Difficult-to-treat primary immune thrombocytopenia in adults: Prevalence and burden. Results from the CARMEN-France registry.

The aim of this study was to assess the prevalence and the burden of difficult-to-treat primary ITP (pITP), defined by the need for another ITP treatment after romiplostim and eltrombopag. Adult patients were selected in the prospective, real-world CARMEN-France registry up to December 2021. Out of 821 adult patients with pITP, 29 had difficult-to-treat ITP (3.5%; 95% confidence interval [CI]: 2.3%-4.8% in total; 7.6%; 95% CI: 4.9%-10.2% of patients needing ≥2nd line treatment). The 3-year cumulative incidence of bleeding, infection and thrombosis was 100%, 24.1% and 13.8% respectively. The median cumulative duration of hospital stays was 31 days (median follow-up: 30.3 months).

Abnormal T-cell phenotype in episodic angioedema with hypereosinophilia (Gleich syndrome): Frequency, clinical implication, and prognosis.

BACKGROUND: Episodic angioedema with eosinophilia (EAE) (Gleich syndrome) is a rare disorder consisting of recurrent episodes of angioedema, hypereosinophilia, and frequent elevated serum IgM level. METHODS: We conducted a retrospective multicenter nationwide study regarding the clinical spectrum and therapeutic management of patients with EAE in France. RESULTS: A total of 30 patients with a median age at diagnosis of 41 years (range, 5-84) were included. The median duration of each crisis was 5.5 days (range, 1-90), with swelling affecting mainly the face and the upper limbs. Total serum IgM levels were increased in 20 patients (67%). Abnormal T-cell immunophenotypes were detected in 12 patients (40%), of whom 5 (17%) showed evidence of clonal T-cell receptor gamma locus gene (TRG) rearrangement. The median duration of follow-up was 53 months (range, 31-99). The presence of an abnormal T-cell population was the sole factor associated with a shorter time to flare (hazard ratio, 4.15; 95% confidence interval, 1.18-14.66; P = .02). At last follow-up, 3 patients (10%) were able to have all treatments withdrawn and 11 (37%) were in clinical and biologic remission with less than 10 mg of prednisone daily. CONCLUSION: EAE is a heterogeneous condition that encompasses several disease forms. Although patients usually respond well to glucocorticoids, those with evidence of abnormal T-cell phenotype have a shorter time to flare.

Splenectomy for primary immune thrombocytopenia revisited in the era of thrombopoietin receptor agonists: New insights for an old treatment.

Although splenectomy is still considered the most effective curative treatment for immune thrombocytopenia (ITP), its use has significantly declined in the last decade, especially since the approval of thrombopoietin receptor agonists (TPO-RAs). The main objective of the study was to determine whether splenectomy was still as effective nowadays, particularly for patients with failure to respond to TPO-RAs. Our secondary objective was to assess, among patients who relapsed after splenectomy, the pattern of response to treatments used before splenectomy. This multicenter retrospective study involved adults who underwent splenectomy for ITP in France from 2011 to 2020. Response status was defined according to international criteria. We included 185 patients, 100 (54.1%) and 135 (73.0%) patients had received TPO-RAs and/or rituximab before the splenectomy. The median follow-up after splenectomy was 39.2 months [16.5-63.0]. Overall, 144 (77.8%) patients had an initial response and 23 (12.4%) experienced relapse during follow-up, for an overall sustained response of 65.4%, similar to that observed in the pre-TPO-RA era. Among patients who received at least one TPO-RA or rituximab before splenectomy, 92/151 (60.9%) had a sustained response. Six of 13 (46%) patients with previous lack of response to both TPO-RAs and rituximab had a sustained response to splenectomy. Among patients with relapse after splenectomy, 13/21 (61.2%) patients responded to one TPO-RAs that failed before splenectomy. In conclusion, splenectomy is still a relevant option for treating adult primary ITP not responding to TPO-RAs and rituximab. Patients with lack of response or with relapse after splenectomy should be re-challenged with TPO-RAs.

Long-term prophylaxis in hereditary angioedema management: Current practices in France and unmet needs.

