Serum tryptase correlates with the KIT D816V mutation burden in adults with indolent systemic mastocytosis

Systemic mastocytosis (SM) is characterized by the growth of neoplastic mast cells (MCs). Most adults with indolent SM carry the KIT D816V mutation. We recently introduced the D816V+ allele fraction as a disease marker in SM using a sensitive and quantitative KIT D816V mutation analysis that consistently allows mutation detection in peripheral blood (PB) and bone marrow (BM). The D816V+ allele fraction represents a quantitative measure which allows KIT D816V‐positivity to be analyzed as a continuous variable instead of a categorical variable (negative/positive) as previously described. Serum tryptase represents an established disease marker in SM, and it remains to be tested whether tryptase and the D816V+ allele fraction are associated or represent independent disease markers. In this study, correlation analysis between serum tryptase, the D816V+ allele fraction in PB and BM, and the MC fraction was performed in 57 indolent systemic mastocytosis (ISM) patients. We detected significant correlations between the D816V+ allele fraction, the mature neoplastic MC fraction, and serum tryptase which represent three different biological measures of disease burden. Mutation analysis was performed in two or more PB samples in 39 patients, and the results demonstrated high stability with no overall tendency to increasing D816V+ allele fractions over time. Considerable variation was nevertheless observed in the correlation analyses. Serum tryptase reflects the mature MC load, whereas the D816V+ allele fraction includes cells other than mature MCs to a variable extent. We conclude that tryptase and the D816V+ allele fraction represent different, although correlated, measures of disease status in SM.     

Systemic mastocytosis: current concepts and treatment advances

Systemic mastocytosis (SM), as opposed to cutaneous-only mastocytosis, implies the presence of neoplastic mast cell infiltration in extracutaneous tissue. Mast cell disease in adults is often systemic and often involves the bone marrow. Typical clinical and laboratory features of SM include urticaria pigmentosa, mast cell mediator symptoms (eg, headache, flushing, lightheadedness, urticaria and pruritus, nausea, diarrhea, abdominal pain, and vasodilatory shock), bone pain (eg, osteoporosis, lytic bone lesions, and fractures), hepatosplenomegaly, cytopenia, eosinophilia, elevated serum tryptase and histamine, and bone marrow fibrosis and angiogenesis. SM may be indolent (no evidence of organ dysfunction), aggressive (presence of organ dysfunction), associated with another often chronic myeloid hematologic disease (SM-AHD), or present as mast cell leukemia or sarcoma. Mast cell-mediator symptoms are treated with histamine antagonists and cromolyn sodium. Indolent SM does not require cytoreductive therapy. Aggressive SM and SM-AHD are managed based on their molecular profile. Recent information suggests that FIP1-like-1-platelet-derived growth factor receptor-alpha(+) SM responds well to imatinib mesylate, whereas interferon-alpha should be considered as a first-line treatment in all of the other cases, including patients with Asp816Val(+) SM. Cladribine has been shown to be effective in patients who develop resistance to interferon treatment.     

Systemic mastocytosis in adults: 2015 update on diagnosis,risk stratification,and management

Disease overview : Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extracutaneous organs. Diagnosis : The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. Risk stratification : The 2008 World Health Organization classification of SM has been shown to be prognostically relevant. Classification of SM patients into indolent SM (ISM), aggressive SM (ASM), SM associated with a clonal non‐MC lineage disease (SM‐AHNMD), and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis. Management : SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom‐directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease‐related organ dysfunction; interferon‐α (+/?corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal, and mediator‐release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib‐sensitive KIT mutation or in KITD816‐unmutated patients. Treatment of SM‐AHNMD is governed primarily by the non‐MC neoplasm; hydroxyurea has modest utility in this setting; there is a role for allogeneic stem cell transplantation in select cases. Investigational Drugs : Recent data confirms midostaurin's significant anti‐MC activity in patients with advanced SM. Am. J. Hematol. 90:251–262, 2015. © 2015 Wiley Periodicals, Inc.     

