Update on targeted treatments for ANCA-associated vasculitis.

Targeted therapy has revolutionized the management of ANCA-associated vasculitis (AAV) over the last fifteen years. Rituximab, an approved induction and maintenance agent for severe AAV, is no less effective than cyclophosphamide as induction therapy and particularly useful in relapsing or refractory disease, or in women. In patients with relapsing AAV, granulomatosis with polyangiitis or PR3-ANCA, it is more effective than cyclophosphamide. Rituximab maintenance is superior to the conventional immunosuppressive drugs that it replaces. Low-dose preemptive rituximab infusions are recommended every 6months for 18months, followed by re-evaluation to decide whether 4 additional biannual infusions should be administered, balancing the probability of relapse and the risk of serious infections on rituximab. A growing body of experimental and clinical data shows that C5a pathway inhibition is a promising therapeutic option for AAV, which could reduce glucocorticoids needs. Avacopan is a first approved oral C5A receptor antagonist, used when there is a high risk that glucocorticoids will cause serious adverse events. In eosinophilic granulomatosis with polyangiitis, the importance of IL-5 for eosinophil activation and survival led to evaluation and approval of mepolizumab, a humanized monoclonal antibody directed against IL-5. Mepolizumab showed a steroid-sparing effect. Its effectiveness in active vasculitis remains uncertain and is currently being evaluated. Benralizumab targeting the IL-5 receptor was recently shown to be noninferior to mepolizumab. Rituximab has had disappointing results in non-severe active vasculitis and is being evaluated as maintenance therapy. Plasma exchange is not indicated as first-line treatment but remains recommended when creatinine levels exceed 300µmol/L.

Advances in the maintenance of ANCA vasculitis remission.

The maintenance treatment of ANCA-associated vasculitides (AAVs) has benefited from the results of several prospective clinical trials focusing on the evaluation of new drugs, therapeutic strategies, and adjuvant treatments. They also showed that rituximab was the most effective agent to maintain remission. However, because treatments can induce adverse events, including facilitating infections, therapeutic strategies should be adapted to find the optimal dose(s) and their administration duration(s) and to make them commensurate to the expected severity of relapse. That task is not easy to achieve because we have not yet been able to identify the clinical or biological parameters that can predict when a relapse will occur and its severity. Among AAVs, eosinophilic granulomatosis with polyangiitis (EGPA) has pathogenic and clinical specificities, and new drugs directly address those features. If rituximab could have a place such as in other AAVs, anti-IL5 biotherapies could also be prescribed successfully for maintenance. Another aim of vasculitis maintenance therapy is to control the disease with less prednisone than in the past. Herein, we emphasize the importance of individually devising a maintenance regimen adapted to the objectives of keeping the patient in remission without the adverse events related to the prescribed treatment(s).

Induction of thrombotic thrombocytopenic purpura by dengue virus infection in a critical patient: Role of therapeutic plasma exchange.

Thrombotic thrombocytopenic purpura (TTP) secondary to dengue fever is a very unusual occurrence. Both conditions are fatal and can result in significant mortality and morbidity if left untreated. In this case, we present a young lady who suffered dengue fever followed by microangiopathic anemia, thrombocytopenic purpura, and altered sensorium. Investigations revealed microangiopathic hemolysis; there was no evidence of disseminated intravascular coagulation. As soon as, we diagnosed the patient as having TTP, we treated her with serial plasma exchange therapy, steroids, and monoclonal antibodies such as rituximab. The patient responded very well to the treatment and completely recovered from neurological symptoms and laboratory parameters also normalized. Hence, timely diagnosis and starting appropriate treatment immediately are key factors for successful outcomes.

