Background: The association that exists between livedo reticularis (LR) and stroke is known as Sneddon’s syndrome (SnS). The disorder is classified as primary SnS (PSnS), if the cause remains unknown and secondary SnS. The condition is rare and it occurs mainly sporadically. In 2014, 2 independent teams described a new genetic disorder with childhood-onset, which was called deficiency of adenosine deaminase 2 (DADA2), characterized by recurrent fevers and vascular pathologic features that included LR and stroke. All the patients carried recessively inherited mutations in cat eye syndrome chromosome region candidate 1 gene (CECR1), encoding the adenosine deaminase 2 (ADA2) protein. Genetic testing is the standard for the diagnosis of DADA2. However, the diagnostic accuracy of more affordable laboratorial analysis in CECR1-mutated individuals remains to be established. We aim to determine whether plasma ADA2 activity and serum immunoglobulin M (IgM) levels can distinguish (1) DADA2 from other adult patients within the SnS spectrum, and (2) healthy CECR1 heterozygous (HHZ) from healthy controls (HC). Methods: ADA2 activity in plasma and serum IgM concentrations was measured in adult patients within the SnS spectrum, healthy first-degree relatives and HC. Genetic results were used as the reference standard. The primary outcome measures were sensitivity and specificity derived from receiver operating curve analysis. Results: A total of 73 participants were included in the study: 26 patients with PSnS with no CECR1 mutation (PSnS), 6 bi-allelic (DADA2 patients) and 7 HHZ CECR1 mutations and 34 HC. Plasma ADA2 activity and serum IgM levels were significantly lower in DADA2 patients than in PSnS. With the use of the best indexes, plasma ADA2 activity differentiated PSnS from DADA2 with a sensitivity and specificity of 100.0% and HHZ from HC with a sensitivity of 97.1% and specificity of 85.7%. Serum IgM levels also differentiated PSnS from DADA2 with a sensitivity of 85.2% and specificity of 83.3%. Conclusion: Serum IgM levels might be used as a triage tool and plasma ADA2 activity performs perfectly as a diagnostic test for DADA2 in adult patients within the SnS spectrum. ADA2 activity in plasma also reliably distinguishes HHZ from HC.
Over the last few years, several cases of statin-induced necrotizing myopathy have been described. This myopathy is characterized by the necrosis of muscle fibers and the presence of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies. Although the diagnosis of myopathies relies on muscle biopsy, which is considered the gold-standard, the search for autoantibodies has proved to be an essential contribution to the diagnosis of immune-mediated myopathies. The detection of anti-HMGCR antibodies in the patient’s serum can be performed by enzyme immunoassays, and more recently, by imunofluorescence. As for the latter, the detection of anti-HMGCR antibodies is performed on tissue sections by indirect immunofluorescence and is characterized by a typical fluorescence pattern called “HMGCR Associated Liver IFL Pattern”. The authors present two case reports that show the importance of diagnosing statin-induced necrotizing myopathy as quickly as possible and the contribution of anti-HMGCR antibody detection for the diagnosis.
5094 Background: Triclonal patterns (TP) in immunofixation (IF), characterized by the presence of three different immunoglobulin bands, are a very rare finding: we have recently reported an incidence of 0.1% (representing 0.82% of all clonal patterns detected), in 0.1% of patients tested, in an 11-year series of 46 249 immunofixation essays, collected from 29 704 patients. We found that for the majority of patients (56.2%) triclonality in IF was a transient feature, with patients acquiring TP and de-escalating to biclonality or monoclonality, and suggested that transiency could be a feature of clonal evolution, involution and selection. Such clonal modifications could be induced by chemotherapy (CHTx) or bone marrow transplant or, on the other hand, could also be an indication of disease progression. The presence of TP could also be an intrinsic spontaneous characteristic of the patient or the disease. Aims: This study aims to clarify whether TP should be interpreted as merely an artifact of ongoing therapy, or if it could be deserving of attention by the clinician, by studying the relationship between the identification of TP in IF in multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) patients and the timing of treatment. Methods: We identified all samples exhibiting a TP among the 47 559 IF essays performed in our center from January 2000 to June 30th 2011. We found 53 sera with TP, from 35 patients, two of whom were external consultation referrals and, therefore, excluded from our analysis. We also excluded an HIV-positive patient who died within 5 days of a single triclonal IF, a liver transplant recipient undergoing immunosuppression, 2 patients with isolated TP during respiratory infections, 3 lymphomas (one marginal zone lymphoma and 2 follicular lymphomas) presenting with TP during CHTx and a renal transplant recipient who acquired a TP and 4 months later was diagnosed with NHL, dying within 10 days. Results: Of the 25 remaining patients with MM and MGUS, we recognized a spontaneous development of triclonality at diagnosis, prior to the institution of any treatment, in 28% (7 patients). One patient with MM had a single triclonal IF, and died within 30 days of the presenting symptoms; one maintained the same TP pattern throughout therapy; one MM and one MGUS, both recent diagnoses, have yet to have follow-up IF; the remaining 3 MM patients lost their TP spontaneously (1 patient) or during treatment (2 patients). An additional 8% (2 patients with MM) had a diagnosis established outside of our centre, with no description of triclonality; the first IF performed in our Hospital had a TP, before the start of therapy, and both lost their TP with treatment. Five patients (20%) acquired a TP spontaneously after diagnosis, but prior to any therapy. Two MGUS later spontaneously lost their TP; one MM lost it with therapy; one patient had MGUS for 3 years before acquiring an inconstant TP, which he subsequently lost after 6 years, progressing to MM one year later; one patient with an indolent myeloma, developed a TP 6 years after diagnosis, on progression to symptomatic myeloma. The remaining 44% (11 patients) acquired their TP only after the introduction of therapy. This includes 5 MM after CHTx (4 after thalidomide-containing regimens), 4 MM after autologous hematopoietic stem cell transplantation, one Waldenström's macroglobulinemia and one patient with essential thrombocytosis and MGUS who acquired TP after starting hydroxicarbamide. Discussion: In this series we found that 28 to 36% of patients with a TP presented with this pattern upon diagnosis, prior to any therapy, with a further 20 to 28%, who were not triclonal at the outset, acquiring it spontaneously without treatment. Therefore, for 56% of patients, triclonality – though frequently transient – is a feature of their disease. On the other hand, for the remaining 44% of patients, the appearance of a TP is temporally associated with CHTx or transplantation (though it is impossible to affirm that the patients would not have acquired the patterns in the absence of CHTx). Conclusions: We conclude that the appearance of a TP on IF, through rare and in most cases transient, should not be discarded as a mere effect of treatment. In over half the cases, there is no association between triclonality and treatment; the clinician should, therefore, interpret the results on a case-by-case basis, as the acquisition of TP could be a marker of disease progression. Disclosures: No relevant conflicts of interest to declare.
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