Severe adult hemophagocytic lymphohistiocytosis (HLHa) correlates with HLH-related gene variants.

BACKGROUND: The contribution of genetic factors to the severity of adult hemophagocytic lymphohistiocytosis (HLHa) remains unclear. OBJECTIVE: We sought to assess a potential link between HLHa outcomes and HLH-related gene variants. METHODS: Clinical characteristics of 130 HLHa patients (age ≥ 18 years and HScore ≥ 169) and genotype of 8 HLH-related genes (LYST, PRF1, UNC13-D, STX11, STXBP2, RAB27A, XIAP, and SAP) were collected. A total of 34 variants found in only 6 genes were selected on the basis of their frequency and criteria predicted to impair protein function. Severity was defined by refractory disease to HLH treatment, death, or transfer to an intensive care unit. RESULTS: HLHa-associated diseases (ADs) were neoplasia (n = 49 [37.7%]), autoimmune/inflammatory disease (n = 33 [25.4%]), or idiopathic when no AD was identified (n = 48 [36.9%]). Infectious events occurred in 76 (58.5%) patients and were equally distributed in all ADs. Severe and refractory HLHa were observed in 80 (61.5%) and 64 (49.2%) patients, respectively. HScore, age, sex ratio, AD, and infectious events showed no significant association with HLHa severity. Variants were identified in 71 alleles and were present in 56 (43.1%) patients. They were distributed as follows: 44 (34.4%), 9 (6.9%), and 3 (2.3%) patients carrying 1, 2, and 3 variant alleles, respectively. In a logistic regression model, only the number of variants was significantly associated with HLHa severity (1 vs 0: 3.86 [1.73-9.14], P = .0008; 2-3 vs 0: 29.4 [3.62-3810], P = .0002) and refractoriness (1 vs 0: 2.47 [1.17-5.34], P = .018; 2-3 vs 0: 13.2 [2.91-126.8], P = .0003). CONCLUSIONS: HLH-related gene variants may be key components to the severity and refractoriness of HLHa.

Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double-blind randomised placebo-controlled trial.

OBJECTIVES: No immunomodulatory drug has been approved for primary Sjögren's syndrome, a systemic autoimmune disease affecting 0.1% of the population. To demonstrate the efficacy of targeting interleukin 6 receptor in patients with Sjögren's syndrome-related systemic complications. METHODS: Multicentre double-blind randomised placebo-controlled trial between 24 July 2013 and 16 July 2018, with a follow-up of 44 weeks, involving 17 referral centres. Inclusion criteria were primary Sjögren's syndrome according to American European Consensus Group criteria and score ≥5 for the EULAR Sjögren's Syndrome Disease activity Index (ESSDAI, score of systemic complications). Patients were randomised to receive either 6 monthly infusions of tocilizumab or placebo. The primary endpoint was response to treatment at week 24. Response to treatment was defined by the combination of (1) a decrease of at least 3 points in the ESSDAI, (2) no occurrence of moderate or severe activity in any new domain of the ESSDAI and (3) lack of worsening in physician's global assessment on a Visual Numeric Scale ≥1/10, all as compared with enrolment. RESULTS: 110 patients were randomised, 55 patients to tocilizumab (mean (SD) age: 50.9 (12.4) years; women: 98.2%) and 55 patients to placebo (54.8 (10.7) years; 90.9%). At 24 weeks, the proportion of patients meeting the primary endpoint was 52.7% (29/55) in the tocilizumab group and 63.6% (35/55) in the placebo group, for a difference of -11.4% (95% credible interval -30.6 to 9.0) (Pr[Toc >Pla]=0.14). CONCLUSION: Among patients with primary Sjögren's syndrome, the use of tocilizumab did not improve systemic involvement and symptoms over 24 weeks of treatment compared with placebo. TRIAL REGISTRATION NUMBER: NCT01782235.

Refining myositis associated with primary Sjögren's syndrome: data from the prospective cohort ASSESS.

