Elena Verrecchia

Familial Mediterranean fever: a review for clinical management

Familial Mediterranean Fever (FMF) is a hereditary autosomal recessive, autoinflammatory disorder characterized by recurrent, self-limiting episodes of short duration (mean 24-72 h) of fever and serositis. FMF is the most frequent periodic febrile syndrome among the autoinflammatory syndromes (AS), a heterogeneous group of recently identified diseases clinically characterized by recurrent febrile attacks, in the absence of autoantibodies and antigen-specific T lymphocytes. In FMF, periodic attacks show inter- and intra-individual variability in terms of frequency and severity. Usually, they are triggered by apparently innocuous stimuli and may be preceded by a prodromal period. The Mediterranean FeVer gene (MEFV) responsible gene maps on chromosome 16 (16p13) encoding the pyrin-marenostrin protein. The precise pathologic mechanism is still to be definitively elucidated; however a new macromolecular complex, called inflammasome, seems to play a major role in the control of inflammation and it might be involved in the pathogenesis of FMF. The most severe long-term complication is type AA amyloidosis, principally affecting the kidney and the cause of chronic renal failure. Two types of risk factors, genetic and non-genetic, have been identified for this complication. Currently, the only effective treatment of Familial Mediterranean Fever is the colchicine. New drugs in a few colchicine resistant patients have been tried, but additional studies on larger series are necessary to draw definitive conclusions.

A Snapshot on the On-Label and Off-Label Use of the Interleukin-1 Inhibitors in Italy among Rheumatologists and Pediatric Rheumatologists: A Nationwide Multi-Center Retrospective Observational Study

Background: Interleukin (IL)-1 inhibitors have been suggested as possible therapeutic options in a large number of old and new clinical entities characterized by an IL-1 driven pathogenesis. Objectives: To perform a nationwide snapshot of the on-label and off-label use of anakinra (ANA) and canakinumab (CAN) for different conditions both in children and adults. Methods: We retrospectively collected demographic, clinical, and therapeutic data from both adult and pediatric patients treated with IL-1 inhibitors from January 2008 to July 2016. Results: Five hundred and twenty-six treatment courses given to 475 patients (195 males, 280 females; 111 children and 364 adults) were evaluated. ANA was administered in 421 (80.04%) courses, CAN in 105 (19.96%). Sixty-two (32.1%) patients had been treated with both agents. IL-1 inhibitors were employed in 38 different indications (37 with ANA, 16 with CAN). Off-label use was more frequent for ANA than CAN (p < 0.0001). ANA was employed as first-line biologic approach in 323 (76.7%) cases, while CAN in 37 cases (35.2%). IL-1 inhibitors were associated with corticosteroids in 285 (54.18%) courses and disease modifying anti-rheumatic drugs (DMARDs) in 156 (29.65%). ANA dosage ranged from 30 to 200 mg/day (or 1.0–2.0 mg/kg/day) among adults and 2–4 mg/kg/day among children; regarding CAN, the most frequently used posologies were 150mg every 8 weeks, 150mg every 4 weeks and 150mg every 6 weeks. The frequency of failure was higher among patients treated with ANA at a dosage of 100 mg/day than those treated with 2 mg/kg/day (p = 0.03). Seventy-six patients (14.4%) reported an adverse event (AE) and 10 (1.9%) a severe AE. AEs occurred more frequently after the age of 65 compared to both children and patients aged between 16 and 65 (p = 0.003 and p = 0.03, respectively). Conclusions: IL-1 inhibitors are mostly used off-label, especially ANA, during adulthood. The high frequency of good clinical responses suggests that IL-1 inhibitors are used with awareness of pathogenetic mechanisms; adult healthcare physicians generally employ standard dosages, while pediatricians are more prone in using a weight-based posology. Dose adjustments and switching between different agents showed to be effective treatment strategies. Our data confirm the good safety profile of IL-1 inhibitors.

Current advances in the understanding and treatment of mevalonate kinase deficiency.

Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory metabolic disease that is caused by mutations in the MVK gene. Patients with MKD typically have an early onset in infancy. MKD is characterized by recurrent episodes of high fever, abdominal distress, diffuse joint pain, and skin rashes. In a subset of patients, MKD is also associated with elevated serum immunoglobulin D (IgD) levels (hyperimmunoglobulinemia D syndrome, HIDS). The clinical phenotype of MKD varies widely and depends on the severity of the impaired mevalonate kinase activity. Complete impairment results in the severe metabolic disease, mevalonic aciduria, while a partial deficiency results in a broad spectrum of clinical presentation, including HIDS. The precise molecular mechanisms behind the elevated serum IgD levels and inflammation that occurs in MKD remain unknown. Children who exhibit symptoms of MKD should be tested for mutations in the MKD gene. However, the complexity of MKD often results in delays in its definitive diagnosis and the outcome in adult age is not completely known. Therapeutic options for MKD are based on limited data and include non-steroidal anti-inflammatory drugs, corticosteroids, and biological agents that target specific cytokine pathways. In recent years, some studies have reported promising results for new biological drugs; however, these cases have failed to achieve satisfactory remission. Therefore, further studies are needed to understand the pathogenesis of MKD and identify innovative therapeutic tools for its management.