Background: Hereditary angioedema (HAE) is characterized by unpredictable and potentially life-threatening attacks of cutaneous and submucosal swelling. Over the past decade, new agents, based on a better understanding of the underlying biologic mechanisms of HAE, have changed the face of long-term prophylaxis (LTP). Objective: The objective was to describe current practices and unmet needs with regard to LTP for HAE in expert centers in France. Methods: The study was conducted in France in 2020. Based on their experience with patients with HAE who had visited their center at least once in the past 3 years, physicians from 25 centers who are expert in the management of HAE were requested to fill in a questionnaire that encapsulated their active patient list, criteria for prescribing LTP, and medications used. They were asked about potential unmet needs with currently available therapies. They were asked to express their expectations with regard to the future of HAE management. Results: Analysis was restricted to 20 centers that had an active patient file and agreed to participate. There were 714 patients with C1 inhibitor (C1-INH) deficiency, of whom 423 (59.2%) were treated with LTP. Altered quality of life triggered the decision to start LTP, as did the frequency and severity of attacks. Ongoing LTP included androgens (28.4%), progestins (25.8%), lanadelumab (25.3%), tranexamic acid (14.2%), intravenous C1-INHs (5.6%), and recombinant C1-INH (0.7%). Twenty-nine percent of the patents with LTP were considered to still have unmet needs. Physicians' concerns varied among therapies: poor tolerability for androgens and progestins, a lack of efficacy for tranexamic acid and progestins, dosage form, and high costs for C1-INHs and lanadelumab. Physicians' expectations encompassed more-efficacious and better-tolerated medications, easier treatment administration for the sake of improved quality of life of patients, and less-expensive therapies. Conclusion: Despite the recent enrichment of the therapeutic armamentarium for LTP, physicians still expressed unmet needs with currently available therapies.

Coronavirus disease 2019 in patients with inborn errors of immunity: An international study.

BACKGROUND: There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense. OBJECTIVE: We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2. METHODS: An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI. RESULTS: We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died. CONCLUSIONS: This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2.

Late clinical failure associated with cytochrome b codon 268 mutation during treatment of falciparum malaria with atovaquone-proguanil in traveller returning from Congo.

BACKGROUND: The drug combination atovaquone-proguanil, is recommended for treatment of uncomplicated falciparum malaria in France. Despite high efficacy, atovaquone-proguanil treatment failures have been reported. Resistance to cycloguanil, the active metabolite of proguanil, is conferred by multiple mutations in the Plasmodium falciparum dihydrofolate reductase (pfdhfr) and resistance to atovaquone by single mutation on codon 268 of the cytochrome b gene (pfcytb). CASE PRESENTATION: A 47-year-old female, native from Congo and resident in France, was admitted in hospital for uncomplicated falciparum malaria with parasitaemia of 0.5%, after travelling in Congo (Brazzaville and Pointe Noire). She was treated with atovaquone-proguanil (250 mg/100 mg) 4 tablets daily for 3 consecutive days. On day 5 after admission she was released home. However, many weeks after this episode, without having left France, she again experienced fever and intense weakness. On day 39 after the beginning of treatment, she consulted for fever, arthralgia, myalgia, photophobia, and blurred vision. She was hospitalized for uncomplicated falciparum malaria with a parasitaemia of 0.375% and treated effectively by piperaquine-artenimol (320 mg/40 mg) 3 tablets daily for 3 consecutive days. Resistance to atovaquone-proguanil was suspected. The Y268C mutation was detected in all of the isolates tested (D39, D42, D47). The genotyping of the pfdhfr gene showed a triple mutation (N51I, C59R, S108N) involved in cycloguanil resistance. CONCLUSION: This is the first observation of a late clinical failure of atovaquone-proguanil treatment of P. falciparum uncomplicated malaria associated with pfcytb 268 mutation in a traveller returning from Congo. These data confirm that the Y268C mutation is associated with delayed recrudescence 4 weeks or more after initial treatment. Although atovaquone-proguanil treatment failures remain rare, an increased surveillance is required. It is essential to declare and publish all well-documented cases of treatment failures because it is the only way to evaluate the level of resistance to atovaquone.