OBJECTIVES: To refine the prevalence, characteristics and response to treatment of myositis in primary SS (pSS). METHODS: The multicentre prospective Assessment of Systemic Signs and Evolution in Sjögren's Syndrome (ASSESS) cohort of 395 pSS patients with ≥60 months' follow-up was screened by the 2017 EULAR/ACR criteria for myositis. Extra-muscular complications, disease activity and patient-reported scores were analysed. RESULTS: Before enrolment and during the 5-year follow-up, myositis was suspected in 38 pSS patients and confirmed in 4 [1.0% (95% CI: 0.40, 2.6)]. Patients with suspected but not confirmed myositis had higher patient-reported scores and more frequent articular and peripheral nervous involvement than others. By contrast, disease duration in patients with confirmed myositis was 3-fold longer than without myositis. Two of the four myositis patients fulfilled criteria for sporadic IBM. Despite receiving three or more lines of treatment, they showed no muscle improvement, which further supported the sporadic IBM diagnosis. The two other patients did not feature characteristics of a myositis subtype, which suggested 'pure' pSS myositis. Steroids plus MTX was then efficient in achieving remission. CONCLUSIONS: Myositis, frequently suspected, occurs in 1% of pSS patients. Especially when there is resistance to treatment, sporadic IBM should be considered and might be regarded as a late complication of this disease.

Thoracic aorta involvement in giant cell arteritis: a case-control analysis of morphological data at diagnosis.

OBJECTIVES: Giant cell arteritis (GCA) is a cause of potentially fatal aortic aneurysms. Descriptive data on thoracic aorta measurements at the beginning of the disease are lacking. We aimed to compare aortic diameters between a recently diagnosed GCA population and an age- and sex-matched control group. METHODS: Patients with GCA and with an available thoracic CT concomitant with diagnosis were included. Controls were patients matched for age and sex and hospitalised in the same care centre for pneumonia. The main criteria were the anteroposterior and lateral diameters of the ascending thoracic aorta, which were measured by a blinded evaluator. RESULTS: 90 cases and 90 controls were included. Each group comprised 30 males and 60 females for a mean age of 75.1±9 and 75.7±10.1 years old. At the time of GCA diagnosis no difference was found between the two groups (anteroposterior diameter 37.1±5 mm for cases vs. 36.7±5 mm for controls, p=0.6; lateral diameter 36.6±5 mm for cases vs. 35.9±4 mm for controls, p=0.3). Thoracic aorta diameter was not significantly higher in patients with aortitis at diagnosis (n=44) than in cases without aortitis (n=46). CONCLUSIONS: Morphologic comparison of thoracic aorta at diagnosis of GCA with an age- and sex-matched control population showed no significant difference. Morphologic evaluation of aorta cannot predict accurately the occurrence of aortic aneurysm. Systematic follow-up according to current recommendations is thus justified.

Is early-onset primary Sjögren's syndrome a worse prognosis form of the disease?

OBJECTIVES: Onset of primary SS is usually between 40 and 60 years of age, with severe systemic complications in 15% of cases. We sought to determine whether early-onset disease is related to a specific phenotype and if it is predictive of a poor outcome. METHODS: Biological and clinical data from 393 patients recruited in the ASSESS cohort, a French multicentre prospective cohort, were compared according to age at diagnosis. RESULTS: Fifty-five patients had early-onset disease, defined as age ⩽35 years at diagnosis, and presented a significantly higher frequency of salivary gland enlargement (47.2% vs 33.3%, P = 0.045), adenopathy (25.5% vs 11.8%, P = 0.006), purpura (23.6% vs 9.2%, P = 0.002) and renal involvement (16.4% vs 4.4%, P = 0.003). They had a higher frequency of hypergammaglobulinaemia (60.8% vs 26.6%, P < 0.001), RF positivity (41.5% vs 20.2%, P < 0.001), low C3 level (18.9% vs 9.1%, P = 0.032), low C4 level (54.7% vs 40.2%, P = 0.048) and autoantibodies [84.6% with anti-SSA vs 54.4% (P < 0.001) and 57.7% with anti-SSB vs 29.7% (P < 0.001)]. The change in ESSDAI scores between baseline and the 5-year follow-up was significantly different (P = 0.005) with a trend for worsening in the early-onset group (0.72, P = 0.27) and a significant improvement in the later onset group (-1.27, P < 0.0001). CONCLUSION: Early-onset primary SS is associated with a specific phenotype defined by clinical and biological features known to be predictive factors of severe systemic disease. Interestingly, we showed a different evolution of the ESSDAI score depending on the age at disease onset, patients with early-onset disease tending to worsen over time.

