Lorenzo Dagna

Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease

Erdheim-Chester disease (ECD) is a rare, non-Langerhans histiocytosis. Recent findings suggest that ECD is a clonal disorder, marked by recurrent BRAFV600E mutations in >50% of patients, in which chronic uncontrolled inflammation is an important mediator of disease pathogenesis. Although ∼500 to 550 cases have been described in the literature to date, increased physician awareness has driven a dramatic increase in ECD diagnoses over the last decade. ECD frequently involves multiple organ systems and has historically lacked effective therapies. Given the protean clinical manifestations and the lack of a consensus-derived approach for the management of ECD, we provide here the first multidisciplinary consensus guidelines for the clinical management of ECD. These recommendations were outlined at the First International Medical Symposium for ECD, comprised of a comprehensive group of international academicians with expertise in the pathophysiology and therapy of ECD. Detailed recommendations on the initial clinical, laboratory, and radiographic assessment of ECD patients are presented in addition to treatment recommendations based on critical appraisal of the literature and clinical experience. These formalized consensus descriptions will hopefully facilitate ongoing and future research efforts in this disorder.

Human γδ T cells: A nonredundant system in the immune-surveillance against cancer

Abstract Down-regulation of expression of MHC alleles, as well as tumor-specific antigens, is observed frequently during tumor progression, resulting in an impairment of MHC-restricted, αβ-T-cell-mediated, tumor-specific immunity. Given the unique set of antigens recognized and the lack of requirement for classical antigen-presenting molecules, γδ T cells might, therefore, represent a nonredundant system in anticancer surveillance, as proposed for the immune response against pathogens. Evidence that γδ and αβ T cells make distinct contributions to anticancer surveillance has been provided recently in mice. Here, we discuss the potential role played by resident Vδ1 + and circulating Vδ2 + T cells in the defense against solid tumors and hematological malignancies.

Pentraxin-3 as a Marker of Disease Activity in Takayasu Arteritis

BACKGROUND Because pentraxin-3 (PTX3) is produced by immune and vascular cells in response to proinflammatory signals, it may be a useful biomarker for defining disease activity in patients with Takayasu arteritis. OBJECTIVE To compare PTX3 levels in patients who have Takayasu arteritis with those in healthy and infected controls, and to compare accuracy of PTX3 levels with that of C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR) for distinguishing active and inactive disease. DESIGN Cross-sectional, noninterventional study conducted between September 2005 and October 2008. SETTING Immunology and rheumatology clinic at a university hospital in Italy. PATIENTS 57 consecutive patients with Takayasu arteritis and known disease activity, 57 healthy blood donor controls, and 15 patients with acute infection. MEASUREMENTS Disease activity by clinical criteria; plasma PTX3 and CRP levels and ESR. RESULTS 27 patients had active Takayasu arteritis; 30 had inactive disease. Levels of PTX3 were higher in patients with active disease (median, >2.14 ng/mL [range, 0.57 to 48.18 ng/mL]) than in those with inactive disease (median, 0.63 ng/mL [range, 0.00 to 1.64 ng/mL]) and were higher than in healthy patients (median, 0.11 ng/mL [range, 0 to 1.20 ng/mL]) or those with acute infection (median, 0.26 ng/mL [range, 0 to 0.75 ng/mL]). A plasma PTX3 level greater than 1 ng/mL was more accurate than normal thresholds of CRP or ESR for distinguishing active from inactive disease. LIMITATION The study excluded patients with unknown or equivocal disease status. CONCLUSION Plasma levels of PTX3 could help distinguish active from inactive Takayasu arteritis but should not be adopted for clinical use until the findings are confirmed in a broader spectrum of patients whose disease activity is unknown or equivocal before testing.

The multifaceted clinical presentations and manifestations of Erdheim–Chester disease: comprehensive review of the literature and of 10 new cases

Objectives Erdheim–Chester disease (ECD) is a rare inflammatory disorder characterised by organ infiltration by non-Langerhans’ histiocytes. Although rare, ECD is clearly an overlooked diagnosis. No data specifically addressing the most frequent presentations of ECD at the time of onset in a large cohort of patients are currently available. Methods We reviewed all the published cases in the English literature of histologically-confirmed ECD. We excluded reports in which data regarding onset and diagnosis were not univocal, as well as repeated reports of the same case(s). We also included in the analysis 10 new unpublished patients from our cohort. We analysed the disease presentation with particular regard to the manifestations that induced patients to seek medical attention and their subsequent evolution. Results In the cumulative cohort of 259 cases, ECD predominantly presented with skeletal symptoms, diabetes insipidus, neurological and constitutional symptoms. Diabetes insipidus and constitutional symptoms, if not present at onset, seemed to only seldom develop. There were differences in ECD presentation and course among different age groups of patients. Conclusions Physicians should be aware of the extraordinarily heterogeneous clinical presentations and manifestations of ECD in order to include ECD in the differential diagnosis of several conditions.

