratification using Genomic Principal Components and Linear Mixed Modelling. Meta-analysis was performed on selected results previously published. Results We identified SNPs associated at genome-wide significant level mapping to the 6p21.33 (HLA) region. In addition to this known signal two potential novel associations on chromosomes 6 and 18 were identified, yet with low minor allele frequencies. Extended meta-analysis reveal a GWS association with the IL12A variant rs17810546 on chromosome 3. Discussion We demonstrate that new statistical techniques enable GWAS analyses in a limited sized cohort of mixed ethnicity. After implementation, we confirmed the central role of the HLA region in the disease and identified new regions of interest. Moreover, we validated the association of a variant in the IL2A gene by meta-analysis with previous work. These findings enhance our knowledge of genetic associations and BD, and provide further justification for pursuing collective initiatives in genetic studies given the low prevalence of this and other rare diseases.

Everything you need to know about distal renal tubular acidosis in autoimmune disease

Abstract Renal acid–base homeostasis is a complex process, effectuated by bicarbonate reabsorption and acid secretion. Impairment of urinary acidification is called renal tubular acidosis (RTA). Distal renal tubular acidosis (dRTA) is the most common form of the RTA syndromes. Multiple pathophysiologic mechanisms, each associated with various etiologies, can lead to dRTA. The most important consequence of dRTA is (recurrent) nephrolithiasis. The diagnosis is based on a urinary acidification test. Potassium citrate is the treatment of choice.

Prevalence of distal renal tubular acidosis in primary Sjögren's syndrome

OBJECTIVES Our objectives were to analyse the prevalence of distal renal tubular acidosis (dRTA) in primary SS (pSS) and to compare a novel urinary acidification test with furosemide and fludrocortisone (FF) with the gold standard ammonium chloride (NH4Cl) to detect dRTA. METHODS Urinary acidification was assessed in 57 pSS patients using NH4Cl and FF. A urinary acidification defect was defined as an inability to reach a urinary pH of <5.3 after NH4Cl. RESULTS The prevalence of complete dRTA (urinary acidification defect with acidosis) was 5% (3/57). All three patients had positive SSA/Ro and SSB/La autoantibodies and impaired kidney function. The prevalence of incomplete dRTA (urinary acidification defect without acidosis) was 25% (14/57). Compared with patients without dRTA, patients with incomplete dRTA had significantly lower venous pH and serum bicarbonate and higher urinary pH. SSB/La antibodies were more prevalent in the dRTA groups (P < 0.05). Compared with NH4Cl, the positive and negative predictive values of FF were 46% and 82%, respectively. Vomiting occurred more often during the urinary acidification test with NH4Cl than with FF (9 vs 0, P < 0.05). CONCLUSION Incomplete dRTA is common in pSS and causes mild acidaemia and higher urinary pH, which may contribute to bone demineralization and kidney stone formation. FF cannot replace NH4Cl in testing urinary acidification in pSS, but may be considered as a screening tool, given its reasonable negative predictive value and better tolerability.

AA Amyloidosis and IgG4-Related Disease

In a letter describing a patient with renal AA amyloidosis associated with IgG4-related disease, the correspondents report that the treatment of IgG4-related disease may modulate inflammatory effects that could lead to secondary amyloidosis.

Calcium and Vitamin D in Sarcoidosis: Is Supplementation Safe?

Granulomas in sarcoidosis express high levels of 1α‐hydroxylase, an enzyme that catalyzes the hydroxylation of 25‐OH vitamin D to its active form, 1,25(OH)2 vitamin D. Overproduction of 1α‐hydroxylase is held responsible for the development of hypercalcemia in sarcoidosis patients. Corticosteroids are used as first‐line treatment in organ‐threatening sarcoidosis. In this light, osteoporosis prevention with calcium and vitamin D (CAD) supplementation is often warranted. However, sarcoidosis patients are at risk for hypercalcemia, and CAD supplementation affects the calcium metabolism. We studied calcium and vitamin D disorders in a large cohort of sarcoidosis patients and investigated if CAD supplementation is safe. Retrospectively, data of 301 sarcoidosis patients from July 1986 to June 2009 were analyzed for serum calcium, 25‐hydroxy vitamin D (25‐(OH)D), 1,25‐dihydroxy vitamin D (1,25(OH)2D), and use of CAD supplementation. Disease activity of sarcoidosis was compared with serum levels of vitamin D. Hypercalcemia occurred in 8%. A significant negative correlation was found between 25‐(OH)D and disease activity of sarcoidosis measured by somatostatin receptor scintigraphy. In our study, 5 of the 104 CAD‐supplemented patients developed hypercalcemia, but CAD supplementation was not the cause of hypercalcemia. Patients without CAD supplementation were at higher risk for developing hypercalcemia. During CAD supplementation, no hypercalcemia developed as a result of supplementation. Hypovitaminosis D seems to be related with more disease activity of sarcoidosis and, therefore, could be a potential risk factor for disease activity of sarcoidosis. Thus, vitamin D–deficient sarcoidosis patients should be supplemented.

