Katia Stankovic Stojanovic

Dramatic beneficial effect of interleukin-1 inhibitor treatment in patients with familial Mediterranean fever complicated with amyloidosis and renal failure

BACKGROUND Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder, for which systemic AA amyloidosis is the major complication revealed most of the time by renal abnormalities. Current treatment is daily colchicine that prevents both recurrent inflammatory attacks and amyloidosis deposition in most patients. However, some patients still develop amyloidosis and renal failure. Functional studies suggest that interleukin (IL)-1 is implicated in the inflammatory reaction in FMF and therefore, IL-1 inhibitors could be a new approach to treat FMF. The aim of this series study was to evaluate anakinra in patients with FMF complicated with amyloidosis and renal failure. METHODS We studied a series of adult patients with FMF complicated with amyloidosis and treated with anakinra in one reference centre were reviewed. A search for published patients with FMF associated amyloidosis treated with anakinra was performed by screening PubMed. RESULTS We report four cases of patients with FMF-associated amyloidosis treated with anakinra and discuss the clinical pertinence of its use in these particular clinical settings. CONCLUSIONS Anakinra has a strong effect on both inflammatory attacks and general status in patients with FMF-associated amyloidosis. It may contribute to changing the prognosis of these patients. Long-term studies are needed to appreciate the effect of anakinra or other IL-1 inhibitors on the natural history of amyloidosis in these patients.

Hemoglobin sickle cell disease complications: a clinical study of 179 cases.

Background Hemoglobin SC disease is one of the most frequent hemoglobinopathies. Surprisingly, few studies have been dedicated to this disease, currently considered to be a mild variant of homozygous SS disease. The aim of this study was to update our knowledge about hemoglobin SC disease. Design and Methods The study involved a single center series of 179 patients. Clinical and biological data were collected with special attention to the assessment of pulmonary arterial hypertension and nephropathy. Results Hemoglobin SC diagnosis was delayed and performed in adulthood in 29% of cases. Prevalence of hospitalized painful vasoocclusive crisis, acute chest syndrome and priapism was 36%, 20% and 20%, respectively. The most common chronic organ complications were retinopathy and sensorineural otological disorders in 70% and 29% of cases. Indeed, prevalence of complications reported in homozygous SS disease, such as nephropathy, suspicion of pulmonary hypertension, strokes and leg ulcers was rather low (13%, 4% and 1%, respectively). Phlebotomy performed in 36% of this population (baseline hemoglobin 11.5 g/dL) prevented recurrence of acute events in 71% of cases. Conclusions Our data suggest that hemoglobin SC disease should not be considered as a mild form of sickle cell anemia but as a separate disease with a special emphasis on viscosity-associated otological and ophthalmological disorders, and with a low prevalence of vasculopathy (strokes, pulmonary hypertension, ulcers and nephropathy). Phlebotomy was useful in reducing acute events and a wider use of this procedure should be further investigated.

A preliminary score for the assessment of disease activity in hereditary recurrent fevers: results from the AIDAI (Auto-Inflammatory Diseases Activity Index) Consensus Conference

Background The systemic autoinflammatory disorders (SAID) share many clinical manifestations, albeit with variable patterns, intensity and frequency. A common definition of disease activity would be rational and useful in the management of these lifelong diseases. Moreover, standardised disease activity scores are required for the assessment of new therapies in constant development. The aim of this study was to develop preliminary activity scores for familial Mediterranean fever, mevalonate kinase deficiency, tumour necrosis factor receptor-1-associated periodic syndrome and cryopyrin-associated periodic syndromes (CAPS). Methods The study was conducted using two well-recognised consensus formation methods: the Delphi technique and the nominal group technique. The results from a two-step survey and data from parent/patient interviews were used as preliminary data to develop the agenda for a consensus conference to build a provisional scoring system. Results 24 of 65 experts in SAID from 20 countries answered the web questionnaire and 16 attended the consensus conference. There was consensus agreement to develop separate activity scores for each disease but with a common format based on patient diaries. Fever and disease-specific clinical variables were scored according to their severity. A final score was generated by summing the score of all the variables divided by the number of days over which the diary was completed. Scores varied from 0 to 16 (0–13 in CAPS). These scores were developed for the purpose of clinical studies but could be used in clinical practice. Conclusion Using widely recognised consensus formation techniques, preliminary scores were obtained to measure disease activity in four main SAID. Further prospective validation study of this instrument will follow.

