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Objective: B‐cell depletion using the anti‐CD20 monoclonal antibody rituximab is a cornerstone in the therapeutic concept of multiple autoimmune diseases. B‐cell depletion is associated with a higher risk for severe infections, and the time span of B‐cell repopulation differs greatly between individuals. Data on factors influencing B‐cell repopulation kinetics are limited. This study aims to identify patient‐specific and therapy‐associated covariates that modulate B‐cell repopulation. Methods: This single‐center retrospective observational study presents data of 839 subjects receiving 2,017 courses of rituximab for autoimmune diseases. Assessed covariates are patient‐specific factors (sex, age, kidney function, and underlying disease) and co‐immunosuppression with common agents (azathioprine, cyclosporine A, cyclophosphamide, hydroxychloroquine, methotrexate, mycophenolate mofetil, tacrolimus, and corticosteroids). The primary end point is the time to B‐cell repopulation (≥5/μl). The secondary end point is the time to B‐cell reconstitution (≥50/μl). Multivariate time‐to‐event analysis and logistic regression models were applied to estimate the influence of covariates. Results: Age over 60 years (hazard ratio [HR] 0.71 for repopulation, P = 0.008), impaired kidney function (HR 0.72, P = 0.001), antineutrophil cytoplasmic antibody‐associated vasculitis (HR 0.61, P < 0.001), solid organ transplantation (HR 0.4, P < 0.001), and co‐immunosuppression with corticosteroids (HR 0.64, P < 0.001) or azathioprine (HR 0.49, P < 0.001) were associated with impaired B‐cell repopulation and reconstitution. Effects of corticosteroids (P = 0.043) and azathioprine (P = 0.025) were dose dependent. Conclusion: Prolonged rituximab dosing intervals may be effective to achieve B‐cell depletion and reduce risk of infection in advanced age or patients with impaired kidney function. Co‐medication with corticosteroids or azathioprine prolongs B‐cell recovery, which may increase therapeutic effects but also the rate of adverse events. [ABSTRACT FROM AUTHOR]

The article discusses review of three trials describing the use of combination therapy with rituximab (RTX) and belimumab in lupus nephritis (LN) and non-renal lupus. Topics covered include the differences in the design of the trials, the characteristics of their study population, and the endpoints and outcomes of the three trials.

To streamline drug development, the United States Food and Drug Administration (FDA) can consider the extrapolation of adult efficacy data to children when the disease and drug effects are sufficiently similar. This study explored whether the relationship between drug exposure and response for selected drugs in systemic lupus erythematosus (SLE) was sufficiently similar to support a consideration of the extrapolation of adult efficacy data to children of ≥5 years of age. An exposure–response analysis of drugs used to treat SLE was conducted using published exposure versus response and efficacy versus time data. Statistical analyses included noncompartmental analysis of a drug's area under the effect curve and direct Imax pharmacodynamic (PD) modeling. Six drugs were included: azathioprine, belimumab, cyclophosphamide, hydroxychloroquine, mycophenolate/mycophenolic acid, and rituximab. For belimumab, the net change in responders at week 52 (the primary end point) was nearly identical between 1 adult trial and the pediatric trial. For mycophenolate, PD modeling suggested no significant differences in exposure and SLE disease activity between adults and children. For azathioprine, cyclophosphamide, hydroxychloroquine, and rituximab the data were not sufficient to quantitatively characterize the exposure–response relationship, but the clinical or pharmacologic response between children and adults was similar overall. Adult SLE data should be leveraged to guide pediatric drug development programs and identify areas with residual uncertainty regarding the effectiveness or safety of a drug in children. The degree to which efficacy extrapolation can reduce clinical trial requirements in pediatric SLE should be individualized for each new drug product, depending in part on the mechanism of action of the drug and the similarity of disease manifestations in children and adults. [ABSTRACT FROM AUTHOR]

The article comments on the ADVOCATE randomized trial which compared the C5a inhibitor avacopan and placebo in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Topics discussed include induction therapy with cyclophosphamide followed by azathioprine as maintenance therapy or rituximab with no maintenance therapy, the primary end point of the treatment and the difficulty in interpreting outcomes due to inadequate maintenance therapy.