Effectiveness of Colchicine Therapy in 4 Cases of Retroperitoneal Fibrosis Associated with Autoinflammatory Diseases

To the Editor: Retroperitoneal fibrosis (RPF) is a fibroinflammatory process affecting the retroperitoneal structures. There are no guidelines for its diagnosis or therapy. We describe 4 cases of RPF associated with autoinflammatory diseases, in which treatment with colchicine allowed RPF regression. RPF is an uncommon disease, with unclear pathogenesis. Systemic manifestations (fever, anorexia, weight loss), often associated with local symptoms (flank pain, leg edema, abdominal discomfort), are related to the entrapment of retroperitoneal structures by the fibrotic plaques. Initial therapy aims at restoring the function of the affected organs with the application of ureteral stents, followed by immunosuppressive therapy. Sometimes, ureteral replacement or kidney autotransplant may be necessary1. Colchicine, a tricyclic alkaloid, interferes with microtubule formation, altering mitosis and inhibiting many steps in the inflammatory process. It reduces adhesion of neutrophils to endothelium, inhibiting neutrophil migration, and blocks the in vitro release of fibronectin from alveolar macrophages2,3. It is approved by the US Food and … Address correspondence to Dr. R. Manna, Department of Internal Medicine, Catholic University, largo A. Gemelli 8, 00168 Rome, Italy. E-mail: rmanna{at}rm.unicatt.it

Diagnostic Criteria for Adult-Onset Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome

Objective To identify a set of variables that could discriminate patients with adult-onset periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome from subjects with fever of unknown origin (FUO). Methods We enrolled 74 adults diagnosed with PFAPA syndrome according to the currently used pediatric diagnostic criteria and 62 additional patients with FUO. After having collected clinical and laboratory data from both groups, univariate and multivariate analyses were performed to identify the variables associated with PFAPA diagnosis. Odds ratio (OR) values, their statistical significance, and corresponding 95% confidence interval (CI) were evaluated for each diagnostic factor both at the univariate and multivariate analyses. Diagnostic accuracy was evaluated by the area under receiver operating characteristic (ROC) curve, while the leave-one-out cross-validation procedure was used to ensure that the model maintains the same diagnostic power when applied to new data. Results According to the multivariate analysis, the clinical variables that discriminated PFAPA patients were: fever episodes associated with cervical lymphadenitis (OR = 92; p < 0.0001), fever attacks associated with erythematous pharyngitis (OR = 231; p < 0.0001), increased inflammatory markers during fever attacks (OR = 588; p = 0.001), and the lack of clinical and laboratory signs of inflammation between flares (OR = 1202; p < 0.0001). These variables were considered for a diagnostic model which accounted for their OR values. The diagnostic accuracy of the proposed set of criteria corresponded to an area under ROC curve of 0.978 (95% CI 0.958–0.998), with a model sensitivity and specificity equal to 93.4% (95% CI 87.5–96.5%) and 91.7% (95% CI 82.8–96.7%), respectively. Conclusion we have provided herein a set of clinical diagnostic criteria for adult-onset PFAPA syndrome. Our criteria represent an easy-to-use diagnostic tool aimed at identifying PFAPA patients among subjects with FUO with a high-predictive potential, as shown by its very high sensitivity and specificity.

Right Ventricular Hypertrophy, Systolic Function, and Disease Severity in Anderson-Fabry Disease: An Echocardiographic Study