The KIT D816V expressed allele burden for diagnosis and disease monitoring of systemic mastocytosis

The activating KIT D816V mutation plays a central role in the pathogenesis, diagnosis, and targeted treatment of systemic mastocytosis (SM). For improved and reliable identification of KIT D816V, we have developed an allele-specific quantitative real-time PCR (RQ-PCR) with an enhanced sensitivity of 0.01–0.1 %, which was superior to denaturing high-performance liquid chromatography (0.5–1 %) or conventional sequencing (10–20 %). Overall, KIT D816 mutations were identified in 146/147 (99 %) of patients (D816V, n?=?142; D816H, n?=?2; D816Y, n?=?2) with SM, including indolent SM (ISM, n?=?63, 43 %), smoldering SM (n?=?8, 5 %), SM with associated hematological non-mast cell lineage disease (SM-AHNMD, n?=?16, 11 %), and aggressive SM/mast cell leukemia?±?AHNMD (ASM/MCL, n?=?60, 41 %). If positive in BM, the KIT D816V mutation was found in PB of all patients with advanced SM (SM-AHNMD, ASM, and MCL) and in 46 % (23/50) of patients with ISM. There was a strong correlation between the KIT D816V expressed allele burden (KIT D816V EAB) with results obtained from DNA by genomic allele-specific PCR and also with disease activity (e.g., serum tryptase level), disease subtype (e.g., indolent vs. advanced SM) and survival. In terms of monitoring of residual disease, qualitative and quantitative assessment of KIT D816V and KIT D816V EAB was successfully used for sequential analysis after chemotherapy or allogeneic stem cell transplantation. We therefore conclude that RQ-PCR assays for KIT D816V are useful complimentary tools for diagnosis, disease monitoring, and evaluation of prognosis in patients with SM.     

The clinical and pathological panoply of systemic mastocytosis

Mastocytosis is a rare disease with varied presentation, myriad symptomatology and variable prognosis. Most patients present with cutaneous disease and mediator-related symptomatology with a small subset having systemic disease (systemic mastocytosis, SM). A subset of the latter develops synchronous or metachronous haematologic neoplasms (SM-AHN), most commonly chronic myelomonocytic leukaemia (CMML). Advanced systemic mastocytosis (ASM) is seen in a relatively small number of patients and is usually associated with organ dysfunction, and may present with hepatosplenomegaly, lymphadenopathy and ascites with progression to leukaemic transformation (mast cell leukaemia/acute myeloid leukaemia) occurring in a few patients. This paper discusses the clinical and pathologic features of the entire spectrum of SM in adults.     

Correlation between the macroscopic severity of Crohn’s disease in resected intestine and bowel wall thickness evaluated by water-immersion ultrasonography

Abstract

Objectives: Transabdominal ultrasonography is a common and accurate tool for managing Crohn’s disease (CD); however, the significance of the resulting data is poorly understood. This study was performed to determine the association between bowel wall thickness evaluated by water-immersion ultrasonography and macroscopic severity, namely, refractory inflammation and subsequent fibrosis in CD surgical specimens.

Materials and methods: We retrospectively evaluated 100 segments of colon and small intestine from 27 patients with CD. The resected specimens were placed in saline postoperatively, and bowel wall thickness was measured by water-immersion ultrasonography and compared with macroscopic findings. Correlations between bowel wall thickness and macroscopic findings were assessed using analysis of variance and receiver operating characteristic curves.

Results: According to the progression of macroscopic severity, the mean bowel wall thickness was increased as follows: macroscopically intact: 4.1?mm, longitudinal ulcer scars: 5.4?mm, longitudinal open ulcers: 6.0?mm, large ulcers: 6.4?mm, cobblestone-like lesions: 7.1?mm, and fibrotic strictures: 7.4?mm. For all lesions except longitudinal ulcer scars, the bowel wall thickness was significantly thicker than that of macroscopically-intact areas (p?<?.001). According to receiver operating characteristic curves, bowel wall thickness >4.5?mm was associated with CD lesions, and thickness >5.5?mm was associated with more severe lesions.