Background: This retrospective study was to understand the clinico-epidemiologic and therapeutic aspects of pemphigus patients attending our clinic. Methods: We analyzed charts of 143 (M: F; 51:92) pemphigus patients having variable severity recorded between 2009 and 2019. Therapies were customized based on patient's age, disease severity, comorbidities, compliance prospects, and affordability. The patients were monitored monthly and as needed for therapeutic outcome in terms of disease control, reduced hospitalization, remission/relapse, and drug toxicity. Results: These patients were aged 15 to 86 years, the majority, 68 (47.5%), was 41 to 60 years of age. The pemphigus vulgaris in 83.9% patients was the commonest variant. Treatment regimens were; dexamethasone-cyclophosphamide-pulse (DCP) therapy in 51.2%, dexamethasone-azathioprine-pulse (DAP) therapy in 11%, dexamethasone-pulse (DP) therapy in 5.5%, rituximab in 24.4%, IVIg in 5.5% patients, and oral corticosteroids with or without adjuvant. Remission occurred after 2–17 (mean 5.8) DCP doses; 14 and 7 patients achieved remission for ≥2 y and ≥5 y, respectively. Rituximab was effective to treat both new and relapsed cases (n = 31). Additional treatment with another adjuvant prolonged remission in seven patients relapsed 12–16 months after treatment with rituximab alone. Overall, oral corticosteroids alone and DAP therapy showed unsatisfactory response. Adverse effects seen in 41.9% of patients were mainly corticosteroids related. Conclusion: The overall clinico-epidemiologic spectrum of pemphigus and therapeutic efficacy of DCP, DAP, or corticosteroids in this study was in sync with the literature. Combining rituximab and corticosteroids plus an immunomodulator initially (phase-1), followed by immunomodulator alone for one year (phase-2) will improve long-term (phase-3) therapeutic outcome. IVIg was effectively useful in patients with concurrent infections. [ABSTRACT FROM AUTHOR]

Purpose of the Study. Antineutrophil cytoplasmic antibody- (ANCA-) associated vasculitis (AAV) is a rare multisystem autoimmune condition with an incidence of 0.4-24 per 1 million person-years. (e severity of renal involvement predicts prognosis. Limited data are available on its management and outcomes; thus, we aim to assess this at our tertiary-care renal facility. Study Design. Retrospective data were collected using our national renal electronic database (eMED) to identify AAV patients over a period of 6 years. Outcomes included progression to end-stage renal disease (ESRD) or death, chronic kidney disease (CKD), and preservation of renal function. Results. (irty-six patients were included in the final study. Cyclophosphamide was used in 24 patients (66.7%) and, comparatively, rituximab in 7 patients (19.4%) for induction. Seven patients (19.4%) had a documented relapse, and six patients (85.7%) had rituximab as induction therapy for relapse. (e majority of patients were on azathioprine (61.1%, 57.1% relapse population) as maintenance therapy. Progression to ESRD occurred in 11 (30.6%), death in 4 (11.1%), established CKD in 15 (41.7%), and preservation of renal function in 6 (16.7%) patients by the end of the follow-up period. Conclusions. While cyclophosphamide remains the choice of induction immunosuppression therapy, we favour rituximab as an induction agent in the relapse of AAV. Despite aggressive immunosuppression therapy, the incidence of ESRD and death remains high in these patients. [ABSTRACT FROM AUTHOR]

The article presents a rare case of a 74-year-old Caucasian man with a history of genetically confirmed facio-scapulo-humeral muscular dystrophy type-1 (FSHD1) diagnosed at the age of 54 years. Topics discussed include findings on physical examination, characteristics of FSHD, and patient's characteristics that led to the anti-synthetase syndrome (ASS) diagnosis.