Long-term efficacy and safety of cladribine (2-CdA) in adult patients with mastocytosis.

Mastocytosis (M) is a clonal myeloid-disabling disorder for which no curative therapy is currently available. Cladribine (2-chlorodeoxyadenosine [2-CdA]) is a synthetic purine analog cytoreductive treatment, for which efficacy is mostly reported in advanced M. Here we report, with a long-term follow-up period (>10 years) efficacy and safety in 68 adult patients with M (36 [53%] had indolent M and 32 [47%] had advanced M) treated by 2-CdA (0.14 mg/kg in infusion or subcutaneously, days 1-5; repeated at 4-12 weeks until 1 to 9 courses). Median 2-CdA courses number was 3.7 (1-9). The overall response rate was 72% (complete remission [R]/major/partial R: 0%/47%/25%) and according to indolent/advanced M was 92% (major/partial R: 56%/36%) and 50% (major/partial R: 37.5%/12.5%), respectively. Clinical improvement was observed for 10 of 11 mediator release and 6 of 7 mast cell infiltration-related symptoms including urticaria pigmentosa and organomegaly (P < .02). Serum tryptase levels decreased (P = .01). Median durations of response were 3.71 (0.1-8) and 2.47 (0.5-8.6) years for indolent and aggressive M, respectively. The most frequent grade 3/4 toxicities were lymphopenia (82%), neutropenia (47%), and opportunistic infections (13%). 2-CdA appears to provide a significant efficacy with some toxicity in various M subtypes, mostly in indolent M, refractory to multiple symptomatic therapies.

Adalimumab for steroid sparing in patients with giant-cell arteritis: results of a multicentre randomised controlled trial.

OBJECTIVES: To evaluate the effect of adding a 10-week treatment of adalimumab to a standardised treatment with corticosteroids on the ability to taper more rapidly corticosteroid doses in patients with newly diagnosed giant cell arteritis (GCA). METHODS: Patients included in this double-blind, multicentre controlled trial were randomly assigned to receive a 10-week subcutaneous treatment of adalimumab 40 mg every other week or placebo in addition to a standard prednisone regimen (starting dose 0.7 mg/kg per day). The primary endpoint was the percentage of patients in remission on less than 0.1 mg/kg of prednisone at week 26. Analysis was performed by intention to treat (ITT). RESULTS: Among the 70 patients enrolled (adalimumab, n=34; placebo, n=36), 10 patients did not receive the scheduled treatment, seven in the adalimumab and three in the placebo group. By ITT, the number of patients achieving the primary endpoint was 20 (58.9%) and 18 (50.0%) in the adalimumab and placebo arm, respectively (p=0.46). The decrease in prednisone dose and the proportion of patients who were relapse free did not differ between the two groups. Serious adverse events occurred in five (14.7%) patients on adalimumab and 17 (47.2%) on placebo, including serious infections in three patients on adalimumab and five on placebo. Two patients died in the placebo arm (septic shock and cancer) and one in the adalimumab group (pneumonia). CONCLUSIONS: In patients with newly diagnosed GCA, adding a 10-week treatment of adalimumab to prednisone did not increase the number of patients in remission on less than 0.1 mg/kg of corticosteroids at 6 months. CLINICAL TRIAL REGISTRATION NUMBER: NCT00305539.