Background: Right ventricular (RV) involvement has been described in Anderson‐Fabry disease (AFD), especially in patients with established Fabry cardiomyopathy (FC). However, few and controversial data on RV systolic function are available, and there are no specific tissue Doppler studies. Methods: Detailed echocardiographic examinations were performed in 45 patients with AFD. FC, defined as maximal left ventricular wall thickness ≥ 15 mm, was present in 12. The Mainz Severity Score Index was calculated for each patient. Pulsed tissue Doppler was applied to the RV free wall at the tricuspid annular level and at the septal and lateral corners at the mitral annular level to obtain systolic tissue Doppler velocities (RV Sa, septal Sa, and lateral Sa, respectively). Twelve patients with amyloid light‐chain cardiac amyloidosis were studied as a control group. Results: Echocardiography revealed RV hypertrophy (RVH) in 31% of patients with AFD, all but one of whom were male and all of whom had concomitant left ventricular hypertrophy (LVH). All patients with AFD had normal RV fractional area change (47.9 ± 6.5%) and tricuspid annular plane systolic excursion (21.7 ± 3.2 mm) and all but one also had normal RV Sa (13.2 ± 2.2 cm/sec). RVH positively correlated with indices of LVH (r = 0.8, P = .0001, for all parameters evaluated), as well as with Mainz Severity Score Index (r = 0.70, P = .0001). Septal and lateral Sa were decreased in almost all patients (means, 7.7 ± 1.8 and 7.9 ± 1.9 cm/sec, respectively), irrespective of the presence of LVH. Compared with control subjects with cardiac amyloidosis, patients with FC showed better indices of RV systolic function (P < .001 for all: tricuspid annular plane systolic excursion, RV fractional area change, and RV Sa) despite similar RV wall thickness (6.2 ± 1.2 vs 6.9 ± 1.9 mm, P = NS). Conclusions: RVH is common in patients with AFD and correlates with disease severity and LVH. RVH, however, does not significantly affect RV systolic function. Patients with FC have better RV systolic function compared with those with cardiac amyloidosis with similar levels of RV thickness. The combination of low LV Sa values and normal RV Sa values might be helpful in the differential diagnosis of infiltrative heart disease.

Switch from anakinra to canakinumab in a severe case of CINCA syndrome

Dear Editor, Chronic infantile neurological cutaneus and articular (CINCA) syndrome is an extremely rare inherited autoinflammatory disorder characterized by urticarialike rash with neonatal onset, deforming arthritis mostly involving knees and epiphyses of long bones, and chronic meningitis, all resulting from dysregulation of interleukin-1b (IL-1b) biosynthesis; this disorder is the most severe expression of cryopyrin-associated periodic syndrome (CAPS). Patients with CAPS have a significant symptom overlap and commonly include fever combined with inflammation of skin, eyes, bones, joints and meninges, often starting from infancy, sometimes on a daily basis. Anti-IL-1 antagonists have been proven to be effective in controlling the systemic multisite manifestations of CINCA syndrome, even the neurological ones, preventing the long-term complication of amyloidosis. We report a Caucasian 18-year-old man born from unrelated healthy parents, diagnosed with a severe form of CINCA syndrome (through the demonstration of the missense mutation F573S in the NLRP3 gene) when he was 3 years old (Fig. 1a), following his typical skin features, bilateral knee contracture in flexion and chronic papilledema with dystrophic retinopathy. At 4 years, a first treatment with etanercept (0.4 mg/kg twice weekly) and low-dose prednisone was established for about 1 year, with partial benefit on his joint signs, although he could not yet walk. At about 7 years (Fig. 1b), after a written informed consent from the parents, treatment with anakinra (1 mg/kg/day subcutaneously injected) was started, leading to remarkable success over the whole picture of the disease. Autonomous walk started at 10 years, when anakinra dosage was slightly adjusted (1.5 mg/kg/day). After extensive evaluation to exclude any infectious disease and after the parents’ written informed consent, at 12 years, the patient was enrolled in an international protocol to evaluate the clinical efficacy of canakinumab (ACZ885, Ilaris), a selective long-acting high-affinity fully humanized monoclonal anti-IL-1b antibody, generated by transgenic mice and designed to neutralize the activity of human IL-1b, with the advantage of being administered by single distanced injections; this treatment at the dosage of 2 mg/kg by subcutaneous injection (total dose: 72 mg) was carried out twice, 8 weeks apart, then the dosage was doubled (to 4 mg/ kg) every 6–7 weeks for further four infusions, due to persistent elevation of inflammatory markers. However, the patient’s participation in the study was stopped by the parents’ decision, as they noted declined visual ability, problems in reading and hampered walk. Visual dysfunction was confirmed by electroretinogram and Flicker visual evoked potentials (VEP), which showed a severe involvement of both retina and optic nerve function. Anakinra was then resumed (at a dosage of 100 mg/day) and continued until the age of 17. At this time, after ascertaining that current canakinumab dose recommendation approved in patients with CAPS is 150 mg every 8 weeks for body weight >40 kg, and after establishing that an insufficient response in some individuals with severe phenotype might require higher canakinumab doses, the parents’ decision was to accept switching from anakinra to canakinumab (300 mg by subcutaneous injection every 4 weeks), after a washout period of 2 days for anakinra. This decision followed also the patient’s will to avoid daily therapy with anakinra. Therefore, since then, the patient has received nine monthly doses of canakinumab, which were well-tolerated without any injection site reactions. Sustained efficacy was noted on skin features of the disease, and a significant improvement was observed in Flicker VEP in the right eye (90% increase in amplitude), while the left eye response showed a smaller increase in amplitude (22%). The overall response to treatment was assessed by auto-inflammatory diseases activity index (AIDAI)-total score and suggested an inactive disease. Acute phase reactants were always

The impact of fever/hyperthermia in the diagnosis of Fabry: A retrospective analysis.