The Risk of Familial Mediterranean Fever in MEFV Heterozygotes: A Statistical Approach

Background Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder due to MEFV mutations and one of the most frequent Mediterranean genetic diseases. The observation of many heterozygous patients in whom a second mutated allele was excluded led to the proposal that heterozygosity could be causal. However, heterozygosity might be coincidental in many patients due to the very high rate of mutations in Mediterranean populations. Objective To better delineate the pathogenicity of heterozygosity in order to improve genetic counselling and disease management. Methods Complementary statistical approaches were used: estimation of FMF prevalence at population levels, genotype comparison in siblings from 63 familial forms, and genotype study in 557 patients from four Mediterranean populations. Results At the population level, we did not observe any contribution of heterozygosity to disease prevalence. In affected siblings of patients carrying two MEFV mutations, 92% carry two mutated alleles, whereas 4% are heterozygous with typical FMF diagnosis. We demonstrated statistically that patients are more likely to be heterozygous than healthy individuals, as shown by the higher ratio heterozygous carriers/non carriers in patients (p<10−7–p<0.003). The risk for heterozygotes to develop FMF was estimated between 2.1×10−3 and 5.8×10−3 and the relative risk, as compared to non carriers, between 6.3 and 8.1. Conclusions This is the first statistical demonstration that heterozygosity is not responsible for classical Mendelian FMF per se, but constitutes a susceptibility factor for clinically-similar multifactorial forms of the disease. We also provide a first estimate of the risk for heterozygotes to develop FMF.

Outcomes of Adult Patients With Sickle Cell Disease Admitted to the Icu: A Case Series*

Objective:Sickle cell disease is associated with a decreased life expectancy, half of the deaths occurring in the ICU. We aimed to describe the characteristics of sickle cell disease patients admitted to ICU and to identify early predictors of a complicated outcome, defined as the need for vital support or death. Design:Retrospective observational cohort study of sickle cell disease patients over a 6-year period. Setting:ICU of a French teaching hospital and sickle cell disease referral center. Patients:Hundred thirty-eight ICU admissions in 119 sickle cell disease patients. Interventions:None. Measurements and Main Results:ICU admission was mainly indicated for sickle cell disease–related events, especially acute chest syndrome. Mechanical ventilation, vasoactive drugs, and renal replacement therapy were administered to 25 (18%), 10 (7%), and 10 (7%) episodes, respectively. The complicated outcome group (n = 28; 20%) was characterized by a more aggressive acute disease within the 48 hours preceding ICU admission, with a higher respiratory rate, a more frequent acute kidney injury, and a more sustained drop of hemoglobin (all p < 0.01). All nine deaths (7%) were sickle cell disease related. None of the sickle cell disease baseline characteristics predicted accurately a complicated outcome. In multivariate analysis, hemoglobin less than or equal to 7.8 g/dL (odds ratio, 3.6; 95% CI, 1.1–11.9), respiratory rate more than or equal to 32 cycles/min (odds ratio, 5.6; 95% CI, 1.8–17.2), and acute kidney injury on ICU admission (odds ratio, 11.5; 95% CI, 2.5–52.6) were independently associated with a complicated outcome. Conclusions:Sickle cell disease patients are at high risk of complications when admitted to the ICU. A sustained drop of hemoglobin, acute respiratory distress, and kidney injury at admission are strong predictors of a complicated outcome.

Myositis in a patient with familial Mediterranean fever and spondyloarthritis successfully treated with anakinra

Familial Mediterranean fever is an autosomal-recessive autoinflammatory disorder more commonly observed in Mediterranean populations and characterized by recurrent episodes of fever, serositis, myalgia and arthritis. There is rarely any association with spondyloarthritis. The most important long-term complication is progressive systemic type AA amyloidosis. Treatment with colchicine is effective in reducing the frequency of attacks and prevents the development of amyloidosis. However, 5% of cases are considered resistant to colchicine. We here describe the case of a 39-year-old man, with a history of arthritis, arthralgias, and sacroiliitis in the course of a familial Mediterranean fever. He is homozygous for the M694I mutation in the MEFV gene. He subsequently developed myositis of the right quadriceps muscle confirmed by magnetic resonance imaging, electromyography and histology. He had frequent and severe arthralgias, despite colchicine, then etanercept and adalimumab, impairing his quality of life. The patient was successfully treated with the IL-1 receptor antagonist anakinra with a dramatic improvement of muscular and articular symptoms. To our knowledge, our patient is the first patient with coexisting FMF, spondyloarthritis and myositis responding to anakinra treatment. Moreover this is the second case in the literature of myositis associated with familial Mediterranean fever.