Effects of hydroxychloroquine on symptomatic improvement in primary Sjögren syndrome: the JOQUER randomized clinical trial.

IMPORTANCE: Primary Sjögren syndrome is a systemic autoimmune disease characterized by mouth and eye dryness, pain, and fatigue. Hydroxychloroquine is the most frequently prescribed immunosuppressant for the syndrome. However, evidence regarding its efficacy is limited. OBJECTIVE: To evaluate the efficacy of hydroxychloroquine for the main symptoms of primary Sjögren syndrome: dryness, pain, and fatigue. DESIGN, SETTING, AND PARTICIPANTS: From April 2008 to May 2011, 120 patients with primary Sjögren syndrome according to American-European Consensus Group Criteria from 15 university hospitals in France were randomized in a double-blind, parallel-group, placebo-controlled trial. Participants were assessed at baseline, week 12, week 24 (primary outcome), and week 48. The last follow-up date for the last patient was May 15, 2012. INTERVENTIONS: Patients were randomized (1:1) to receive hydroxychloroquine (400 mg/d) or placebo until week 24. All patients were prescribed hydroxychloroquine between weeks 24 and 48. MAIN OUTCOMES AND MEASURES: The primary end point was the proportion of patients with a 30% or greater reduction between weeks 0 and 24 in scores on 2 of 3 numeric analog scales (from 0 [best] to 10 [worst]) evaluating dryness, pain, and fatigue. RESULTS: At 24 weeks, the proportion of patients meeting the primary end point was 17.9% (10/56) in the hydroxychloroquine group and 17.2% (11/64) in the placebo group (odds ratio, 1.01; 95% CI, 0.37-2.78; P = .98). Between weeks 0 and 24, the mean (SD) numeric analog scale score for dryness changed from 6.38 (2.14) to 5.85 (2.57) in the placebo group and 6.53 (1.97) to 6.22 (1.87) in the hydroxychloroquine group. The mean (SD) numeric analog scale score for pain changed from 4.92 (2.94) to 5.08 (2.48) in the placebo group and 5.09 (3.06) to 4.59 (2.90) in the hydroxychloroquine group. The mean (SD) numeric analog scale for fatigue changed from 6.26 (2.27) to 5.72 (2.38) in the placebo group and 6.00 (2.52) to 5.94 (2.40) in the hydroxychloroquine group. All but 1 patient in the hydroxychloroquine group had detectable blood levels of the drug. Hydroxychloroquine had no efficacy in patients with anti-SSA autoantibodies, high IgG levels, or systemic involvement. During the first 24 weeks, there were 2 serious adverse events in the hydroxychloroquine group and 3 in the placebo group; in the last 24 weeks, there were 3 serious adverse events in the hydroxychloroquine group and 4 in the placebo group. CONCLUSIONS AND RELEVANCE: Among patients with primary Sjögren syndrome, the use of hydroxychloroquine compared with placebo did not improve symptoms during 24 weeks of treatment. Further studies are needed to evaluate longer-term outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00632866.

Identification of distinct subgroups of Sjögren's disease by cluster analysis based on clinical and biological manifestations: data from the cross-sectional Paris-Saclay and the prospective ASSESS cohorts.

