IgM Autoantibodies to Complement Factor H in Atypical Hemolytic Uremic Syndrome.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS), a severe thrombotic microangiopathy, is often related to complement dysregulation, but the pathomechanisms remain unknown in at least 30% of patients. Researchers have described autoantibodies to complement factor H of the IgG class in 10% of patients with aHUS but have not reported anti-factor H autoantibodies of the IgM class. METHODS: In 186 patients with thrombotic microangiopathy clinically presented as aHUS, we searched for anti-factor H autoantibodies of the IgM class and those of the IgG and IgA classes. We used immunochromatography to purify anti-factor H IgM autoantibodies and immunoenzymatic methods and a competition assay with mapping mAbs to characterize interaction with the target protein. RESULTS: We detected anti-factor H autoantibodies of the IgM class in seven of 186 (3.8%) patients with thrombotic microangiopathy presented as aHUS. No association was observed between anti-factor H IgM and homozygous deletions involving CFHR3-CFHR1. A significantly higher proportion of patients with bone marrow transplant-related thrombotic microangiopathy had anti-factor H IgM autoantibodies versus other patients with aHUS: three of 20 (15%) versus four of 166 (2.4%), respectively. The identified IgM autoantibodies recognize the SCR domain 19 of factor H molecule in all patients and interact with the factor H molecule, inhibiting its binding to C3b. CONCLUSIONS: Detectable autoantibodies to factor H of the IgM class may be present in patients with aHUS, and their frequency is six-fold higher in thrombotic microangiopathy forms associated with bone marrow transplant. The autoantibody interaction with factor H's active site may support an autoimmune mechanism in some cases previously considered to be of unknown origin.

Low-dose rituximab is poorly effective in patients with primary membranous nephropathy.

BACKGROUND: The optimal dosing and the efficacy of rituximab for primary membranous nephropathy (PMN) has not been established. This multicentric prospective study evaluates the efficacy and safety of low-dose rituximab (RTX) therapy in patients with PMN in clinical practice. METHODS: Thirty-four consecutive patients with PMN and nephrotic syndrome were included and received RTX (375 mg/m2) once (18 patients) or twice (16 patients). RTX was the first-line therapy for 19 (56%) and the second line for 15 (44%) patients. All patients were followed for 12 months after RTX and 24 for at least 18 months (mean 23.9 ± 18.6 months). RESULTS: At 12 months, 5 patients (14.7%) achieved complete response, 10 (29.4%) partial and 19 (55.8%) no response. Response occurred ∼6 months after RTX. At 24 months, the clinical situation was unchanged: two non-responders achieved partial response and two responders relapsed. Responders had significantly higher baseline GFR and lower anti-PLA2R antibodies compared with non-responders. Outcome was similar between one or two doses of RTX (non-responders 55.5 versus 56%, respectively) and between patients who had received previous therapy versus those receiving RTX as first-line therapy (non-responders 40 versus 68%, respectively). In the 15 patients already treated, the response to RTX was comparable to that of previous therapies. CONCLUSION: Low-dose RTX obtains remission in <50% of PMN patients. Probably, higher doses and longer treatments are needed to induce and maintain a response. The balance between the costs and benefits should guide the selection of the patient and the optimal dosage.

Lupus nephritis: When and how often to biopsy and what does it mean?

Renal disease is a frequent complication of SLE which can lead to significant illness and even death. Today, a baseline renal biopsy is highly recommended for all subjects with evidence of lupus nephritis. Biopsy allows the clinician to recognize and classify different forms of autoimmune lupus glomerulonephritis, and to detect other glomerular diseases with variable pathogenesis which are not directly related to autoimmune reactivity, such as lupus podocytopathy. Moreover, not only glomerular diseases, but other severe forms of renal involvement, such as tubulo-interstitial nephritis or thrombotic microangiopathy may be detected by biopsy in lupus patients. Thus, an accurate definition of the nature and severity of renal involvement is mandatory to assess the possible risk of progression and to establish an appropriate treatment. The indications to repeat biopsy are more controversial. Some physicians recommend protocol biopsies to recognize the possible transformation from one class to another one, or to identify silent progression of renal disease, others feel that good clinical monitoring is sufficient to assess prognosis and to make therapeutic decisions. At any rate, although any decision should always be taken by considering the clinical conditions of the patient, there are no doubts that repeat renal biopsy may represent a useful tool in difficult cases to evaluate the response to therapy, to modulate the intensity of treatment, and to predict the long-term renal outcome both in quiescent lupus and in flares of activity.

Angioedema and emergency medicine: From pathophysiology to diagnosis and treatment.