BACKGROUND Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency of alpha-galactosidase A enzyme, which leads to the accumulation of its substrate, the globotriaosylceramide or Gb3, in many organs and tissues. Main clinical manifestations of FD are neuropathic pain, angiokeratomas, proteinuria and renal failure, left ventricular hypertrophy and stroke. Fever is also a possible symptom at the onset of the disease during childhood and adolescence, but it is frequently misdiagnosed, causing a delay in FD diagnosis. METHODS We retrospectively analysed the medical records in our series of 58 Fabry patients, focusing on the proportion of patients who exhibited fever as the main symptom at the onset of FD in order to evaluate the diagnostic delay in these patients. FINDINGS In our series, we found a significant proportion of patients with a history of fevers at the beginning of their medical history (20.7%; 12/58). 83% of patients with fever also exhibited acroparesthesias (10/12). Inflammatory markers were elevated in few of those cases (2/12). The mean diagnostic delay was 15.6±SD 12.8years. INTERPRETATION Fever emerged to be common as part of the FD clinical spectrum and it significantly contributed to the diagnostic delay encountered with this rare disease. Furthermore, our retrospective analysis indicated that FD patients commonly exhibit episodes of fever in association with other symptoms suggestive of FD (such as episodic pain crisis, acroparesthesias, hypo/anhydrosis, heat intolerance, fatigue and gastrointestinal distress). A careful analysis of the medical history in patients suffering fever could lead to an early and correct FD diagnosis. We believe that fever/hyperthermia, acroparesthesias and angiokeratoma should be considered for inclusion in the algorithm for Intermittent Fever of Unknown Origin (FUO) in order to improve the recognition of FD.

Functional and pharmacological evaluation of novel GLA variants in Fabry disease identifies six (two de novo) causative mutations and two amenable variants to the chaperone DGJ

BACKGROUND Allelic heterogeneity is an important feature of the GLA gene for which almost 900 known genetic variants have been discovered so far. Pathogenetic GLA variants cause alpha-galactosidase A (α-Gal A) enzyme deficiency leading to the X-linked lysosomal storage disorder Fabry disease (FD). Benign GLA intronic and exonic variants (e.g. pseudodeficient p.Asp313Tyr) have also been described. Some GLA missense variants, previously deemed to be pathogenetic (e.g. p.Glu66Gln and p.Arg118Cys), they have been reclassified as benign after re-evaluation by functional and population studies. Hence, the functional role of novel GLA variants should be investigated to assess their clinical relevance. RESULTS We identified six GLA variants in 4 males and 2 females who exhibited symptoms of FD: c.159C>G p.(Asn53Lys), c.400T>C p.(Tyr134His), c.680G>C (p.Arg227Pro), c.815A>T p.(Asn272Ile), c.907A>T p.(Ile303Phe) and c.1163_1165delTCC (p.Leu388del). We evaluated their impact on the α-Gal A protein by bioinformatic analysis and homology modelling, by analysis of the GLA mRNA, and by site-directed mutagenesis and in vitro expression studies. We also measured their responsiveness to the pharmacological chaperone DGJ. CONCLUSIONS The six detected GLA variants cause deficient α-Gal A activity and impairment or loss of the protein wild-type structure. We found p.Asn53Lys and p.Ile303Phe variants to be susceptible to DGJ.

Small Intestinal Bacterial Overgrowth Affects the Responsiveness to Colchicine in Familial Mediterranean Fever

Objective Familial Mediterranean fever (FMF) is an autosomal recessive disease due to a MEFV gene mutation. Since Helicobacter pylori infection has been described to increase the severity and frequency of FMF attacks, we evaluate if overgrowth of small intestinal bacterial (SIBO), associated with a release of bacterial products, can affect the response to colchicine in FMF patients poorly responsive to colchicine. Methods We revised our Periodic Fever Centre database to detect FMF patients who were poorly responsive to colchicine, without a well-defined cause of drug resistance. They were evaluated for SIBO presence, then treated with decontamination therapy. Results Among 223 FMF patients, 49 subjects show colchicine resistance, and no other known causes of colchicine unresponsiveness has been found in 25 patients. All 25 patients underwent glucose breath test; 20 (80%) of them were positive, thus affected by SIBO. After a successful decontamination treatment, 11 patients (55%) did not show FMF attacks during the following three months (p < 0.01), while 9 of them revealed a significant reduction of the number of attacks compared to three months before (p < 0.01). Conclusion The SIBO eradication improves laboratory and clinical features of FMF patients. Thus, patients with unresponsiveness to colchicine treatment should be investigated for SIBO.