BACKGROUND: Sjögren's disease is a heterogenous autoimmune disease with a wide range of symptoms-including dryness, fatigue, and pain-in addition to systemic manifestations and an increased risk of lymphoma. We aimed to identify distinct subgroups of the disease, using cluster analysis based on subjective symptoms and clinical and biological manifestations, and to compare the prognoses of patients in these subgroups. METHODS: This study included patients with Sjögren's disease from two independent cohorts in France: the cross-sectional Paris-Saclay cohort and the prospective Assessment of Systemic Signs and Evolution of Sjögren's Syndrome (ASSESS) cohort. We first used an unsupervised multiple correspondence analysis to identify clusters within the Paris-Saclay cohort using 26 variables comprising patient-reported symptoms and clinical and biological manifestations. Next, we validated these clusters using patients from the ASSESS cohort. Changes in disease activity (measured by the European Alliance of Associations for Rheumatology [EULAR] Sjögren's Syndrome Disease Activity Index [ESSDAI]), patient-acceptable symptom state (measured by the EULAR Sjögren's Syndrome Patient Reported Index [ESSPRI]), and lymphoma incidence during follow-up were compared between clusters. Finally, we compared our clusters with the symptom-based subgroups previously described by Tarn and colleagues. FINDINGS: 534 patients from the Paris-Saclay cohort (502 [94%] women, 32 [6%] men, median age 54 years [IQR 43-64]), recruited between 1999 and 2022, and 395 patients from the ASSESS cohort (370 [94%] women, 25 [6%] men, median age 53 years [43-63]), recruited between 2006 and 2009, were included in this study. In both cohorts, hierarchical cluster analysis revealed three distinct subgroups of patients: those with B-cell active disease and low symptom burden (BALS), those with high systemic disease activity (HSA), and those with low systemic disease activity and high symptom burden (LSAHS). During follow-up in the ASSESS cohort, disease activity and symptom states worsened for patients in the BALS cluster (67 [36%] of 186 patients with ESSPRI score <5 at month 60 vs 92 [49%] of 186 at inclusion; p<0·0001). Lymphomas occurred in patients in the BALS cluster (five [3%] of 186 patients; diagnosed a median of 70 months [IQR 42-104] after inclusion) and the HSA cluster (six [4%] of 158 patients; diagnosed 23 months [13-83] after inclusion). All patients from the Paris-Saclay cohort with a history of lymphoma were in the BALS and HSA clusters. This unsupervised clustering classification based on symptoms and clinical and biological manifestations did not correlate with a previous classification based on symptoms only. INTERPRETATION: On the basis of symptoms and clinical and biological manifestations, we identified three distinct subgroups of patients with Sjögren's disease with different prognoses. Our results suggest that these subgroups represent different heterogeneous pathophysiological disease mechanisms, stages of disease, or both. These findings could be of interest when stratifying patients in future therapeutic trials. FUNDING: Fondation pour la Recherche Médicale, French Ministry of Health, French Society of Rheumatology, Innovative Medicines Initiative 2 Joint Undertaking, Medical Research Council UK, and Foundation for Research in Rheumatology.

Characterisation of airway disease associated with Sjögren disease.

OBJECTIVE: Although airway disease associated with Sjögren's disease (Sjo-AD) is common, it is poorly studied compared with interstitial lung disease (ILD). In this study, we aimed to assess factors associated with Sjo-AD, the characteristics and prognosis of this manifestation. METHODS: We performed a retrospective multicentric study involving nine centres. We included Sjo-AD patients confirmed by at least one clinician and one CT scan report. Clinical and biological data, pulmonary function test (PFT), and CT scans were collected. A single radiologist specialist in thoracic diseases reviewed CT scans. Sjo-AD patients were compared with Sjo controls without pulmonary involvement, randomly selected after matching for age and disease duration. RESULTS: We included 31 Sjo-AD and 62 Sjo controls without pulmonary history. Sjo-AD had a higher disease activity (ESSDAI) compared with controls, even when excluding the pulmonary domain of the score (7 vs 3.8, p<0.05), mainly due to the biological activity. Sjo-AD was multilobar (72%) and associated with signs of both bronchiectasis and bronchiolitis (60%). Obstructive lung disease occurred in 32% at the time of Sjo-AD diagnosis. Overall, PFT was stable after 8.7±7 years follow-up but repeated CT scans showed extended lesions in 41% of cases within 6±3.2 years. No patient developed Sjo-ILD. Sjo-AD progression was independent of the global disease activity. CONCLUSIONS: Sjo-AD preferentially affects Sjo patients with higher biological activity. It is often characterised as a diffuse disease, affecting both proximal and distal airways, with a slow evolution over time and no progression to Sjo-ILD.