Conclusions: The bowel wall thickness of CD lesions was evaluated by water-immersion ultrasonography correlated with macroscopic disease severity.     

Systemic mastocytosis in adults: 2012 Update on diagnosis, risk stratification, and management

DISEASE OVERVIEW: Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extra-cutaneous organs. DIAGNOSIS: The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. RISK STRATIFICATION: The prognostic relevance of the 2008 World Health Organization (WHO) classification of SM has recently been confirmed. Classification of SM patients into indolent (SM), aggressive SM (ASM), SM associated with a clonal non-MC lineage disease (SM-AHNMD) and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis. MANAGEMENT: SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom-directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease-related organ dysfunction; interferon-α (±corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal, and mediator-release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib-sensitive KIT mutation or in KITD816-unmutated patients. Treatment of SM-AHNMD is governed primarily by the non-MC neoplasm; hydroxyurea has modest utility in this setting. INVESTIGATIONAL DRUGS: Dasatinib's in vitro anti-KITD816V activity has not translated into significant therapeutic activity in most SM patients. In contrast, preliminary data suggest that Midostaurin may produce significant decreases in MC burden in some patients.     

Systemic mastocytosis in adults: 2011 update on diagnosis, risk stratification, and management

DISEASE OVERVIEW: Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extracutaneous organs. DIAGNOSIS: The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. RISK STRATIFICATION: The prognostic relevance of the 2008 World Health Organization (WHO) classification of SM has recently been confirmed. Classification of SM patients into indolent (SM), aggressive SM (ASM), SM associated with a clonal non-MC lineage disease (SM-AHNMD), and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis. Risk-adapted therapy: SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom-directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease-related organ dysfunction; interferon-α (±corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal, and mediator-release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib-sensitive KIT mutation or in KITD816-unmutated patients. Treatment of SM-AHNMD is governed primarily by the non-MC neoplasm; hydroxyurea has modest utility in this setting. Dasatinib's in vitro anti- KITD816V activity has not translated into significant therapeutic activity in most SM patients. In contrast, preliminary data suggest that Midostaurin may produce significant decreases in MC burden in some patients.     

Dosage de la tryptase : un guide d'utilisation pour le clinicien

Tryptase is the most abundant endopeptidase released by mast cells degranulation, involved in many pro and anti-inflammatory processes. Normal serum tryptase range is 0–11.4 μg/L. Tryptase is a useful diagnostic tool for anaphylaxis, systemic mastocytosis (SM) and mast cell activation syndrome (MCAS), where specific threshold values must be used. SM diagnosis criteria include evidence of dense mast cell infiltrate either in the bone marrow or the affected organ (such as skin), presence of KIT D816V mutation and elevated serum tryptase level (>20 μg/L). In SM, tryptase level is correlated with the burden of mast cells in bone marrow. MCAS should be considered in case of severe and recurrent typical clinical signs of systemic mast cell activation involving at least two organs, associated with an increase in serum tryptase level of 20% + 2 μg/L from the individual's baseline. Anaphylaxis is the most severe among hypersensitivity reactions. A clonal mast cell disorder is a central question in anaphylaxis and appropriate explorations should be conducted in these patients. Triggers for anaphylactic reactions vary significantly in the general population and in patients with MS or MCAS. Finally, physicians must be aware of the many pathological and physiological situations that affect tryptase levels.     