Angioedema is a self-limiting edema of the subcutaneous or submucosal tissues due to localised increase of microvascular permeability whose mediator may be histamine or bradykinin. Patients present to emergency department when angioedema involves oral cavity and larynx (life-threatening conditions) or gut (mimicking an acute abdomen). After initial evaluation of consciousness and vital signs to manage breathing and to support circulation if necessary, a simple approach can be applied for a correct diagnosis and treatment. Forms of edema such as anasarca, myxedema, superior vena cava syndrome and acute dermatitis should be ruled out. Then, effort should be done to differentiate histaminergic from non-histaminergic angioedema. Concomitant urticaria and pruritus suggest a histaminergic origin. Exposure to allergens and drugs (mainly ACE inhibitors and non steroidal anti-inflammatory drugs) should be investigated as well as a family history of similar symptoms. Allergic histaminergic angioedema has a rapid course (minutes) whereas non histaminergic angioedema is slower (hours). Since frequently the intervention needs to be immediate, the initial diagnosis is only clinical. However, laboratory tests can be subsequently confirmatory. Allergic angioedema is sensitive to standard therapies such as epinephrine, glucocorticoids and antihistamines whereas non histaminergic angioedema is often resistant to these drugs. Therapeutic options for angioedema due C1-inhibitor deficiencies are C1-inhibitor concentrates, icatibant and ecallantide. If these drugs are not available, fresh frozen plasma can be considered. All these medications have been used also in ACE inhibitor-induced angioedema with variable results thus they are not currently recommended whereas experts agree on the discontinuation of the causative drug.

Validation of the Predictive Model of the European Society of Cardiology for Early Mortality in Acute Pulmonary Embolism.

Background Acute pulmonary embolism (PE) is burdened by high mortality, especially within 30 days from the diagnosis. The development and the validation of predictive models for the risk of early mortality allow to differentiate patients who can undergo home treatment from those who need admission into intensive care units. Methods To validate the prognostic model for early mortality after PE diagnosis proposed by the European Society of Cardiology (ESC) in 2014, we analyzed data of a cohort of 272 consecutive patients with acute PE, observed in our hospital during a 10-year period. Moreover, we evaluated the additional contribution of D-dimer, measured at PE diagnosis, in improving the prognostic ability of the model. All cases of PE were objectively diagnosed by angiography chest CT scan or perfusion lung scan. Results The overall mortality rate within 30 days from PE diagnosis was 10% (95% confidence interval [CI]: 6.4-13.5%). According to the ESC prognostic model, the risk of death increased 3.23 times in the intermediate-low-risk category, 5.55 times in the intermediate-high-risk category, and 23.78 times in the high-risk category, as compared with the low-risk category. The receiver operating characteristic analysis showed a good discriminatory power of the model (area under the curve [AUC] = 0.77 [95% CI: 0.67-0.87]), which further increased when D-dimer was added (AUC = 0.85 [95% CI: 0.73-0.96]). Conclusion This study represents a good validation of the ESC predictive model whose performance can be further improved by adding D-dimer plasma levels measured at PE diagnosis.

Pulmonary embolism in elderly patients: prognostic impact of the Cumulative Illness Rating Scale (CIRS) on short-term mortality.

BACKGROUND: Pulmonary embolism (PE) is associated with high short-term mortality in elderly patients, even when hemodynamically stable. METHODS: One hundred and seventy hemodynamically stable patients with confirmed PE (41<65years and 129≥65years) were prospectively followed for one month in order to assess whether comorbidities can predict short-term mortality in elderly patients. Upon admission, patients' clinical characteristics (including instrumental and laboratory parameters) were evaluated, and two clinical scores were calculated: the Cumulative Illness Rating Scale (CIRS), commonly used to evaluate comorbidities in elderly patients, and the Pulmonary Embolism Severity Index (PESI). RESULTS: Fifteen patients (all elderly) died within one month from their PE diagnosis (mortality rate=8.8%; 95%CI:4.6-13.1%). In these non survivors, arterial partial oxygen pressure (p<0.0001) and saturation (p<0.0001), pH (p=0.001) and systolic blood pressure (p=0.017) at admission were significantly lower than in survivors, whereas their respiratory rate (p<0.0001), white blood cells (p<0.0001), lactate dehydrogenase (p<0.0001), troponin T (p=0.001) and D-dimer (p=0.023) were significantly higher. CIRS correlated with PESI (rho=0.54, p<0.0001), and was higher in non-survivors (p=0.002). The age- and sex-adjusted odds ratio of 1-month mortality was 1.91 (95%CI:1.24-2.95) for every 1-point increase in CIRS. The AUC was 0.78 (95%CI:0.67-0.89) for the logistic model containing CIRS, and 0.88 (95%CI:0.79-0.96) for that containing PESI (p=0.059). CONCLUSIONS: In elderly patients with PE, CIRS demonstrated a fairly good performance in predicting short-term mortality. Its easiness and suitability for use in common clinical practice make CIRS a potentially useful prognostic score for short-term mortality in these patients.

Salvage therapy with high dose Intravenous Immunoglobulins in acquired Von Willebrand Syndrome and unresponsive severe intestinal bleeding.

A 91-year-old woman affected with acquired Von Willebrand (VW) syndrome and intestinal angiodysplasias presented with severe gastrointestinal bleeding (hemoglobin 5 g/dl). Despite replacement therapy with VW factor/factor VIII concentrate qid, bleeding did not stop (eleven packed red blood cell units were transfused over three days). High circulating levels of anti-VW factor immunoglobulin M were documented immunoenzimatically. Heart ultrasound showed abnormalities of the mitral and aortic valves with severe flow alterations. When intravenous immunoglobulins were added to therapy, prompt clinical and laboratory responses occurred: complete cessation of bleeding, raise in hemoglobin, VW factor antigen, VW ristocetin cofactor and factor VIII levels as well as progressive reduction of the anti-VWF autoantibody levels.