Thalidomide in systemic mastocytosis: results from an open-label, multicentre, phase II study.

Mastocytosis can lead to organ failure as well as systemic symptoms that can be disabling, with considerable deterioration in quality of life. Beside symptomatic treatments, interferon-α and purine analogues have been shown to be effective but complete or long-term remission is rarely obtained with these drugs. We conducted a phase II, multicentre, study to investigate thalidomide in severely symptomatic indolent and aggressive systemic mastocytosis. Twenty patients were enrolled of whom 16 were analysed for response. The overall response rate was 56%. Responses were observed in the skin in 61% of patients with a significant decrease in the pruritus score. Mast cell mediator-related symptoms responded in 71% of cases and 25% of aggressive systemic mastocytosis patients had a response in terms of B/C findings (borderline/cytoreduction needed). Bone marrow mast cell infiltration decreased in five of the eight evaluable patients. There was no significant improvement in the AFIRMM (Association Française pour les Initiatives de Recherche sur le Mastocyte et Les Mastocytoses), Quality of Life or Hamilton scores. Grade 3-4 toxicities consisted of peripheral neuropathy (11%) and myelosuppression (neutropenia: 5%; thrombocytopenia: 11%). In conclusion, thalidomide might be useful in mastocytosis and in the treatment of mast cell-related symptoms. It might be considered in selected patients, taking into account the benefit/risk balance and the individual patient evaluation.

Efficacy of rituximab in systemic manifestations of primary Sjogren's syndrome: results in 78 patients of the AutoImmune and Rituximab registry.

OBJECTIVES: To evaluate the efficacy and safety of rituximab in patients with primary Sjögren's syndrome (pSS). METHODS: The AutoImmune and Rituximab registry has included 86 patients with pSS treated with rituximab, prospectivey followed up every 6 months for 5 years. RESULTS: Seventy-eight patients with pSS (11 men, 67 women), who already had at least one follow-up visit, were analysed. Median age was 59.8 years (29-83), median duration of disease was 11.9 years (3-32). Indications for treatment were systemic involvement for 74 patients and only severe glandular involvement in four patients. The median European Sjögren's Syndrome disease activity index (ESSDAI) was 11 (2-31). 17 patients were concomitantly treated with another immunosuppressant agent. Median follow-up was 34.9 months (6-81.4) (226 patient-years). Overall efficacy according to the treating physician was observed in 47 patients (60%) after the first cycle of rituximab. Median ESSDAI decreased from 11 (2-31) to 7.5 (0-26) (p<0.0001). Median dosage of corticosteroid decreased from 17.6 mg/day (3-60) to 10.8 mg/day (p=0.1). Forty-one patients were retreated with rituximab. Four infusion reactions and one delayed serum sickness-like disease resulted in rituximab discontinuation. Three serious infections (1.3/100 patient-years) and two cancer-related deaths occurred. CONCLUSIONS: In common practice, the use of rituximab in pSS is mostly restricted to patients with systemic involvement. This prospective study shows good efficacy and tolerance of rituximab in patients with pSS and systemic involvement.

Association Between Bruton's Tyrosine Kinase Gene Overexpression and Risk of Lymphoma in Primary Sjögren's Syndrome.