Mastocytosis: the puzzling clinical spectrum and challenging diagnostic aspects of an enigmatic disease

Mastocytosis is a complex disorder characterized by the accumulation of abnormal mast cells (MC) in the skin, bone marrow and/or other visceral organs. The clinical manifestations result from MC‐derived mediators and, less frequently, from destructive infiltration of MCs. Patients suffer from a variety of symptoms including pruritus, flushing and life‐threatening anaphylaxis. Whilst mastocytosis is likely to be suspected in a patient with typical skin lesions [i.e. urticaria pigmentosa (UP)], the absence of cutaneous signs does not rule out the diagnosis of this disease. Mastocytosis should be suspected in cases of recurrent, unexplained or severe insect‐induced anaphylaxis or symptoms of MC degranulation without true allergy. In rare cases, unexplained osteoporosis or unexplained haematological abnormalities can be underlying feature of mastocytosis, particularly when these conditions are associated with elevated baseline serum tryptase levels. The diagnosis is based on the World Health Organization criteria, in which the tryptase level, histopathological and immunophenotypic evaluation of MCs and molecular analysis are crucial. A somatic KIT mutation, the most common of which is D816V, is usually detectable in MCs and their progenitors. Once a diagnosis of systemic mastocytosis (SM) is made, it is mandatory to assess the burden of the disease, its activity, subtype and prognosis, and the appropriate therapy. Mastocytosis comprises seven different categories that range from indolent forms, such as cutaneous and indolent SM, to progressive forms, such as aggressive SM and MC leukaemia. Although prognosis is good in patients with indolent forms of the disease, patients with advanced categories have a poor prognosis.     

Venom immunotherapy in patients with mastocytosis and hymenoptera venom anaphylaxis

Systemic mastocytosis (SM) is typically suspected in patients with cutaneous mastocytosis (CM). In recent years, the presence of clonal mast cells (MCs) in a subset of patients with systemic symptoms associated with MC activation in the absence of CM has been reported and termed monoclonal MC activation syndromes or clonal systemic MC activation syndromes. In these cases, bone marrow (BM) MC numbers are usually lower than in SM with CM, there are no detectable BM MC aggregates, and serum baseline tryptase is often <20 μg/l; thus, diagnosis of SM in these patients should be based on careful evaluation of other minor WHO criteria for SM in reference centers, where highly sensitive techniques for immunophenotypic analysis and investigation of KIT mutations on fluorescence-activated cell sorter-purified BM MCs are routinely performed. The prevalence of hymenoptera venom anaphylaxis (HVA) among SM patients is higher than among the normal population and it has been reported to be approximately 5%. In SM patients with IgE-mediated HVA, venom immunotherapy is safe and effective and it should be prescribed lifelong. Severe adverse reactions to hymenoptera stings or venom immunotherapy have been associated with increased serum baseline tryptase; however, presence of clonal MC has not been ruled out in most reports and thus both SM and clonal MC activation syndrome might be underdiagnosed in such patients. In fact, clonal BM MC appears to be a relevant risk factor for both HVA and severe reactions to venom immunotherapy, while the increase in serum baseline tryptase by itself should be considered as a powerful surrogate marker for anaphylaxis. The Spanish Network on Mastocytosis has developed a scoring system based on patient gender, the clinical symptoms observed during anaphylaxis and serum baseline tryptase to predict for the presence of both MC clonality and SM among individuals who suffer from anaphylaxis.     

A case of systemic mastocytosis mimicking POEMS syndrome: A case report

Rationale:POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome is a rare and complicated disease related to multiple organs and systems. Here, we report a case of systemic mastocytosis (SM) that was misdiagnosed as a POEMS syndrome.Patient concerns:A 42-year-old man presented with skin changes, diarrhea, and limb numbness.Diagnoses:Positron emission tomography/computed tomography revealed extravascular volume overload, organomegaly, lymphadenopathy, and bone lesions with mixed lesions of osteosclerosis and osteolysis. Therefore, POEMS syndrome was suspected. Further histopathological and immunohistochemical examination of the bone marrow, lymph nodes, and gastric mucosa suggested a diagnosis of mastocytosis. The c-Kit D816V mutation confirmed the diagnosis of SM.Interventions:The patient received the treatment of pegylated interferon-alpha weekly and glucocorticoid daily.Outcomes:The symptoms relieved significantly.Lessons:There are many similar features between POEMS syndrome and SM, probably leading to misdiagnosis. This study analyzed the different points between them which can provide help for differentiation.     