Treatment regimens for neuromyelitis optica spectrum disorder attacks: a retrospective cohort study.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) attacks require an urgent probabilistic anti-inflammatory therapeutic strategy. As inadequately treated attacks result in disability, there is a need to identify the optimal attack-treatment regimen. Our study aimed to identify predictors of outcome after a first attack in patients with an NMOSD presentation and propose the best treatment strategy. METHODS: We performed a retrospective cohort study on the French national NMOSD registry (NOMADMUS), a nested cohort of the French multiple sclerosis observatory (OFSEP) recruiting patients with NMOSD presentations in France. We studied the first attack for any independent locations of clinical core characteristic of NMOSD, in treatment-naïve patients. The primary outcome was the evolution of the Expanded Disability Status Scale (EDSS) score at 6 months, stratified in two ways to account for recovery (return to baseline EDSS score) and treatment response (classified as "good" if the EDSS score decreased by ≥ 1 point after a nadir EDSS score ≤ 3, or by ≥ 2 points after a nadir EDSS score > 3). We used ordinal logistic regression to infer statistical associations with the outcome. RESULTS: We included 211 attacks among 183 patients (104 with anti-AQP4 antibodies, 60 with anti-MOG antibodies, and 19 double seronegative). Attack treatment regimens comprised corticosteroids (n = 196), plasma exchanges (PE; n = 72) and intravenous immunoglobulins (n = 6). Complete recovery was reached in 40 attacks (19%) at 6 months. The treatment response was "good" in 134 attacks (63.5%). There was no improvement in EDSS score in 50 attacks (23.7%). MOG-antibody seropositivity and short delays to PE were significantly and independently associated with better recovery and treatment response. CONCLUSIONS: We identified two prognostic factors: serostatus (with better outcomes among MOG-Ab-positive patients) and the delay to PE. We, therefore, argue for a more aggressive anti-inflammatory management of the first attacks suggesting an NMOSD presentation, with the early combination of PE with corticosteroids.

Anti-Factor H Antibody-Associated Atypical Hemolytic Uremic Syndrome: A Case Report.

Introduction: Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy, caused by dysregulation of the complement alternative pathway. Deletion of the complement factor H-related genes, CFHR1 and CFHR3, together with the presence of CFH autoantibodies are reported in aHUS patients, representing 10% of cases of patients with aHUS. Case presentation: We report here on a case of 4-year-old girl with anti-CFH antibody-associated aHUS. The measurement of complement factors and anti-factor H antibodies, was the main guideline for making an accurate diagnosis and providing the appropriate therapy, with the patient responding positively to plasma exchanges (PEs) and cyclophosphamide pulses. We then, one year after disease onset, continued with glucocorticoids and mycophenolate mofetil (MMF), as maintenance therapy. There were no complications during the therapy other than neutropenia. Now, one year after the cessation of the immune suppression therapy, she is in remission with normal kidney function, no signs of hemolysis, normal C3 levels, and normal range proteinuria. The anti-factor H autoantibody titer decreased but still remained positive, the factor H antigen values remained low all throughout. Close follow-up is applied with frequent urine testing and complete blood count with an intention for early detection of relapse of the disease. Conclusion: The purpose of this case report is to emphasize the value of complement factor measurements and also to separate anti-CFH antibody-associated aHUS as an entity, because immunosuppressive therapy provides an excellent response..

Plasma Exchange to Rescue Patients with Autoantibodies Against Type I Interferons and Life-Threatening COVID-19 Pneumonia.