OBJECTIVE: We undertook this study to analyze whole blood gene expression and to investigate the role of B cell genes in primary Sjögren's syndrome-related non-Hodgkin lymphoma (primary SS-NHL). METHODS: Peripheral whole blood samples were collected from 345 well-phenotyped patients with primary SS enrolled in the prospective Assessment of Systemic Signs and Evolution in Sjögren's Syndrome (ASSESS) cohort. Transcriptomic analysis was performed using human Clariom S Arrays (Affymetrix). In our primary analysis, we considered patients with incident lymphoma (i-primary SS-NHL) as the case group and all patients without lymphoma as the comparison group. In our sensitivity analyses, we considered all patients with primary SS-NHL, including those with a history of lymphoma (h-primary SS-NHL), as the case group and primary SS patients without lymphoma, stratified on their risk factors of lymphoma, as the comparison group. RESULTS: Twenty-one patients with primary SS-NHL (including 8 with i-primary SS-NHL and 13 h-primary SS-NHL) were eligible for transcriptomic analysis; we compared these patients to 324 primary SS controls without lymphoma, including 110 with moderate to severe disease activity and 61 with no risk factor of lymphoma. Functional clustering analyses revealed an enrichment of genes related to innate and adaptive immunity, including B cell-related genes. Bruton's tyrosine kinase (BTK) and a proliferation-inducing ligand (APRIL) genes were overexpressed before the occurrence of lymphoma in patients with incident lymphoma compared with patients without lymphoma. In sensitivity analyses, BTK was consistently up-regulated across all comparisons performed. BTK expression was associated with risk of lymphoma on multivariate analyses, which considered 9 validated predictors of lymphoma in primary SS. CONCLUSION: BTK and APRIL were overexpressed in the peripheral blood of primary SS patients prior to lymphoma. The association between BTK, APRIL, and primary SS-NHL requires confirmation in other prospective cohorts.

Rituximab in central nervous system manifestations of patients with primary Sjögren's syndrome: results from the AIR registry.

OBJECTIVES: To evaluate the efficacy of rituximab in central nervous system (CNS) manifestations of patients with primary Sjögren's syndrome (pSS). METHODS: Prospective data from patients with pSS and CNS involvement included in the French AutoImmunity and Rituximab registry were analysed. All patients had diffuse white matter T2-weigted hypersignals. Neurological response was defined as improvement or disappearance of neurological signs. RESULTS: Eleven patients (mean age 55 years [38-77]) were treated with rituximab for their neurological involvement. The mean duration of pSS was 9 years (4-24). Mean baseline ESSDAI score was 17 (5-25). Neurological features were progressive multiple sclerosis-like manifestations (n=6), transverse myelitis (n=1), anxiety and depression disorder (n=1) and cognitive dysfunction (n=3). Mean Expanded Disability Status Score (EDSS) before rituximab was 4 (3-5.5). The mean follow-up was of 13 months (6-58). No neurological change occurred in all 6 patients with multiple sclerosis-like symptoms, in 2/3 patients with cognitive dysfunction or in the patient with anxiety-depression. One patient with depression and cognitive dysfunction disclosed subjective improvement. One patient with transverse myelitis, refractory to cyclophosphamide had an improvement of his walk perimeter (160 meters vs. 116). Mean EDSS score and ESSDAI remained stable. CONCLUSIONS: Rituximab does not seem to be effective in progressive multiple sclerosis-like manifestations of patients with pSS-related CNS involvement.

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.

Efficacy and safety of rituximab in common variable immunodeficiency-associated immune cytopenias: a retrospective multicentre study on 33 patients.

Patients with common variable immunodeficiency (CVID) are at high risk of developing immune thrombocytopenia (ITP) and/or autoimmune haemolytic anaemia (AHA). Given their underlying immunodeficiency, immunosuppressive treatment of these manifestations may increase the risk of infection. To assess efficacy and safety of rituximab in patients with CVID-associated ITP/AHA, a multicentre retrospective study was performed. Thirty-three patients, 29 adults and four children, were included. Patients received an average of 2·6 treatments prior to rituximab including steroids, intravenous immunoglobulin and splenectomy (21%). The median ITP/AHA duration at time of first rituximab administration was 12 months [range 1-324] and the indication for using rituximab was ITP (22 cases), AHA (n = 5) or both (n = 7); 1 patient was treated sequentially for ITP and then AHA. The overall initial response rate to rituximab was 85% including 74% complete responses. After a mean follow-up of 39 ± 30 months after rituximab first administration, 10 of the initial responders relapsed and re-treatment with rituximab was successful in 7/9. Severe infections occurred after rituximab in eight adults (24%), four of whom were not on immunoglobulin replacement therapy. In conclusion, rituximab appears to be highly effective and relatively safe for the management of CVID-associated severe immune cytopenias.