Iguratimod,a synthetic disease modifying anti-rheumatic drug inhibiting the activation of NF-κB and production of RANKL: Its efficacy,radiographic changes,safety and predictors over two years’ treatment for Japanese rheumatoid arthritis patients

Abstract

Objective: To elucidate the clinical and radiographic outcomes for rheumatoid arthritis (RA) patients treated with a synthetic disease-modifying antirheumatic drug, iguratimod (IGU).

Methods: Clinical outcomes for 213 RA patients treated with 25?mg/day oral IGU or 50?mg/day after 4 weeks of 25?mg/day treatment for one day to 104 weeks were assessed.

Results: A total of 142 active RA patients (DAS28-ESR ≥3.2) treated for more than 12 weeks showed a significant reduction in both DAS and simplified disease activity index (SDAI) scores at week 4 (p?<?.001) to week 104. Good and moderate DAS responses were achieved in 54 (38%) and 66 (46%) patients, respectively. Total Genant-modified Sharp scores (GSS) of 31 patients at week 104 showed no progression (total GSS ≤0.84: the smallest detectable change) in 16 (52%) patients with a mean score reduction (95%CI) of ?4.3 (?8.1～?0.5) (p?<?.05). Predictors were an early response, moderate disease activity at baseline, and male gender. Eleven of the 213 patients had gastric and/or duodenal ulcer. A peculiar haemorrhage was seen in two patients treated concomitantly with IGU and warfarin potassium.

Conclusion: IGU treatment shows an early and sustained efficacy. Radiographically, no progression of GSS was evident in 16 (52%) patients at week 104. Gastric bleeding or gastric perforation warrants careful attention, especially in patients with concomitant use of both a non-steroidal anti-inflammatory drug and oral prednisolone.     

Next‐generation sequencing in systemic mastocytosis: Derivation of a mutation‐augmented clinical prognostic model for survival

In routine practice, the World Health Organization classification of systemic mastocytosis (SM) is also the de facto prognostic system; a core value is distinguishing indolent (ISM) from advanced SM (includes aggressive SM [ASM], SM with associated hematological neoplasm [SM‐AHN] and mast cell leukemia [MCL]). We sequenced 27 genes in 150 SM patients to identify mutations that could be integrated into a clinical‐molecular prognostic model for survival. Forty four patients (29%) had ISM, 25 (17%) ASM, 80 (53%) SM‐AHN and 1 (0.7%) MCL; overall KITD816V prevalence was 75%. In 87 patients, 148 non‐KIT mutations were detected; the most frequently mutated genes were TET2 (29%), ASXL1 (17%), and CBL (11%), with significantly higher mutation frequency in SM‐AHN > ASM > ISM (P < 0.0001). In advanced SM, ASXL1 and RUNX1 mutations were associated with inferior survival. In multivariate analysis, age > 60 years (HR = 2.4), hemoglobin < 10 g/dL or transfusion‐dependence (HR = 1.7), platelet count < 150 × 10⁹/L (HR = 3.2), serum albumin < 3.5 g/dL (HR = 2.6), and ASXL1 mutation (HR = 2.3) were associated with inferior survival. A mutation‐augmented prognostic scoring system (MAPSS) based on these parameters stratified advanced SM patients into high‐, intermediate‐, and low‐risk groups with median survival of 5, 21 and 86 months, respectively (P < 0.0001). These data should optimize risk‐stratification and treatment selection for advanced SM patients. Am. J. Hematol. 91:888–893, 2016. © 2016 Wiley Periodicals, Inc.     