BRAFV600E-mutation is invariably present and associated to oncogene-induced senescence in Erdheim-Chester disease

Objectives Erdheim-Chester disease (ECD) is a rare form of histiocytosis characterised by uncontrolled chronic inflammation. The oncogenic BRAFV600E mutation has been reported in biopsies in 19 out of 37 patients with ECD from the largest published cohort, but never found in the patients’ peripheral blood. Also, the role of the mutation in the pathogenesis of the disease has not been elucidated yet. BRAFV600E has been associated with oncogene-induced senescence (OIS), a protective mechanism against oncogenic events, characterised by the induction of proinflammatory pathways. Methods We verified the BRAF status in biopsies and peripheral blood from 18 patients with ECD from our cohort and matched controls by means of immunohistochemistry and of an ultrasensitive assay, based on the combination of a locked nucleic acid PCR and pyrosequencing. Droplet digital PCR was used to confirm the findings. We also evaluated the presence of senescence markers in ECD histiocytes. Results BRAFV600E mutation was present in all the biopsy and peripheral blood samples from patients with ECD and in none of the controls. ECD histiocytes and a fraction of circulating monocytes from patients with ECD showed signs of a constitutive activation of the MAPK pathway. Moreover, BRAF-mutated histiocytes expressed markers of OIS. Conclusions The oncogenic BRAFV600E mutation is present in biopsies and in the peripheral blood from all patients with ECD who were evaluated and is associated with OIS. These findings have significant implications for the pathogenesis, diagnosis and treatment of ECD.

Efficacy of traditional and biologic agents in different clinical phenotypes of adult-onset Still's disease

OBJECTIVE To evaluate the efficacy of antiinflammatory agents, steroids, immunosuppressants, and biologic agents in patients with adult-onset Stills disease (AOSD) who have either chronic articular disease or nonchronic disease. METHODS Forty-five patients with AOSD were seen and followed up for at least 2 years at our institution, from 1991 to 2008. The majority of patients were treated with several therapeutic regimens; a total of 152 efficacy trials were administered. Data regarding the type of medication, the dosage used, and the outcome of these trials were collected and analyzed. RESULTS Our data showed that the efficacy of monotherapy with a nonsteroidal antiinflammatory drug was very low (16%) and confirmed good efficacy of steroid therapy (63%), particularly in patients without chronic articular disease (78%). Patients whose disease did not respond to steroid therapy at the time of disease onset were at risk of the subsequent development of chronic arthritis. Disease-modifying antirheumatic drug (DMARD) monotherapy was successful in controlling steroid-resistant or steroid-dependent disease in 60% of patients. Methotrexate and cyclosporine showed the best response rates. The combination of high-dose steroids and cyclosporine was administered to successfully control some acute life-threatening complications. Only 6 patients had disease that was both steroid resistant and DMARD resistant. Treatment with biologic agents eventually led to satisfactory control of disease manifestations in 5 (83%) of these 6 patients. CONCLUSION Steroids were less effective in patients with chronic articular disease than in those with nonchronic disease. The administration of DMARDs early after disease onset could be beneficial in patients with steroid-resistant disease who are at risk of the development of chronic articular disease. Biologic agents proved to be highly effective in both steroid-resistant and DMARD-resistant AOSD.

Takayasu Arteritis: Intravascular Contrast Medium for MR Angiography in the Evaluation of Disease Activity

OBJECTIVE Takayasu arteritis is difficult to diagnose, and the evaluation of disease activity is even more challenging. Laboratory, clinical, and radiologic criteria are limited indicators of disease activity. Gadofosveset trisodium is a recently introduced intravascular contrast agent. In this study we sought to investigate a correlation between clinical activity and enhancement of vascular wall thickening in patients with Takayasu arteritis who underwent MR angiography with gadofosveset. SUBJECTS AND METHODS Twenty-three consecutively registered patients (21 women, two men) with Takayasu arteritis underwent MR angiography of the supraaortic trunks, aorta, and visceral vessels. Intravascular contrast medium was used to correlate thickened vessel wall enhancement with clinical criteria of disease activity. ECG-triggered black-blood first-pass high-resolution steady-state imaging was performed for all patients. RESULTS Before MR angiography, 14 patients were considered to have active disease. Heterogeneous structural involvement of the vascular tree was found. Twenty of 23 patients (87.0%) had supraaortic trunk involvement, including 12 of the 14 patients (85.7%) with active disease. Seventeen of the 23 patients (73.9%) had aortic and visceral vessel involvement, including 12 of the 14 patients (85.7%) with active disease. On steady state images in the active disease group, the mean signal-to-noise-ratio increased from 17.4 to 35.3 after gadofosveset injection (p > 0.0001), while in the nonactive disease group it increased from 52.8 to 69.6 (p = 0.08). A cutoff of 40% was best for differentiating active from inactive disease (sensitivity, 100%; specificity, 89%; positive predictive value, 92%; negative predictive value, 100%). CONCLUSION Use of intravascular contrast medium significantly increases the effectiveness of MR angiography in differentiating active and inactive disease.