Efficacy and safety of rituximab in the treatment of refractory inflammatory myopathies in adults: results from the AIR registry.

OBJECTIVES: To assess the efficacy and safety of rituximab (RTX) in patients with refractory idiopathic inflammatory myopathies (IIMs). METHODS: RTX efficacy was based on improvement in three criteria: creatine phosphokinase (CPK) level, daily CS dose and physicians' opinion. A decrease in CPK level or CS dose was significant if it was >25%. RESULTS: Thirty patients were studied (21 women; age 52.5 years, disease duration 6.1 years). All had previously received immunosuppressors (ISs). Twenty-five patients received 1 g of RTX twice 2 weeks apart and five received 4 weekly RTX infusions (375 mg/m(2)). RTX was given in association with IS in 21 patients. Twenty-eight patients received CS (mean dose 21.2 mg/day). Mean follow-up was 17.2 months. Thirteen adverse events were reported, including seven infections and one serious infection (pyelonephritis). RTX was effective in 16 patients. Duration of efficacy was 15.5 months. Of the 20 patients with baseline CPK level ≥2 × upper limit of normal (ULN), 11 (55%) improved. The main level fell from 20.7 to 11 × ULN. CS decreased in 15 patients, stopped in 4, remained stable in 8 and increased in the remaining 3. The CS dose decreased from 21.2 to 9.9 mg/day. The physicians' opinion was favourable in 21 patients. Manual muscle testing was performed in only five patients: it increased from 87 to 91/100 at 6 months. CONCLUSIONS: RTX was well tolerated and had some beneficial effects on patients with IIM, the main limitation of this study resulted in a lack of manual muscle testing.

Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and Rituximab registry.

OBJECTIVE: A number of open-label studies have suggested the potential benefit of rituximab (RTX) in systemic lupus erythematosus (SLE). However, in 2 recent randomized controlled trials (RCTs) of RTX, the primary end points were not met. We undertook this study to evaluate the safety and efficacy of RTX in off-trial patients with SLE seen in regular clinical practice. METHODS: We analyzed prospective data from the French AutoImmunity and Rituximab (AIR) registry, which includes data on patients with autoimmune disorders treated with RTX. RESULTS: One hundred thirty-six patients received treatment for SLE. The mean +/- SD score on the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI) was 11.3 +/- 8.9 at baseline. Severe infections were noted in 12 patients (9%), corresponding to a rate of 6.6/100 patient-years. Most severe infections occurred within the first 3 months after the last RTX infusion. Five patients died, due to severe infection (n = 3) or refractory autoimmune disease (n = 2). Overall response was observed in 80 of 113 patients (71%) by the SELENA-SLEDAI assessment. Efficacy did not differ significantly between patients receiving RTX monotherapy and those receiving concomitant immunosuppressive agents (who had higher baseline disease activity). Articular, cutaneous, renal, and hematologic improvements were noted in 72%, 70%, 74%, and 88% of patients, respectively. Among responders, 41% experienced a relapse of disease, with a response in 91% after retreatment with RTX. CONCLUSION: Data from the AIR registry show a satisfactory tolerance profile and clinical efficacy of RTX in patients with SLE. The contrasting results with those from recent RCTs leave open the question of the therapeutic use of RTX in SLE. Additional controlled studies with new designs are needed to define the place of RTX in the therapeutic arsenal for SLE.