Aggressive systemic mastocytosis presenting with hepatic cholestasis

Systemic mastocytosis results in the accumulation of mast cells in various tissues. We report a rare case of systemic mastocytosis presenting with cholestatic liver disease. Our patient was a 60-year-old African-American woman who presented with diarrhea, weight loss, hepatosplenomegaly and cholestatic pattern of serum liver chemistry tests. Immunohistological stains with mast-cell tryptase and CD117 antibodies performed on the liver-biopsy tissue showed prominent mast cells. Subsequently, bone-marrow biopsy and small-bowel biopsies also showed mast-cell infiltration confirming the diagnosis of systemic mastocytosis. The patient underwent treatment with imatinib mesylate without response. Her disease transformed into acute myeloid leukemia and she ultimately died from sepsis. This case underscores the importance of including rare conditions like systemic mastocytosis in the differential diagnosis of cholestatic disorders.     

Success and safety of high infliximab trough levels in inflammatory bowel disease

Objective: A prospective trial suggests target infliximab trough levels of 3–7?μg/mL, yet data on additional therapeutic benefits and safety of higher trough levels are scarce.

Aim: To explore whether high infliximab trough levels (≥7?μg/mL) are more effective and still safe.

Material and methods: In this cohort study of 183 patients (109 Crohn’s disease and 74 ulcerative colitis) on infliximab maintenance treatment at a tertiary referral center we correlated fecal calprotectin and C-reactive protein to trough levels (426 samples) at different time points during treatment. Rates of infections were compared in quadrimesters (four-month periods) with high trough levels to quadrimesters with trough levels <7?μg/mL during 420 patient-years.

Results: Fecal calprotectin and C-reactive protein (median [interquartile range]) were lower in patients with high trough levels (fecal calprotectin 66?mg/kg [30–257]; C-reactive protein 3?mg/L [3–3]) compared to trough levels below 7?μg/mL (fecal calprotectin 155?mg/kg [72–474]; C-reactive protein 3?mg/L [3–14.5]) (p?p?=?.32). Maintaining high trough levels resulted in 32% (interquartile range: 2–54%) increase of infliximab consumption.

Conclusion: High infliximab trough levels provide better control of inflammation in inflammatory bowel disease without increasing the risk of infection.     

Concurrent immunomodulator therapy is associated with higher adalimumab trough levels during scheduled maintenance therapy

Introduction: Combination therapy with infliximab and immunomodulators is superior to monotherapy, resulting in better outcomes and higher trough levels of infliximab. The role of concurrent immunomodulatory therapy on adalimumab trough levels has not been adequately investigated. We evaluated the impact of concomitant immunomodulation on adalimumab trough levels in patients on scheduled maintenance therapy.

Method: We conducted a prospective observational, cross-sectional study of all inflammatory bowel disease patients on maintenance therapy who had adalimumab trough levels measured between January 2013 and January 2016. Drug level and anti-drug antibody measurements were performed on sera using a solid phase assay. Pairwise comparison of means was used to compare trough levels in patients with and without concomitant immune modulator therapy.

Results: In total, 79 patients were included. Twenty-three patients (29.1%) were on weekly dosing whereas 56 (70.9%) were on alternate weeks. Median adalimumab trough levels were comparable in patients with and without clinical remission (6.8?μg/ml (IQR 5.6–8.1) versus 6.7?μg/ml (IQR 3.9–8.1), respectively. Patients with an elevated faecal calprotectin?>250?μg/g had lower adalimumab trough levels (median 6.7, IQR 3.9–8) compared to patients with faecal calprotectin?<250?μg/g (median 7.7, IQR 6.1–8.1) though this did not achieve statistical significance (p?=?.062). Median adalimumab trough levels among patients on concurrent immunomodulators was 7.2?μg/ml (IQR 5.7–8.1) compared to those not on concurrent immunomodulator, 6.1?μg/ml (IQR 2.7–7.7, p?=?.0297).

Conclusion: Adalimumab trough levels were significantly higher in patients on concurrent immunomodulators during maintenance therapy. There was a trend towards a lower adalimumab trough level in patients with elevated calprotectin.     