IgG4-related disease in Italy: clinical features and outcomes of a large cohort of patients

Objectives: To describe the clinical features, treatment response, and follow-up of a large cohort of Italian patients with immunoglobulin (Ig)G4-related disease (IgG4-RD) referred to a single tertiary care centre. Method: Clinical, laboratory, histological, and imaging features were retrospectively reviewed. IgG4-RD was classified as ‘definite’ or ‘possible’ according to international consensus guidelines and comprehensive diagnostic criteria for IgG4-RD. Disease activity was assessed by means of the IgG4-RD Responder Index (IgG4-RD RI). Results: Forty-one patients (15 females, 26 males) were included in this study: 26 with ‘definite’ IgG4-RD and 15 with ‘possible’ IgG4-RD. The median age at diagnosis was 62 years. The median follow-up was 36 months (IQR 24–51). A history of atopy was present in 30% of patients. The pancreas, retroperitoneum, and major salivary glands were the most frequently involved organs. Serum IgG4 levels were elevated in 68% of cases. Thirty-six patients were initially treated with glucocorticoids (GCs) to induce remission. IgG4-RD RI decreased from a median of 7.8 at baseline to 2.9 after 1 month of therapy. Relapse occurred in 19/41 patients (46%) and required additional immunosuppressive drugs to maintain long-term remission. Multiple flares occurred in a minority of patients. A single case of orbital pseudotumour did not respond to medical therapy and underwent surgical debulking. Conclusions: IgG4-RD is an elusive inflammatory disease to be considered in the differential diagnosis of isolated or multiple tumefactive lesions. Long-term disease control can be achieved with corticosteroids and immunosuppressive drugs in the majority of cases.

Erdheim–Chester disease: report on a case and new insights on its immunopathogenesis

Disclosure statement: J.-Y.F. and M.H. are employees of Amgen Inc. and have received stock/stock options. A.K. has received grants/research support from Amgen, Centocor, UCB and Abbott. E.K. has received funding for research from Abbott Laboratories, Amgen Inc., AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb, Centocor Inc., F. Hoffmann-La Roche Inc., Novartis Pharmaceuticals, Schering-Plough Corporation, UCB and Wyeth Pharmaceuticals. E.K. has consulting agreements/ advisory board membership with Abbott Laboratories, Amgen Inc., Bristol-Myers Squibb Company, Centocor Inc., F. Hoffmann-La Roche Inc., Genetech Inc., GlaxoSmithKline, Schering-Plough Corporation, UCB and Wyeth Pharmaceuticals. E.K. also has Speaker Bureau/ honorarium agreements with Abbott Laboratories, Amgen Inc., Bristol-Myers Squibb Company, Centocor Inc., F. Hoffmann-La Roche Inc., Genetech Inc., Schering-Plough Corporation and Wyeth Pharmaceuticals.

Engagement of CD30 shapes the secretion of cytokines by human γ δ T cells

CD30 is a member of the TNF receptor superfamily, previously shown to be expressed on Hodgkins lymphoma cells and on normal activated lymphocytes. We here show that CD30 is highly expressed on recently activated human γ δ T cells. Elevated surface levels of this molecule persisted in long‐term cultures of γ δ cells, without further cell stimulation. CD30 acted as a co‐stimulus in γ δ T cells by potentiating the intracellular Ca2+ fluxes induced by CD3 cross‐linking. The engagement of CD30 enhanced the expression of several cytokines induced upon CD3 stimulation such as IL‐4 and IFN‐γ but not IL‐10. The CC chemokines RANTES and macrophage inflammatory protein‐1β were constitutively expressed and not affected by stimulation. The inducible expression of the neutrophil chemoattractant IL‐8 was enhanced by CD30 co‐stimulation, as well as that of the CC chemokines I‐309 and MDC, whereas the secretion of the monocyte chemotactic protein‐1 was not detected. Triggering of CD30 may therefore modulate the expression of several cytokines released by γ δ cells; the expression of its physiologic ligand by APC and neutrophils at the site of infection may contribute to determine the outcome of an immune response.