PURPOSE: To report four cases of life-threatening COVID-19 pneumonia in patients with high blood concentrations of neutralizing autoantibodies against type I interferons (IFNs), who were treated with plasma exchange (PE) as a rescue therapy. METHODS: Prospective case series, which included patients, diagnosed with RT-PCR-confirmed SARS-CoV-2 infection and positive autoantibodies against type I IFNs in two French intensive care units (ICUs) between October 8 and November 14, 2020. Six critically ill COVID-19 patients with no anti-IFN antibodies were used as controls. Anti-IFN autoantibodies and IFN concentrations, together with the levels of anti-SARS-CoV-2 antibodies, were measured sequentially in serum. Viral load was determined in the upper and lower respiratory tract. Patients were followed during hospital stay. RESULTS: Three men and one woman were included. Three of the patients had four PE sessions each, while another had three PE sessions. PE decreased the concentrations of autoantibodies against type I IFN in all four patients, whereas anti-SARS-CoV-2 antibody levels remained stable. Autoantibodies against type I IFN levels were high in tracheal aspirates of one patient and decreased after three PE sessions. By contrast, anti-IFN autoantibodies were not detected in tracheal aspirates from five control patients without detectable anti-IFN autoantibodies in serum. During PE, serum IFN-α levels slightly increased in three out of four patients, and upper respiratory tract viral load decreased in all patients. All patients were alive at day 28 of ICU admission. Two patients eventually died in the ICU, while the two survivors were discharged from the ICU at days 50 and 66. CONCLUSIONS: PE efficiently removes autoantibodies against type I IFNs, including those detected in tracheal aspirates, without affecting anti-SARS-CoV-2 antibody levels, in patients with life-threatening COVID-19 pneumonia. The clinical benefit of PE in patients with autoantibodies against type I IFNs should be tested in a larger study.

ANCA-associated vasculitides: Recommendations of the French Vasculitis Study Group on the use of immunosuppressants and biotherapies for remission induction and maintenance.

Treatment of vasculitides associated with anti-neutrophil cytoplasm antibodies (ANCA) (AAVs) has evolved dramatically in recent years, particularly since the demonstration of rituximab efficacy as remission induction and maintenance therapy for granulomatosis with polyangiitis and microscopic polyangiitis. In 2013, the French Vasculitis Study Group (FVSG) published recommendations for its use by clinicians. Since then, new data have made it possible to better specify and codify prescription of rituximab to treat AAVs. Herein, the FVSG Recommendations Committee, an expert panel comprised of physicians with extensive experience in the treatment and management of vasculitides, presents its consensus guidelines based on literature analysis, the results of prospective therapeutic trials and personal experience.

Treatment of systemic necrotizing vasculitides: The 40-year experience of the French Vasculitis Study Group.

Treatment of vasculitides has benefited from the results of several prospective clinical trials focusing on the evaluation of new drugs, therapeutic strategies and adjuvant treatments. In the field of autoimmunity, vasculitides are the group of diseases for which the most important medical progress has been made, combining advances in understanding the pathogenetic mechanisms, classification of the various entities and willingness to evaluate treatments. Several international groups have been actively involved in these tasks. The French Vasculitis Study Group was the first to design and organize prospective trials in the field and to contribute to these medical advances. In this review, we analyze the different treatments and therapeutic strategies evaluated over the last few decades and, more precisely, the last 39 years by the French Vasculitis Study Group.

Double-blind, randomized controlled trial of therapeutic plasma exchanges vs sham exchanges in moderate-to-severe relapses of multiple sclerosis.

INTRODUCTION: No randomized controlled clinical trial of therapeutic plasma exchanges (TPE) has yet been performed for moderate-to-severe relapses of multiple sclerosis (MS). OBJECTIVE: To compare TPE to sham-TPE in patients with a recent steroid-resistant moderate-to-severe MS relapse. METHODS: Patients presenting with an MS relapse of less than 2 months without improvement and 15 days after a course of steroids were randomized. Specific criteria were used for each relapse type to define moderate-to-severe disability. The primary endpoint was the proportion of patients with at least a moderate improvement based on objective and functional evaluation after 1 month. RESULTS: Thirty-eight patients were randomized. The intention-to-treat analysis included 14 patients in the TPE group and 17 in the Sham-TPE group. The proportion of patients with at least moderate improvement at 1 month did not differ between the groups (P = .72), although 57.1% of the TPE group had full recovery compared with 17.6% of the sham group. Considering optic neuritis (ON), a significant difference in the proportion of different levels of improvement was observed in favor of the TPE group (P = .04). The combined Kurtzke's functional systems scores were significantly more improved in the TPE group than in the sham-TPE group at months 1 (P < .01), 3 (P < .05), and 6 (P < .05). No major side effects were observed. CONCLUSIONS: A significant difference between TPE and Sham-TPE at the primary endpoint was only observed in patients with ON. Neurological function improved significantly more often in the TPE group than in the sham-TPE group.