Adalimumab versus azathioprine to halt the progression of bowel damage in Crohn’s disease: application of Lémann Index

Abstract

Background: The Lémann Index (LI) was recently developed to evaluate the cumulative bowel damage in patients with Crohn’s disease (CD).

Aims: To search for a difference between adalimumab and azathioprine to halt the progression of bowel damage in active CD, using the LI.

Methods: A single-centre, retrospective study was conducted. Patients with CD were included if they had colonoscopy and magnetic resonance enterography performed within 4?months from the start of adalimumab or azathioprine and repeated after 12?months of therapy. Primary outcome was reached if the increase of LI after 12?months of treatment was <0.3, the drug was not stopped, and the use of systemic steroids was continued for no more than 3?months.

Results: Ninety-one patients were enrolled, 31 (34.1%) of them treated with adalimumab and 60 (65.9%) with azathioprine. Sixty-seven percent of patients treated with adalimumab reached the primary outcome compared to 28.3% of patients treated with azathioprine (p?=?.0006). The LI in the group on adalimumab therapy decreased after 12?months (from 9.9 to 8.8), while in the group on azathioprine therapy it increased (from 7.7 to 8.8).

Conclusion: Treatment with adalimumab halts the progression of bowel damage in CD while that with azathioprine does not.     

Mast cell leukemia: identification of a new c-Kit mutation, dup(501-502), and response to masitinib, a c-Kit tyrosine kinase inhibitor

Objective: Most patients with systemic mastocytosis bear mutations in the tyrosine kinase receptor gene c‐Kit. Limited treatment options exist for mast cell leukemia, a rare form of systemic mastocytosis associated with a dire prognosis. Our aim was to investigate c‐Kit mutations associated with mast cell leukemia and find new treatment for this severe form of mastocytosis. Patient and methods: We describe here a patient with mast cell leukemia characterized by 42% of circulating mast cells associated with a previously unidentified c‐Kit mutation in adult mastocytosis: dup(501‐502). Main findings: This patient was treated with masitinib, a novel c‐Kit tyrosine kinase inhibitor, with a dramatic response observed following 3 months of treatment, including clinical improvement, disappearance of circulating mast cells, and decrease in both serum histamine and tryptase levels. In vitro and ex vivo research was performed on the patient’s cells and revealed constitutive c‐Kit phosphorylation in mast cell leukemia. Conclusions: This case highlights the importance of sequencing all c‐Kit exons when the classical D816V c‐Kit mutation is not found, even in adults with SM. It also indicates that masitinib may be safe and effective for the treatment for some mast cell leukemia.     

Clinical course in Crohn’s disease: factors associated with behaviour change and surgery

Abstract

Background: Crohn’s disease (CD) is a chronic and progressive disease that changes its behaviour over time. Transmural inflammation in CD leads to stricturing and/or penetrating complications.

Aim: To evaluate the frequency of long-term progression of CD phenotypes, the need of abdominal surgery, and the main factors associated with these outcomes.

Methods: A retrospective study was conducted with a prospective follow-up. Montreal classification was assessed at the moment of the diagnosis and at the end of the follow-up period.

Results: Two hundred and ninety patients were included, with mean follow-up duration of nine years. A change in behaviour was observed in 46 patients (15.9%). Ileocolic location (60.9% vs. 45.1%; p?=?.049), age at diagnosis <16 years (8.7% vs. 2.0%; p?=?.017), the use of steroids at diagnosis (43.2% vs. 27.0%; p?=?.031) and shorter exposure time to biological therapy (15.9 months vs 41.3 months; p?p?=?.048), stricturing behaviour (50% vs. 18.4%; p?p?p?p?p?Conclusions: A behaviour progression was observed in about one-sixth of the patients. Progression to a stricturing pattern was the most frequent change in behaviour. Stricturing and penetrating behaviour, higher number of hospitalisations in the first year of diagnosis, use of steroids at diagnosis, smoking status, age at diagnosis <16 years and ileocolic disease location were associated with an unfavourable clinical evolution.