Efficacy and safety of biologics in relapsing polychondritis: a French national multicentre study.

OBJECTIVES: To assess the efficacy and the safety of biologics in a cohort of patients with relapsing polychondritis (RP). METHODS: We conducted a French multicentre retrospective cohort study including patients treated with biologics for RP. Efficacy outcomes were clinical response (partial or complete) and complete response during the first 6 months of exposure, plus daily corticosteroid dose at 6 months. Other outcomes were adverse drug reactions (ADRs), persistence of biologics and factors associated with a response. RESULTS: This study included 41 patients exposed to 105 biologics (tumour-necrosis factor (TNF) inhibitors, n=60; tocilizumab, n=17; anakinra, n=15; rituximab, n=7; abatacept, n=6). Overall response rate during the first 6 months of exposure was 62.9%. Complete response rate was 19.0%. Reduced corticosteroid doses were highly variable among patients. ADRs were mostly infections (n=42). Reasons for biologic withdrawal (73.3%) were insufficient efficacy (34.3%; ranging from 23.5% for tocilizumab to 72.7% for etanercept), loss of efficacy (18.1%) and ADRs (20.9%; mostly for anakinra: 46.7%). Persistence was comparable among biologic classes. Among TNF inhibitors, the highest persistence was observed with adalimumab. Differences in clinical response rates were observed depending on biologics and organ involvement. There were trends towards a lower response rate in cases with associated myelodysplastic syndrome and for a higher response rate for nasal/auricular chondritis, sternal chondritis and concomitant exposure to non-biologic disease-modifying antirheumatic drugs. CONCLUSIONS: This study describes the efficacy of biologics for refractory RP. However, the number of complete responses was low and there were concerns about the risk of ADRs, particularly infections.

Unraveling the Hygiene Hypothesis of helminthes and autoimmunity: origins, pathophysiology, and clinical applications.

BACKGROUND: The Hygiene Hypothesis (HH) attributes the dramatic increase in autoimmune and allergic diseases observed in recent decades in Western countries to the reduced exposure to diverse immunoregulatory infectious agents. This theory has since largely been supported by strong epidemiological and experimental evidence. DISCUSSION: The analysis of these data along with the evolution of the Western world's microbiome enable us to obtain greater insight into microorganisms involved in the HH, as well as their regulatory mechanisms on the immune system. Helminthes and their derivatives were shown to have a protective role. Helminthes' broad immunomodulatory properties have already begun to be exploited in clinical trials of autoimmune diseases, including inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and type-1 diabetes. SUMMARY: In this review, we will dissect the microbial actors thought to be involved in the HH as well as their immunomodulatory mechanisms as emphasized by experimental studies, with a particular attention on parasites. Thereafter, we will review the early clinical trials using helminthes' derivatives focusing on autoimmune diseases.

Treating prolactinoma can prevent autoimmune diseases.

Prolactin (PRL) is a pleiotropic hormone; in addition to a wide variety of endocrine effects, PRL also exhibits immunostimulating effects. Therefore, there is increasing evidence linking PRL with a large number of systemic and organ specific autoimmune diseases. Herein, we report the case of an adolescent girl diagnosed with multiple sclerosis (MS) occurring in the context of untreated prolactinoma evolving since childhood. This raises the exciting question of the involvement of PRL in the pathogenesis of MS. It is likely that early treatment of hyperprolactinemia in this case would have significantly reduced the risk of developing MS or even prevented its occurrence.

Visceral leishmaniasis due to Leishmania infantum with renal involvement in HIV-infected patients.