High lactate dehydrogenase levels at admission for painful vaso-occlusive crisis is associated with severe outcome in adult SCD patients

OBJECTIVES The aim of this study is to assess biological prognostic factors at the onset of vaso-occlusive crisis (VOC) in adults with sickle cell disease (SCD). METHODS A monocentric prospective study including all patients admitted for VOC in a reference center for SCD was utilized. We used multivariate logistic regression to find independent predictors of severe evolution, defined by death or a worsening clinical state indicating transfusion or transfer to the intensive care unit. RESULTS Eighty eight patients were included, 63% were women, median age of 23 years, and 90% of patients were homozygous SCD, 10% compound heterozygous. VOC became severe in 17 patients. Patients with severe VOC were more frequently males, who also had higher white blood cell (WBC) count, procalcitonin (PCT), and lactate dehydrogenase (LDH) levels. LDH level was the best predictor of the outcome; WBC and PCT had no significant added predictive values when coupled with LDH in multivariable models, even in patients with fever or acute chest syndrome. Severe evolution always occurred when LDH levels were over 4 times the upper limit of the normal range at admission and never occurred when LDH levels were within the normal range. CONCLUSION Further studies should confirm the predictive value of LDH before its widespread use as a prognostic factor. If it is confirmed, the benefit of preemptive transfusion when LDH levels at admission are very high could be investigated.

Prevalence and Correlates of Metabolic Acidosis among Patients with Homozygous Sickle Cell Disease

BACKGROUND AND OBJECTIVES Very few studies report acid base disorders in homozygous patients with sickle cell anemia (SCA) and describe incomplete renal acidosis rather than true metabolic acidosis, the prevalence of which is unknown and presumably low. This study aimed to assess the prevalence of metabolic acidosis and to identify its risk factors and mechanisms. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study retrospectively analyzed 411 homozygous patients with SCA with a GFR ≥ 60 ml/min per 1.73 m(2), referred in a single center between 2007 and 2012. Acidosis and nonacidosis groups were compared for clinical and biologic data including SCA complications and hemolytic parameters. A subgroup of 65 patients with SCA, referred for a measured GFR evaluation in the setting of sickle cell-associated nephropathy, was further analyzed in order to better characterize metabolic acidosis. RESULTS Metabolic acidosis was encountered in 42% of patients with SCA, with a higher prevalence in women (52% versus 27% in men; P<0.001). Several hemolytic biomarkers, such as lactate dehydrogenase, were different between the acidosis and nonacidosis groups (P=0.02 and P=0.03 in men and women, respectively), suggesting higher hemolytic activity in the former group. To note, fasting urine osmolality was low in the whole study population and was significantly lower in men with SCA in the acidosis group (392 versus 427 mOsm/kg; P=0.01). SCA subgroup analysis confirmed metabolic acidosis with a normal anion gap in 14 patients, characterized by a lower urinary pH (P<0.02) and no increase in urinary ammonium. Serum potassium, plasma renin, and aldosterone were similar between the two groups and thus could not explain impaired urinary ammonium excretion. CONCLUSIONS These results suggest that the prevalence of metabolic acidosis in patients with SCA is underestimated and related to impaired ammonium availability possibly due to an altered corticopapillary gradient. Future studies should evaluate whether chronic metabolic acidosis correction may be beneficial in this population, especially in bone remodeling.

Chronic myeloid leukaemia and sickle cell disease: could imatinib prevent vaso-occlusive crisis?