Treatment Patterns and Costs of Chronic Inflammatory Demyelinating Polyneuropathy: A Claims Database Analysis.

BACKGROUND: Corticosteroids, plasma exchange, and intravenous immunoglobulin (IVIG) have been standard-of-care treatments for chronic inflammatory demyelinating polyneuropathy (CIDP) for more than 2 decades. Despite guideline recommendations for best clinical practices, heterogeneity in patient presentation and the course of treatment for CIDP remains. There is limited literature regarding the real-world treatment patterns of and costs associated with CIDP. OBJECTIVE: To analyze and describe the real-world treatment patterns of and economic burden associated with CIDP. METHODS: This retrospective cohort study evaluated the treatment patterns and CIDP-related healthcare costs over a 2-year follow-up period for patients with newly diagnosed CIDP who had commercial insurance, using claims data from the IMS LifeLink PharMetrics Plus Claims database between 2009 through 2014. Treatment-naïve patients with newly diagnosed CIDP were evaluated for 2 years postdiagnosis, which captured the treatments used and the resource utilization. The patients were defined as receiving active CIDP therapy (ie, IVIG, immunosuppressants, oral or intravenous steroids, or plasma exchange) or active surveillance. RESULTS: Of the 525 patients identified with newly diagnosed CIDP, 55.2% of patients were prescribed only steroid therapy, and 25.3% of patients were prescribed an IVIG therapy during the 2-year follow-up. The median time to the initial treatment was shortest for patients receiving plasma exchange alone (0.03 months) or in combination with a steroid (0.03 months), followed by IVIG plus another therapy (0.53 months), and then IVIG alone (0.71 months). Initiating therapy with steroids alone took the longest mean time (6.51 months) to start the treatment. The median length of time to receive therapy was longest for the steroid plus plasma exchange cohort (21.8 months), followed by the steroid plus immunosuppressant cohort (10.1 months), and the 2 IVIG cohorts (9.04 months for IVIG alone and 9.82 months for IVIG plus another therapy). The mean total CIDP-specific 2-year follow-up costs were highest for the cohort that received IVIG alone ($119,928) or with an additional therapy ($133,334) and lowest for patients who received active surveillance ($3723) or steroids alone ($3101). CONCLUSIONS: Steroid therapy was initiated later and resulted in a shorter duration of treatment than other treatment options for patients with CIDP, which may reflect diagnostic uncertainty, disease severity or remission, therapeutic challenge to determine diagnosis, or the side-effect profile of steroids. The use of steroids alone was the most common prescribed treatment for CIDP. Further research is needed to understand the rationale for treatment decisions in this patient population and their potential impact on patients and health plans.

Influence of vascular access devices upon efficiency of therapeutic plasma exchange.

BACKGROUND: An efficient vascular access is mandatory for the proper conduction of therapeutic plasma exchanges (TPE). Peripheral and central venous catheters may be used, with respective advantages and limitations. In this study, vascular access devices (IV catheter, dialysis cannula, central venous catheter) and anatomic vein characteristics were evaluated. METHOD: From January to June 2016, 162 TPE in 29 patients were reviewed. Only TPE using centrifugation method (Spectra Optia apheresis system) were evaluated. Volume exchanged, procedure duration, mean flow rate, number of inlet, and return pressure pauses were recorded. Site, width, and depth of punctured veins were studied. RESULTS: Median exchange volume planned was 3500 mL, and 152 (94%) procedures could be completed. Peripheral venous catheter was inserted in 103 (64%) cases (IV catheter: 61, dialysis cannulae: 42). Ultrasound guidance was used in 12 (11%) cases. Median procedure duration was shorter with central venous catheter (94 minutes), rather than dialysis cannula (133 minutes) or IV catheter (133 minutes). Median numbers of inlet pressure pauses were lower with central venous catheter (0) and dialysis cannulae (6), rather than IV catheter (10). There were no complications with peripheral venous access. There were no anatomic differences between catheterized veins with IV catheter or dialysis cannula. CONCLUSION: The use of peripheral venous access is possible in most of TPE, for emergency and during maintenance therapy. Dialysis cannulae are good compromise between classic IV catheters and central venous catheters, as it allows high flow rates, are easy to insert and associated with few complications.

