Laurent Frenzel

Mast cells and inflammation.

The prominent role for mast cells in the inflammatory response has been increasingly well documented in recent years. Mast cells not only contribute to maintain homeostasis via degranulation and to generate IgE-mediated allergic reactions, but also sit at a major crossroads for both innate and adaptive immune responses. The part played by mast cells in chronic inflammatory diseases such as rheumatoid arthritis and multiple sclerosis identifies mast cells as a valuable treatment target in these diseases. Tyrosine-kinase inhibitors targeting the c-Kit mast cell receptor have been found effective in treating rheumatoid arthritis, asthma, and multiple sclerosis. When used in combination with other available drugs, tyrosine-kinase inhibitors may improve the therapeutic management of these diseases.

Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: a randomised, placebo-controlled, phase 3 study

BACKGROUNDnIndolent systemic mastocytosis, including the subvariant of smouldering systemic mastocytosis, is a lifelong condition associated with reduced quality of life. Masitinib inhibits KIT and LYN kinases that are involved in indolent systemic mastocytosis pathogenesis. We aimed to assess safety and efficacy of masitinib versus placebo in severely symptomatic patients who were unresponsive to optimal symptomatic treatments.nnnMETHODSnIn this randomised, double-blind, placebo-controlled, phase 3 study, we enrolled adults (aged 18-75 years) with indolent or smouldering systemic mastocytosis, according to WHO classification or documented mastocytosis based on histological criteria, at 50 centres in 15 countries. We excluded patients with cutaneous or non-severe systemic mastocytosis after a protocol amendment. Patients were centrally randomised (1:1) to receive either oral masitinib (6 mg/kg per day over 24 weeks with possible extension) or matched placebo with minimisation according to severe symptoms. The primary endpoint was cumulative response (≥75% improvement from baseline within weeks 8-24) in at least one severe baseline symptom from the following: pruritus score of 9 or more, eight or more flushes per week, Hamilton Rating Scale for Depression of 19 or more, or Fatigue Impact Scale of 75 or more. We assessed treatment effect using repeated measures methodology for rare diseases via the generalised estimating equation model in a modified intention-to-treat population, including all participants assigned to treatment minus those who withdrew due to a non-treatment-related cause. We assessed safety in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00814073.nnnFINDINGSnBetween Feb 19, 2009, and July 15, 2015, 135 patients were randomly assigned to masitinib (n=71) or placebo (n=64). By 24 weeks, masitinib was associated with a cumulative response of 18·7% in the primary endpoint (122·6 responses of 656·5 possible responses [weighted generalised estimating equation]) compared with 7·4% for placebo (48·9 of 656·5; difference 11·3%; odds ratio 3·6; 95% CI 1·2-10·8; p=0·0076). Frequent severe adverse events (>4% difference from placebo) were diarrhoea (eight [11%] of 70 in the masitinib group vs one [2%] of 63 in the placebo group), rash (four [6%] vs none), and asthenia (four [6%] vs one [2%]). The most frequent serious adverse events were diarrhoea (three patients [4%] vs one [2%]) and urticaria (two [3%] vs none), and no life-threatening toxicities occurred. One patient in the placebo group died (unrelated to study treatment).nnnINTERPRETATIONnThese study findings indicate that masitinib is an effective and well tolerated agent for the treatment of severely symptomatic indolent or smouldering systemic mastocytosis.nnnFUNDINGnAB Science (Paris, France).

Efficacy of Anakinra for Various Types of Crystal-Induced Arthritis in Complex Hospitalized Patients: A Case Series and Review of the Literature

Background. There are few data on anakinra use after failure of conventional medications for crystal-induced peripheral arthritis and/or crowned dens syndrome among complex hospitalized patients. Methods. We retrospectively analyzed the outcome of six patients affected with subacute crystal-induced arthritis who had received anakinra in second or third line therapy, including three patients with crowned dens syndrome and three others with gouty arthritis. Patients comorbidities, reasons for anakinra use and associated drugs, and outcomes were recorded. Results. All patients presented with elevated inflammatory syndrome, systemic symptoms with poly/oligoarthritis. Except for absolute contraindications, all patients were previously treated with full or decreased dose of NSAID, colchicine, and/or glucocorticoids, with unsatisfactory response. All three gouty patients exhibited complete responses in all acute involvements under anakinra within 3 to 5 days, including one of them who needed the reintroduction of colchicine treatment that was previously unsuccessful. Crowned dens syndrome patients, including two with pseudogout and one with subacute hydroxyapatite deposition disease, needed 9 to 11 days to achieve complete response. Tolerance to anakinra was good. Conclusion. In case series of complex hospitalized patients, anakinra showed good activity in crowned dens syndrome and associated crystal-induced peripheral arthritis, with longer treatment duration than in gouty arthritis.

HTLV-1-associated arthropathy treated with anti-TNF-alpha agent.

Human T cell leukemia virus type 1 or HTLV-1 infection is a public health problem in endemic regions like Japan, Central America or Africa. Although the majority of HTLV-1 carriers remain asymptomatic throughout their lives, some patients could develop neurological disorder, inflammatory arthropathy also called HTLV-1-associated arthropathy or T-cell malignancy, the adult T-cell leukemia/lymphoma or ATL with a very poor prognosis. Described to be very close to rheumatoid arthritis, HTLV-1-associated arthropathy patients have few or no response to the first line therapy with corticosteroids and disease modifying antirheumatic drugs or DMARDs. The use of anti-TNF-α agents in these patients is an interesting alternative but asks the question of risk of developing an adult T-Cell leukemia/lymphoma. We reported an exceptional case of a smoldering ATL patient with an HTLV-1-associated arthropathy, refractory to corticosteroid, DMARDs and rituximab therapy, treated successfully with etanercept, without progression to aggressive ATL after 5xa0years.