BACKGROUND: We describe histological, clinical findings and outcomes of renal involvement during Leishmania infantum infection in four HIV-infected patients in South France and North Italy hospital settings. CASES PRESENTATION: Four HIV-infected Caucasian patients (age 24-49) performed renal biopsy during episodes of visceral leishmaniasis. They presented severe immunosuppression, frequent relapses of visceral leishmaniasis during a follow-up period of several years and partial or complete recovery of renal function after anti-parasitic treatment. Main clinical presentations were nephrotic or nephritic syndrome and/or acute renal failure secondary to membranoproliferative type III glomerulonephritis or acute interstitial nephritis. Clinical outcome was poor, probably as a consequence of insufficient immuno-virological control of the HIV infection. CONCLUSIONS: Our findings suggest that the main histological findings in case of renal involvement due to Leishmania infantum infection in HIV-infected patients are type III MPGN and acute interstitial nephritis, with a histological specificity similar to that observed in canine leishmaniasis. Poor immune status in HIV-infected patients, altering the capacity for parasite clearance, and prolonged course of chronic active VL in this population may lead to the development of specific renal lesions.

Efficacy and Safety of Rituximab-Based Treatments in Angioedema With Acquired C1-Inhibitor Deficiency.

BACKGROUND: Angioedema (AE) due to acquired C1-inhibitor (C1-INH) deficiency (AAE-C1-INH) is related to excessive consumption of C1-INH or to anti-C1-INH antibodies, and is frequently associated with lymphoproliferative syndromes or monoclonal gammopathies. Standard of care for prophylactic treatment in this condition is not established. Rituximab may be effective to prevent attacks, especially if the lymphoid hemopathy is controlled, but data are scarce. OBJECTIVE: To evaluate efficacy of rituximab in AAE-C1-INH. METHODS: A retrospective multicenter study was carried out in France, including patients with AAE-C1-INH treated with rituximab between April 2005 and July 2019. RESULTS: Fifty-five patients with AAE-C1-INH were included in the study, and 23 of them had an anti-C1-INH antibody. A lymphoid malignancy was identified in 39 patients, and a monoclonal gammopathy in 9. There was no associated condition in 7 cases. Thirty patients received rituximab alone or in association with chemotherapy (n = 25). Among 51 patients with available follow-up, 34 patients were in clinical remission and 17 patients had active AE after a median follow-up of 3.9 years (interquartile range, 1.5-7.7). Three patients died. The presence of anti-C1-INH antibodies was associated with a lower probability of AE remission (hazard ratio, 0.29 [95% CI, 0.12-0.67]; P = .004). Relapse was less frequent in patients with lymphoma (risk ratio, 0.27 [95% CI, 0.09-0.80]; P = .019) and in patients treated with rituximab and chemotherapy (risk ratio, 0.31 [95% CI, 0.12-0.79]; P = .014). CONCLUSIONS: Rituximab is an efficient and well-tolerated therapeutic option in AE, especially in lymphoid malignancies and in the absence of detectable anti-C1-INH antibodies.

Emergence of Lyme Disease on the French Riviera, a Retrospective Survey.

Background: The French Riviera has been declared free of Lyme Borreliosis (LB) for years. Many patients are referred for presumed LB, sometimes with atypical clinical signs and/or doubtful serology, calling the diagnosis into question. Methods: Patients were assessed for LB diagnosis, depending on clinical presentation, laboratory findings, and further examination by other medical professionals. Results: Among 255 patients, 45 (18%) were classified as confirmed LB cases [including 28 ongoing LB (10%) and 17 past LB (8%)], and for 210 (82%) a Lyme borreliosis diagnosis was ruled out. Among ongoing LB, 56% had been exposed to or bitten by ticks, exclusively in rural locations of the Alpes-Maritimes. As a result of the diagnostic procedure, 132 (52%) patients had been treated. An alternative diagnosis was established for 134 (52%) patients, covering a wide range of conditions, including mainly psychological (28%) and neurological conditions (25%) or inflammatory and systemic diseases (22%). Conclusions: Our results strongly suggest the endemicity of LB in the Alpes-Maritimes region. Confirmed LB accounted for 18% of patients while 52% were diagnosed with other conditions.

Tolerance and efficacy of targeted therapies prescribed for off-label indications in refractory systemic autoimmune diseases: data of the first 100 patients enrolled in the TATA registry (TArgeted Therapy in Autoimmune Diseases).