Plasma exchanges for severe acute neurological deterioration in patients with IgM anti-myelin-associated glycoprotein (anti-MAG) neuropathy.

Monoclonal IgM anti-myelin-associated glycoprotein (MAG) antibody-related peripheral neuropathy (anti-MAG neuropathy) is predominantly a demyelinating sensory neuropathy with ataxia and distal paresthesia. The clinical course of anti-MAG neuropathy is usually slowly progressive making difficult the identification of clear criteria to start a specific treatment. Although no consensus treatment is yet available, a rituximab-based regimen targeting the B-cell clone producing the monoclonal IgM may be proposed, alone or in combination with alkylating agents or purine analogs. However, in some rare cases, an acute and severe neurological deterioration can occur in few days leading to a rapid loss of autonomy. In these cases, a treatment rapidly removing the monoclonal IgM from the circulation might be useful before initiating a specific therapy. We report successful treatment with plasma exchanges (PE) in four patients presenting with acute neurological deterioration. PE allowed a dramatic and rapid neurological improvement in all patients. PE are safe and may be useful at the initial management of these cases of anti-MAG neuropathy.

A new prescription model for regional citrate anticoagulation in therapeutic plasma exchanges.

BACKGROUND: Regional citrate anticoagulation (RCA) is proposed for various extracorporeal purification techniques to overcome the risk of bleeding that might result from systemic anticoagulation. Yet, no individualized treatment protocol has been proposed for therapeutic plasma exchange (TPE) so far. The objective of this study was to assess the determinants of blood citrate concentration needed and to develop an individualized RCA protocol useful for clinical practice. METHODS: The study population included 14 patients who underwent a total of 47 TPE sessions. Citrate was infused pre-plasmafilter. Post-plasmafilter and systemic plasma ionized calcium concentrations were measured at standardized time intervals. An algorithm was proposed for the supplementation of calcium. During the discovery phase, citrate was infused at a fixed starting rate, and adapted accordingly to obtained post-plasmafilter ionized calcium levels. Using a mathematical approach, an algorithm was thereafter developed for individualized prescriptions of citrate. RESULTS: Pre-treatment values of hematocrit and plasma ionized calcium were the main determinants of the required rate of citrate infusion. These can be integrated into a final equation enabling to individualize the prescription. A prefilter ionized calcium concentration between 0.24 and 0.33 mmol/l prevented coagulation of the extracorporeal circuit. Significant hypocalcemia occurred in 8.5% of treatments. There were no significant acid-base disturbances. CONCLUSION: We propose a new protocol, which enables for the first time to individualize the prescription of regional citrate anticoagulation during TPE, in an efficient manner. The immediately obtained regional anticoagulation protects against both the risk of coagulation of the membrane and the exposure to an excess of citrate.

[Plasmapheresis failure in the treatment of auto-immune pulmonary alveolar proteinosis]. / Échec de plasmaphérèse dans une protéinose alvéolaire pulmonaire auto-immune.

INTRODUCTION: Auto-immune pulmonary alveolar proteinosis is a rare disorder characterized by the accumulation of surfactant proteins in the alveoli. CASE REPORT: We report a case of a 41-year-old smoker, presenting initially with acute respiratory failure. Whole lung lavages were effective initially but only for a few weeks. GM-CSF subcutaneous injections were not effective, and then plasmapheresis were tried. CONCLUSION: This is the fifth report of the use of this treatment in auto-immune pulmonary alveolar proteinosis. Plasmapheresis was not effective in our patient.