Ivory vertebra and systemic mastocytosis

The ivory vertebra sign seen on a standard radiograph of the spine should prompt investigations for a cause, which is most likely to be a bone metastasis, a lymphoma, or Pagets disease of bone. A diagnosis of idiopathic ivory vertebra can be given if no cause is identified. We report an unusual case of ivory vertebra sign that was due to systemic mastocytosis and improved with specific treatment. Although osteoporosis is the most common bone abnormality in systemic mastocytosis, an isolated sclerotic or lytic lesion may be found. The ivory vertebra sign should not be considered idiopathic until tests are done for mastocytosis, particularly given the availability of effective treatments.

Association of mastocytosis with inflammatory joint diseases: A series of 31 patients

OBJECTIVESnWe studied the clinical phenotypes and tolerance to treatments in a series of patients affected by both inflammatory joint diseases and mastocytosis.nnnMETHODSnThis retrospective multicenter study was conducted on behalf of 3 networks focused on mastocytosis, pediatric, and adults inflammatory joint diseases. Patients who displayed both mastocytosis and inflammatory joint diseases were included.nnnRESULTSnA total of 31 patients were included. They had spondyloarthritis (SpA) (16 patients), rheumatoid arthritis (6 patients), juvenile idiopathic arthritis (2 patients), and undifferentiated arthritis (7 patients). The median ages at diagnosis of arthritis and mastocytosis were 44 and 40.5 years, respectively. Disease-modifying anti-rheumatic drugs (DMARDs) were required in 22 patients, comprising mostly methotrexate (13 patients), salazopyrin (8 patients), anti-tumor-necrosis-factor agents (7 patients), and corticosteroids (9 patients). They were well tolerated. Adverse events occurred in 2/24 patients receiving non-steroidal anti-inflammatory drugs. The prevalence of SpA among the 600 patients included in the mastocytosis cohort was 2.33%, which is significantly higher than the prevalence of SpA in the French population (p < 0.001).nnnCONCLUSIONSnThis study suggests that mastocytosis is associated with a higher prevalence of SpA than expected, and that DMARDs, notably anti-TNFα agents, are well tolerated in patients with mastocytosis. Mast cells might be involved in the development of SpA.

Extending autologous transplantation as first line therapy in multiple myeloma patients with severe renal impairment: a retrospective study by the SFGM-TC

Renal impairment is a common complication of multiple myeloma (MM), accounting for 20–30% of MM patients at diagnosis and 40–50% of patients during the course of their disease. This feature is associated with poor prognosis and shorter survival as compared to patients with normal renal function (NRF). Therefore, therapeutic management is challenging as autologous stem cell transplantation (ASCT) is often not considered as a valuable strategy, mainly due to concerns of toxicity. In this retrospective and multicenter study, we included 55u2009MM patients with dialysis-dependent or independent renal failure who underwent high-dose melphalan-based ASCT in order to assess the efficacy outcomes and toxicities of this strategy. Response to ASCT was at least VGPR (very good PR) in 58% of patients and 96% of patients who also received bortezomib-based induction were at least in PR after ASCT. Median OS was 76 months and median PFS was 55 months, similarly to MM patients with NRF. In multivariate analysis, dose of melphalan (140u2009mg/m2) was correlated with better PFS (18 months, Pu2009=u20090.005). Toxicities included febrile neutropenia (75%) and severe mucositis (34%). Overall, this work confirmed that ASCT conditioned by 140u2009mg/m2 melphalan is a beneficial procedure for MM patients with renal failure.

MB4-2 breakpoint in MMSET combined with del(17p) defines a subset of t(4;14) multiple myeloma with very poor prognosis

Multiple myeloma (MM) is a clonal plasma cell disorder, which remains incurable. The t(4;14) translocation is present in 15% of patients with symptomatic disease and, despite recent therapeutic improvements such as bortezomib treatment, still indicates a poor prognosis.[1][1],[2][2] However, t(4;14

Reply to Marhadour et al. regarding their comment about our article entitled "Ivory vertebra and systemic mastocytosis".

Thank you for your attention to our article [1]. Your case-report s extremely interesting, since systemic mastocytosis led to sympomatic polyostotic bone lesions. As you point out, bone pain was the only symptom, in marked ontradiction to the presentation in our patient. We agree fully with our decision to use intravenous bisphosphonate therapy based on he analgesic effect of this intervention. Bisphosphonates probably elieve pain by diminishing the inflammatory edema, as described n vertebral crush fractures and certain osteoarthritic lesions. The se of anti-cancer agents such as 2-chlorodeoxyadenosine (2-CDA) ight have deserved consideration in the event the patient failed to espond to bisphosphonate therapy. An important point, however, s that bisphosphonates do not constitute a direct treatment of the ast cell proliferation, as shown by the persistence of the sclerotic one lesions. In addition to constituting a treatment for osteoporosis, bishosphonates seem particularly valuable for relieving the pain ue to bone involvement by systemic mastocytosis. Combining isphosphonates with more specific agents, such as tyrosine inase inhibitors, would probably result in improved efficacy. ur reference center for systemic mastocytosis is preparing recmmendations on bisphosphonate therapy in this indication, in articular regarding the selection of the best agents, dosage, and umber of infusions.