OBJECTIVES: To assess the tolerance and efficacy of targeted therapies prescribed off-label in refractory low-prevalence autoimmune and inflammatory systemic diseases. METHODS: The TATA registry (TArgeted Therapy in Autoimmune Diseases) is a prospective, observational, national and independent cohort follow-up. The inclusion criteria in the registry are as follows: age >18 years; low-prevalence autoimmune and inflammatory systemic disease treated with off-label drugs started after 1 January 2019. RESULTS: Hundred (100) patients (79 women) were enrolled. The median age was 52.5 years (95% CI 49 to 56) and the median disease duration before enrolment was 5 years (3 to 7). The targeted therapies at enrolment were as follows: Janus kinase/signal transducers and activators of transcription inhibitors (44%), anti-interleukin (IL)-6R (22%), anti-IL-12/23, anti-IL-23 and anti-IL-17 (9%), anti-B cell activating factor of the tumour necrosis factor family (5%), abatacept (5%), other targeted treatments (9%) and combination of targeted treatments (6%). 73% of patients were receiving corticosteroid therapy at enrolment (median dose 10 mg/day). The current median follow-up time is 9 months (8 to 10).Safety: 11 serious infections (incidence rate of 14.8/100 patient-years) and 1 cancer (1.3 cancers/100 patient-years) were observed. Two patients died from severe COVID-19 (2.7 deaths/100 patient-years).Efficacy: the targeted treatment was considered effective by the clinician in 56% of patients and allowed, in responders, a median reduction of oral corticosteroids of 15 (9 to 21) mg/day, below 7.5 mg/day in 76% of patients, while 28% discontinued. CONCLUSION: These initial results of the TATA registry confirm the diversity of targeted treatments prescribed off-label in refractory autoimmune diseases and their corticosteroid-sparing effect when effective. Tolerance was acceptable in these refractory patients with a long history of treatment with immunosuppressive drugs.

Case Report: Autoimmune Hemolysis Anemia After Dihydroartemisinin and Piperaquine for Uncomplicated Plasmodium falciparum Malaria.

Malaria is still an endemic disease in Africa, with many imported cases in Europe. The standard treatment is intravenous artesunate for severe malaria and oral artemisinin-based combination therapy (ACT) for uncomplicated malaria. Delayed hemolytic anemia (DHA) after intravenous artesunate has been extensively described, and guidelines recommend biological monitoring until 1 month after the end of the treatment. A link with an autoimmune process is still unsure. Nevertheless, cases with positive direct antiglobulin test (DAT) have been reported. Conversely, DHA is not recognized as an adverse effect of oral ACT. Previously, only few cases of DHA occurring after oral ACT without intravenous artesunate administration have been reported. We report the case of a 42-year-old man returning from Togo. He was treated with dihydroartemisinin/piperaquine combination for uncomplicated Plasmodium falciparum malaria, with low parasitemia. Nine days after the end of the treatment, the patient developed hemolytic anemia with positive DAT. Eventually, the patient recovered after corticotherapy. After excluding common causes of autoimmune hemolytic anemia, we considered that dihydroartemisinin/piperaquine treatment was involved in this side effect.

HIBISCUS: Hydroxychloroquine for the secondary prevention of thrombotic and obstetrical events in primary antiphospholipid syndrome.

The relapse rate in antiphospholipid syndrome (APS) remains high, i.e. around 20%-21% at 5 years in thrombotic APS and 20-28% in obstetrical APS [2, 3]. Hydroxychloroquine (HCQ) appears as an additional therapy, as it possesses immunomodulatory and anti-thrombotic various effects [4-16]. Our group recently obtained the orphan designation of HCQ in antiphospholipid syndrome by the European Medicine Agency. Furthermore, the leaders of the project made the proposal of an international project, HIBISCUS, about the use of Hydroxychloroquine in secondary prevention of obstetrical and thrombotic events in primary APS. This study has been launched in several countries and at now, 53 centers from 16 countries participate to this international trial. This trial consists in two parts: a retrospective and a prospective study. The French part of the trial in thrombosis has been granted by the French Minister of Health in December 2015 (the academic trial independent of the pharmaceutical industry PHRC N PAPIRUS) and is coordinated by one of the members of the leading consortium of HIBISCUS.