Plasma exchanges for the treatment of severe systemic necrotizing vasculitides in clinical daily practice: Data from the French Vasculitis Study Group.

The use of plasma exchanges (PLEX) in systemic necrotizing vasculitides (SNV) still need to be codified. To describe indications, efficacy and safety of PLEX for the treatment of SNV, we conducted a multicenter retrospective study on patients with ANCA-associated vasculitis (AAV) or non-viral polyarteritis nodosa (PAN) treated with PLEX. One hundred and fifty-two patients were included: GPA (n = 87), MPA (n = 56), EGPA (n = 4) and PAN (n = 5). PLEX were used for rapidly progressive glomerulonephritis (RPGN) in 126 cases (86%), alveolar hemorrhage in 64 cases (42%), and severe mononeuritis multiplex in 23 cases (15%). In patients with RPGN, there was a significant improvement in renal function compared to baseline value (P < 0.0001), the plateau being reached at month 3 after PLEX initiation, and estimated glomerular filtration rate improved especially as the number of PLEX increased. In patients with alveolar hemorrhage, mechanical ventilation was discontinued in all patients after a median time of 15 days. Patients treated for mononeuritis multiplex showed improvement of severe motor weakness. After a median follow of 22 months, 18 deaths (12%) were recorded, mainly in patients with RPGN and within the first 6 months. Incidence of end-stage renal disease and/or death was similar between groups of different baseline renal function, but was increased in MPO-ANCA compared to PR3-ANCA. Adverse events attributable to PLEX were recorded in 63%. No death occurred during PLEX. This large series describes indications, efficacy and safety of PLEX in daily practice. Randomized controlled studies are ongoing to define optimal indications, PLEX regimen and concomitant medications.

Challenges in the treatment of chronic inflammatory demyelinating polyradiculoneuropathy.

Chronic idiopathic demyelinating polyradiculoneuropathy (CIDP) is a rare disease, the most frequent one within the spectrum of the so-called "chronic immune-mediated neuropathies". Challenges in the treatment of CIDP firstly concern its diagnosis, which may be difficult, mainly for the atypical forms. Secondly, challenges encompass the choice of the first-line treatment, such as corticosteroids, intravenous immunoglobulins (IVIg), and plasma exchanges (PE) that have been proven as efficacious by several randomized controlled trials (RCT). Recent reports have focused on both different regimens of corticosteroids, and the occurrence of relapses following treatment with either corticosteroids or IVIg. These data may be helpful for the choice of the first-line treatment and may result in changing the guidelines for treatment of CIDP in clinical practice. The third and more difficult challenge is to manage long-term treatment for CIDP, since no immunomodulatory treatment has to date been proven as efficacious in this situation. Lastly, challenges in the treatment concern the choice of the best outcome measure for CIDP in RCT and clinical practice. The aim of this article is to overview the results of the more recently reported published trials for CIDP, and to give some insights for the current and future management of CIDP.

[Severe cholestatic hepatitis revealing a DRESS syndrome]. / Hépatite cholestatique sévère révélant un Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome.

INTRODUCTION: Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a drug-induced hypersensitivity syndrome, characterized by rash, hyereosinophilia and multiorgan failure, including cytolytic hepatitis. CASE REPORT: A 75-year-old man, treated with amoxicillin/clavulanic acid, presented with jaundice and disabling pruritus associated with severe cholestatic hepatitis, related to a DRESS syndrome. Because of the persistence of cholestasis and the severity of pruritus, a treatment with corticosteroids and plasma exchanges was initiated, allowing a rapid and complete remission. CONCLUSION: Amoxicillin/clavulanic acid, although rarely described in the literature, is a rare cause of DRESS syndrome. Severe cholestatic hepatitis associated with disabling pruritus may be one of the systemic manifestations, with a good prognosis using corticosteroids and plasma exchanges.