Caplacizumab use for immune thrombotic thrombocytopenic purpura: the Milan thrombotic thrombocytopenic purpura registry.

•Data on caplacizumab use for thrombotic thrombocytopenic purpura (TTP) in Italy are missing.•Twenty-six Italian patients were treated with caplacizumab for an acute immune TTP episode.•Caplacizumab was effective in treating acute TTP in the Italian real-world clinical setting.•Two major bleeds leading to drug discontinuation were observed.

The HLA Variant rs6903608 Is Associated with Disease Onset and Relapse of Immune-Mediated Thrombotic Thrombocytopenic Purpura in Caucasians.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) deficiency, recurring in 30-50% of patients. The common human leukocyte antigen (HLA) variant rs6903608 was found to be associated with prevalent iTTP, but whether this variant is associated with disease relapse is unknown. To estimate the impact of rs6903608 on iTTP onset and relapse, we performed a case-control and cohort study in 161 Italian patients with a first iTTP episode between 2002 and 2018, and in 456 Italian controls. Variation in rs6903608 was strongly associated with iTTP onset (homozygotes odds ratio (OR) 4.68 (95% confidence interval (CI) 2.67 to 8.23); heterozygotes OR 1.64 (95%CI 0.95 to 2.83)), which occurred over three years earlier for each extra risk allele (ß -3.34, 95%CI -6.69 to 0.02). Of 153 survivors (median follow-up 4.9 years (95%CI 3.7 to 6.1)), 44 (29%) relapsed. The risk allele homozygotes had a 46% (95%CI 36 to 57%) absolute risk of relapse by year 6, which was significantly higher than both heterozygotes (22% (95%CI 16 to 29%)) and reference allele homozygotes (30% (95%CI 23 to 39%)). In conclusion, HLA variant rs6903608 is a risk factor for both iTTP onset and relapse. This newly identified biomarker may help with recognizing patients at high risk of relapse, who would benefit from close monitoring or intensified immunosuppressive therapy.

Evaluation of a New, Rapid, Fully Automated Assay for the Measurement of ADAMTS13 Activity.

Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy (TMA) characterized by the severe deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity (< 10%). Rapid ADAMTS13 testing is crucial for an early diagnosis and optimal management of acute TTP. We evaluated the performance of the HemosIL AcuStar ADAMTS13 activity assay (Instrumentation Laboratory, Bedford, Massachusetts, United States), a fully automated chemiluminescent immunoassay with an analytical time of 33 minutes. A method comparison study was performed on 176 samples from 49 healthy donors and 127 TMA patients (109 TTP, 7 atypical hemolytic uremic syndrome, 11 other TMAs), comparing this new assay with an in-house FRETS-VWF73 assay and a commercial enzyme-linked immunosorbent assay (ELISA) (TECHNOZYM ADAMTS-13 Activity, Technoclone GmbH, Vienna, Austria). Agreement between methods was assessed with focus on ADAMTS13 activity less than 10%, the medical decision level relevant for TTP diagnosis. The HemosIL AcuStar ADAMTS13 Activity showed good correlation with both the FRETS-VWF73 (r = 0.96) and ELISA (r = 0.96) methods. Slope of the Passing-Bablok regression was 1.05 for FRETS-VWF73 and 1.02 for ELISA, and absolute bias at the medical decision level was +0.1 and +0.3%, respectively. The study also revealed high agreement with FRETS-VWF73 (kappa 0.97) and ELISA (kappa 0.98) methods in classifying TTP patients with a severe deficiency of ADAMTS13 activity. Because of its short turnaround time and full automation, the HemosIL AcuStar ADAMTS13 activity assay might become the assay of choice to rapidly test ADAMTS13 activity in plasma and thus establish the diagnosis of acute TTP in emergency settings.

Sclerostin is overexpressed by plasma cells from multiple myeloma patients.

Sclerostin, an osteocyte-expressed negative regulator of bone formation, is one of the inhibitors of Wnt signaling that is a critical pathway in the correct process of osteoblast differentiation. It has been demonstrated that Wnt signaling through the secretion of Wnt inhibitors, such as DKK1, sFRP-2, and sFRP-3, plays a key role in the decreased osteoblast activity associated with multiple myeloma (MM) bone disease. We provide evidence that sclerostin is expressed by myeloma cells that are human myeloma cell lines and plasma cells (CD138(+) cells) obtained from the bone marrow (BM) of a large number of MM patients with bone disease. Moreover, we show that there are no differences in sclerostin serum levels between MM patients and controls. Thus, our data indicate that MM cells, as a sclerostin source in the BM, could create a microenvironment with high sclerostin concentration that could contribute toward inhibiting osteoblast differentiation.

Spontaneous remission of "methotrexate-associated lymphoproliferative disorders" after discontinuation of immunosuppressive treatment for autoimmune disease. Review of the literature.

There are a number of intriguing reports of lymphoproliferative disorders (LPDs) diagnosed during immunosuppressive treatment for underlying autoimmune disease, and spontaneously abated shortly after treatment discontinuation. Such LPDs, completely or partially regressing, occur in the clinical setting of "Methotrexate (MTX)-associated LPDs", recognized by the World Health Organization (WHO) among the "Immunodeficiency-associated LPDs". We identified 26 literature patients achieving spontaneous complete remission (CR) of their LPD, and eight others showing partial remission (PR). Most of them were affected by rheumatoid arthritis, received low-dose and long-term pulsed MTX alone or combined with other immunosuppressants, and developed a lymphoma. By reviewing the patients achieving CR, the following can be drawn: the absence of a unique type of LPD, the occurrence of an increased incidence of diffuse large B cell lymphoma as well as of frequent extranodal involvement, and EBV-infection. Further, CR mostly occurred within 4 weeks after discontinuation of immunosuppressant, and appeared to be persistent overtime. Conversely in the patients experiencing PR, the interval between discontinuation of immunosuppressive treatment and clinical response was mostly reported as longer than 4 weeks; moreover, in many cases the persistence of LPD or its progression induced to start cytotoxic therapy. Increased awareness is needed on the possible occurrence of LPD spontaneous remission following immunosuppressant discontinuation, after that it is therefore advisable to have a careful monitoring of the patient for some weeks, before starting cytotoxic therapy.

Schnitzler's syndrome: monoclonal gammopathy associated with chronic urticaria.

Schnitzler's syndrome (SS) is defined by monoclonal gammopathy and chronic urticaria combined with at least two of the following features: fever, arthralgia or arthritis, bone pain, hepato- and/or splenomegaly, palpable lymph nodes, elevated ESR, and leukocytosis. We report a 49-year-old man with monoclonal IgM gammopathy and a 4-year history of recurrent urticarial rash, unexplained fever and arthralgias. The skin biopsy from an acute lesion revealed perivascular lymphocytic infiltrates consisting of CD4+ and CD8+ T lymphocytes. To our knowledge, this is the first report of an immunophenotypic characterization of skin infiltrates in SS. A lower CD4+/CD8+ ratio of circulating T lymphocytes was also detected. SS usually has a benign course, but in 15% of patients a lymphoproliferative disorder develops.