J.J. van Doormaal

Mastocytosis and insect venom allergy: diagnosis, safety and efficacy of venom immunotherapy

The most important causative factor for anaphylaxis in mastocytosis are insect stings. The purpose of this review is to analyse the available data concerning prevalence, diagnosis, safety and effectiveness of venom immunotherapy (VIT) in mastocytosis patients. If data were unclear, authors were contacted personally for further information. Quality of evidence (A: high, B: moderate, C: low and D: very low) and strength of recommendation (strong 1 and weak 2) concerning VIT in mastocytosis patients are assessed according to the Grading of Recommendations Assessment, Development and Evaluation and are marked in square brackets. Results of VIT were described in 117 patients to date. The mean rate of side‐effects during treatment in studies published so far is 23.9% (7.6% requiring adrenaline) with an overall protection rate of 72%. Based on the review we conclude that (1) mastocytosis patients have a high risk of severe sting reactions in particular to yellow jacket, (2) VIT could be suggested [2] in mastocytosis, (3) probably should be done life long [2], (4) VIT in mastocytosis is accompanied by a higher frequency of side‐effects, so (5) special precautions should be taken into account notably during the built up phase of the therapy [2], (6) VIT is able to reduce systemic reactions, but to a lesser extent compared to the general insect venom allergic population [2], so (7) patients should be warned that the efficacy of VIT might be less than optimal and they should continue carrying two adrenaline auto injectors [2].

Tryptase and histamine metabolites as diagnostic indicators of indolent systemic mastocytosis without skin lesions.

Risk indicators of indolent systemic mastocytosis (ISM) in adults with clinical suspicion of ISM without accompanying skin lesions [urticaria pigmentosa (UP)] are lacking. This study aimed at creating a decision tree using clinical characteristics, serum tryptase, and the urinary histamine metabolites methylimidazole acetic acid (MIMA) and methylhistamine (MH) to select patients for bone marrow investigations to diagnose ISM.

Long-term follow-up of indolent mastocytosis in adults

Objective. To evaluate the natural course of indolent mastocytosis in adults.

Interleukin‐13 promoter gene polymorphism ‐1112C/T is associated with the systemic form of mastocytosis

Background:  Mastocytosis is a heterogenous disease involving mast cells (MC) and their progenitors. Cutaneous and systemic variants of the disease have been reported. In contrast to cutaneous mastocytosis (CM), patients with systemic mastocytosis (SM) are at risk to develop disease progression or a nonMC‐lineage haematopoietic neoplasm. Little is known, however, about factors predisposing for the development of SM. One factor may be cytokine regulation of MC progenitors.

Gene expression profile, pathways, and transcriptional system regulation in indolent systemic mastocytosis.

To cite this article: Niedoszytko M, Oude Elberink JNG, Bruinenberg M, Nedoszytko B, de Monchy JGR, te Meerman GJ, Weersma RK, Mulder AB, Jassem E, van Doormaal JJ. Gene expression profile, pathways, and transcriptional system regulation in indolent systemic mastocytosis. Allergy 2011; 66: 229–237.

Gene expression analysis predicts insect venom anaphylaxis in indolent systemic mastocytosis

To cite this article: Niedoszytko M, Bruinenberg M, van Doormaal JJ, de Monchy JGR, Nedoszytko B, Koppelman GH, Nawijn MC, Wijmenga C, Jassem E, Oude Elberink JNG. Gene expression analysis predicts insect venom anaphylaxis in indolent systemic mastocytosis. Allergy 2011; 66: 648–657.

Contribution of highly sensitive diagnostic methods to the diagnosis of systemic mastocytosis in the absence of skin lesions

We have read with interest the article entitled ‘Tryptase and histamine metabolites as diagnostic indicators of indolent systemic mastocytosis without skin lesions’ by Doormaal et al. (1). Results of this study related to the higher risk for systemic mastocytosis (SM) conferred by male gender, insectinduced anaphylaxis and tryptase levels support previous findings from our group, based on which we have proposed a score to predict for SM in patients with mast cell (MC) activation symptoms without skin lesions (2), such score being further validated (3) in the largest cohort of SM patients without urticaria pigmentosa (UP) (n = 80) published so far. On the basis of our findings in both studies, which Doormal et al. failed to cite, we would like to comment on some of the specific methods used by the authors to rule out/diagnose SM that may impact their results and conclusions. It is well established that indolent SM (ISM) patients without UP typically display a low MC burden, which translates into a substantial proportion of cases lacking bone marrow (BM) MC aggregates (2). Consequently, highly sensitive diagnostic methods including multiparameter flow cytometry immunophenotyping for the identification of BMMC down to frequencies as low as <10 4 to 10 , and the KIT mutation analysis of highly purified BMMC (4), should be routinely applied in these patients to avoid false-negative results. In fact, 10% of our ISM patients without UP showed <0.01% [the detection limit reported by the authors (1)] immunophenotypically aberrant BMMC (3), and even higher frequencies (18%) have been reported by Bonadonna et al. (5) in a series of 17 ISM patients without UP presenting with insect venom anaphylaxis. In addition, 11/78 patients (14%) from our series showed KIT-mutated BMMC in the absence of criteria for SM, which currently leads to the diagnosis of the socalled clonal MC activation syndrome (c-MCAS) or monoclonal MC activation syndrome (MMAS) (2,6); noteworthy, more than half (6/11) of these patients showed <0.01% of BMMC by flow cytometry. Investigation of the KIT mutation in whole (unfractionated) BM samples, specifically for the identification of the D816V KIT mutation without investigating other exon 17 mutations, as conducted by Doormaal et al. (1) may lead to a lower rate of detection of mutated BMMC as previously demonstrated (4). In fact, in their study, Doormaal et al. (1) reported an overall frequency of KIT mutation of 85% among the SM group, a frequency significantly lower than that found in our series where molecular studies were performed in highly purified BMMC: overall frequency of KIT mutation among evaluable cases of 98%, including 7% of cases with KIT mutations involving exon 17 other than the D816V KIT mutation (3), supporting the need to screen for mutations in the entire exon 17 of KIT in cases lacking the classical D816V KIT mutation. Finally, we would also like to support the authors’ conclusion that serum tryptase levels <20 lg/l exclude neither SM nor MMAS and that such cut-off could be lowered (5). However, caution should be taken in systematically refraining from BM examination in suspected patients with serum tryptase <10 lg/l, as proposed by the authors. In fact, 4/14 (28%) patients who presented with MC mediator release symptoms without UP and tryptase <10 lg/l referred to our centre were finally diagnosed with SM (n = 2) and MMAS (n = 2), when the above-described diagnostic methods were followed (3). Consequently, neither SM nor MMAS can be ruled out, as proposed by the authors, based exclusively on both normal histology and cytology, and we strongly recommend that such BM studies are performed in experienced reference centres where the most sensitive diagnostic procedures available nowadays are routinely applied.

Antineutrophil cytoplasmatic antibodies in patients with premature atherosclerosis: prevalence and association with risk factors

Abstract. van Haelst PL, Asselbergs FW, van Doormaal JJ, Veeger NJGM, May JF, Holvoet P, Gans ROB, Cohen Tervaert JW (University Hospital Groningen, Groningen, The Netherlands; University of Leuven, Leuven, Belgium). Antineutrophil cytoplasmatic antibodies in patients with premature atherosclerosis: prevalence and association with risk factors. J. Intern Med 2002; 251: 29–34.