Systemic mastocytosis: A cohort study on clinical characteristics of 136 patients in a large tertiary centre

BACKGROUND Systemic mastocytosis (SM) is a rare heterogeneous disease which is characterized by the aberrant proliferation of mast cells. It can be divided into various subtypes with different phenotypes and prognoses. Here, we report on the clinical characteristics of 136 SM patients. METHODS A retrospective cohort study was conducted from January 2009 to September 2014 in a large tertiary centre in The Netherlands. We included all patients who fulfilled WHO criteria for SM. Data were collected from electronic patient files. RESULTS A total of 124 patients had indolent SM (ISM) (91.2%), 7 had aggressive SM (ASM) (5.1%) and 5 had SM with associated hematological non-mast cell lineage disease (SM-AHNMD) (3.7%). There was no progression from ISM to advanced SM subtypes, but 1 patient with ASM developed chronic myelocytic leukemia 2years after diagnosis. The average time to diagnosis for the whole population was 8.1years (range, 0-49years). The most frequent triggers for work-up-skin involvement, anaphylaxis and osteoporosis-were characterized by an interval to diagnosis of 10.9, 2.9 and 7.5years, respectively. A total of 32 patients (23.5%) had a serum tryptase levels below the cutoff value of 20ng/mL at the time of diagnosis, but these patients did not have significant differences in clinical phenotype. CONCLUSIONS SM comprises a wide spectrum of signs and symptoms and its often atypical presentation can delay the establishment of the diagnosis substantially. Skin involvement, anaphylaxis and unexplained osteoporosis should trigger analysis for mastocytosis. A normal serum tryptase does not exclude the diagnosis of SM.

Expansion of blood IgG4+ B, TH2, and regulatory T cells in patients with IgG4-related disease

Background IgG4‐related disease (IgG4‐RD) is a systemic fibroinflammatory condition affecting various organs and has a diverse clinical presentation. Fibrosis and accumulation of IgG4+ plasma cells in tissue are hallmarks of the disease, and IgG4‐RD is associated with increased IgG4 serum levels. However, disease pathogenesis is still unclear, and these cellular and molecular parameters are neither sensitive nor specific for the diagnosis of IgG4‐RD. Objective Here we sought to develop a flow cytometric gating strategy to reliably identify blood IgG4+ B cells to study their cellular and molecular characteristics and investigate their contribution in disease pathogenesis. Methods Sixteen patients with histologically confirmed IgG4‐RD, 11 patients with sarcoidosis, and 30 healthy subjects were included for 11‐color flow cytometric analysis of peripheral blood for IgG4‐expressing B cells and TH subsets. In addition, detailed analysis of activation markers and chemokine receptors was performed on IgG4‐expressing B cells, and IgG4 transcripts were analyzed for somatic hypermutations. Results Cellular and molecular analyses revealed increased numbers of blood IgG4+ memory B cells in patients with IgG4‐RD. These cells showed reduced expression of CD27 and CXCR5 and increased signs of antibody maturation. Furthermore, patients with IgG4‐RD, but not patients with sarcoidosis, had increased numbers of circulating plasmablasts and CD21low B cells, as well as TH2 and regulatory T cells, indicating a common disease pathogenesis in patients with IgG4‐RD. Conclusion These results provide new insights into the dysregulated IgG4 response in patients with IgG4‐RD. A specific “peripheral lymphocyte signature” observed in patients with IgG4‐RD, could support diagnosis and treatment monitoring. Graphical abstract Figure. No Caption available.

Chest Radiographic Screening for Sarcoidosis in the Diagnosis of Patients with Active Uveitis

Rationale: Although chest radiography is currently recommended for the initial evaluation of patients with new‐onset uveitis, the efficacy of this diagnostic screening modality is not known. Objectives: To evaluate the diagnostic value of chest radiographs in patients with active uveitis of recent onset in a tertiary center in Western Europe. Methods: A retrospective cross‐sectional study was conducted by reviewing all chest imaging for adults with new‐onset (<1 yr) uveitis of unknown origin undergoing initial evaluation in the Department of Ophthalmology at Erasmus University Medical Center (Rotterdam, the Netherlands). Radiographic findings were related to clinical and other imaging characteristics and to final diagnoses. Results: Screening chest radiographs were abnormal for 30 of 200 patients (15%) included in this study. Twenty‐two of the 200 patients (11%) had biopsy‐confirmed sarcoidosis, and an additional 12 patients were presumed to have sarcoidosis. The finding of chest radiographic abnormalities interpreted as typical of sarcoidosis was specific (91%; 95% confidence interval, 85.9‐94.4%) but not sensitive (64%; 95% confidence interval, 43.0‐80.3%) for biopsy‐confirmed sarcoidosis. The combination of elevated serum angiotensin‐converting enzyme level and chest radiographic findings typical of sarcoidosis increased the sensitivity to 79%. Biopsy‐confirmed sarcoidosis was more common in patients with panuveitis (17 of 84; 20%) compared to patients with other anatomical locations of uveitis (5 of 116, 4%; P < 0.001). One patient was diagnosed with active pulmonary and ocular tuberculosis. Conclusions: Abnormal chest radiographs were found in 15% of patients with active uveitis of unknown origin and onset within 1 year of referral to a tertiary center in the Netherlands. A majority of the abnormal chest radiographs showed findings compatible with a diagnosis of sarcoidosis.