We report the case of a patient with homozygous sickle cell disease (SCD) and chronic myeloid leukaemia (CML) whose vaso-occlusive crises were resolved with imatinib therapy. The patient, born in 1983, underwent a splenectomy at the age of 7 years for acute splenic sequestration. Hospitalization for vaso-occlusive crisis (VOC) occurred about once a year until 2007. The patient was never treated with hydroxycarbamide. In 2008, the patient was hospitalized five times for bone VOC with high fever (40 C) but no clinical signs of infection and negative microbiologic cultures were found; the white blood cell (WBC) count was elevated to 43Æ2 · 10/l, and neutrophils were 34Æ56 · 10/l, but these normalized after the VOC. In September 2008, the patient was hospitalized twice for recurrent VOC, with WBC count elevated to 73Æ2 · 10/l (neutrophils, 43Æ96 · 10/l; eosinophils 1Æ47 · 10/l; basophils, 1Æ47 · 10/l; monocytes, 2Æ21 · 10/l). Myelocytosis appeared, and WBC count remained elevated after the VOC (68Æ3 · 10/ l). The diagnosis of CML was confirmed by bone marrow aspiration, karyotype, and conventional cytogenetic tests, which showed t(9;22) chromosomal translocation and b2/a2 and b3/a2 transcripts in moderate levels (27Æ7% M-BCR/copies ABL1). Imatinib was started in November 2008, and the WBC count decreased rapidly. The patient had no more VOC and was not hospitalized again. The patient was lost to follow-up for 1 year. After this delay, the patient was evaluated and a complete karyotypic and major molecular response was recorded. No VOC had occurred since the administration of imatinib. The red blood cell count (3Æ2–3Æ4 · 10/l) and morphology (mean cell volume = 80 fl) did not change, nor did the haemoglobin concentration (around 82 g/l), f HbS (76Æ9%), HbF (8%) and lactate dehydrogenase (LDH) levels. Each time that the patient forgot to take imatinib for several days, VOC recurred after 2 or 3 days, and stopped immediately when the patient took imatinib again. No recurrence of elevated WBC count was subsequently observed (7Æ5 · 10/l; neutrophils, 5Æ25 · 10/l). The association of CML and SCD has been reported in nine cases (Nowell et al, 1975; Papayannopoulou et al, 1978; Sarma et al, 1986; Stricker et al, 1986; Phillips et al, 1988; Rosner & Grünwald, 1989; Schultz & Ware, 2003; Chen et al, 2005). There is probably no link between these two diseases since their association is rare. However, high-level and constant stimulation of inflammatory cells due to the vaso-occlusive phenomenon could enhance changes in the granulocytic cell differentiation and thus lead to CML. The causative role of high WBC counts in the occurrence of VOC has been documented, and the efficacy of chemotherapy against CML in the prevention of recurrence of VOC has been observed in two cases (Sarma et al, 1986; Phillips et al, 1988). Several different drugs (vincristine, busulfan) have been used successfully; this suggests that the beneficial effect on VOC was due not to the drug itself but rather a result of the decreased of WBC. To our knowledge, this is the first reported case where a patient with SCD received imatinib, a tyrosine kinase inhibitor. The treatment was perfectly tolerated. The link between imatinib and the efficacy on the prevention of VOC is not clear. The recurrence of VOC after discontinuation of imatinib was not explained by the recurrence of increased WBC counts, nor by changes in haemoglobin concentration or HbF level, or haemolysis tests, which suggests that another mechanism was involved in the prevention of acute VOC due to sickle cell disease. Thus, tyrosine kinase inhibitors should be added to the list of potential treatments for SCD.

Association of hidradenitis suppurativa and familial Mediterranean fever: A case series of 6 patients

OBJECTIVES Familial mediterranean fever (FMF) is the most common monogenic autoinflammatory disease. Hidradenitis suppurativa (HS) is an inflammatory cutaneous disease. Those diseases can occur simultaneously among the same individual. Our objective was to describe the features of patients displaying both FMF and HS. METHODS We screened the French adult FMF reference center for FMF patients with HS. RESULTS Six patients out of 151 (4%) with a median age of 36 years old were concerned. Among them, FMF was symptomatic at a median age of 11.5years old and colchicine was introduced at a median age of 20.5years old. HS was diagnosed at a median age of 31.5years old. An elderly patient displayed AA amyloidosis in the outcome of FMF, with a late diagnosis of HS, with response to anakinra. There was no temporal relation between FMF and HS attacks. Some patients had a persistent inflammatory syndrome under treatment. CONCLUSION FMF and HS are both inflammatory diseases involving young patients, with HS possibly being an autoinflammatory disease. Although their association seems to be fortuitous, both can induce an important inflammation state that could lead to AA amyloidosis and require a close monitoring of clinical signs and acute-phase reactants. Anakinra was successful in treating the only patient with both HS, FMF and amyloidosis.