Objectives To compare the treatment approaches and disease outcomes of children with JDM followed in two European tertiary care peadiatric rheumatology centres. Methods The medical notes of patients with JDM seen at Istituto Giannina Gaslini (IGG) of Genoa, Italy or Great Ormond Street Hospital (GOSH) of London, UK between January 2000 and December 2015 within 6 months after disease onset and followed for at least 6 months were reviewed. Demographic, clinical and therapeutic data were collected. At each visit, the caring physician was asked to rate the disease state subjectively. Results A total of 127 patients were included, 88 at GOSH and 39 at IGG. At 24 months, the median values of muscle strength and disease activity were at the normal end of the scale and around three quarters of patients were said to have inactive disease. Also, at 2 years, 38.6% and 36% of British and Italian patients, respectively, had damage. Cyclophosphamide, azathioprine, infliximab, rituximab and mycophenolate mofetil were used more frequently by UK physicians, whereas ciclosporin, intravenous immunoglobulin and hydroxychloroquine were prescribed by Italian physicians. Conclusion This study shows a significant difference in the choice of medications between pediatric rheumatologists practising in the two centres. Despite this, a high proportion of patients had inactive disease at 2 years and there was a low frequency of damage: modern treatments have improved outcomes. [ABSTRACT FROM AUTHOR]

The antineutrophil cytoplasmic antibody (ANCA) vasculitides include several closely related, often severe, multisystem autoimmune diseases characterized by antibodies against serine proteinase 3 or myeloperoxidase. Loss of tolerance to these antigens triggers a cascade of events, beginning with the priming of neutrophils by proinflammatory cytokines and complement activation, translocation of ANCA-specific antigens to the plasma membrane, neutrophil hyperactivation, and further activation of the alternative complement pathway, leading to tissue damage and the clinical manifestations of ANCA vasculitis. Due to the heterogeneity in presentation of these diseases, diagnosis is often substantially delayed, leading to poor outcomes. The current treatment pathway for most patients involves induction with cyclophosphamide or rituximab in combination with glucocorticoids, followed by a maintenance phase with rituximab, azathioprine, or methotrexate, during which time glucocorticoids are tapered. Current therapies are often effective in inducing and maintaining remission but are associated with a range of toxicities. Several new therapies are in development for ANCA vasculitis. Avacopan, an orally administered inhibitor of the complement fragment 5a (C5a) receptor, has been assessed in a phase 3 clinical trial and may play a role in reducing the cumulative glucocorticoid dose. Preliminary data suggest that cluster of differentiation (CD) 80 and CD86 blockade with abatacept may also have a role in the management of ANCA vasculitis. There is an unmet need for additional therapeutic options for patients with these diseases. [ABSTRACT FROM AUTHOR]

Drug survival reflects the real-life efficacy and safety of therapeutic agents. Evidence regarding the durability of adjuvant agents in the treatment of pemphigus is sparse. The aims of this study were to investigate the survival of adjuvant agents used to manage patients with pemphigus, and to identify predictors of treatment dropout. A retrospective population-based cohort study was designed to follow patients with pemphigus managed by adjuvant agents. The study population included 436 patients with pemphigus managed by 608 adjuvant agent courses. The highest median drug survival time was observed for rituximab (43.6 months, 95% confidence interval (95% CI) 5.3-81.9), followed by cyclophosphamide (30.5 months; 95% CI 10.5-50.5), azathioprine (22.9 months; 95% CI 15.6-30.2), and mycophenolate mofetil (20.2 months; 95% CI 10.0-30.4). Compared with azathioprine, cyclosporine (adjusted hazard ratio 2.98; 95% CI 1.57-5.62; p = 0.005) and dapsone (adjusted hazard ratio 1.83; 95% CI 1.07-3.15; p = 0.027) were associated with a significantly increased risk of drug discontinuation. To conclude, rituximab, azathioprine, and mycophenolate mofetil demonstrated better durability, whilst dapsone and cyclosporine were associated with low drug survival and high dropout. [ABSTRACT FROM AUTHOR]

The article describes the case of refractory antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in a 41-year-old White male. Topics discussed include the medical history of the patient such as epistaxis, breathlessness, arthralgia, skin blisters, tingling of the left arm and weight loss, use of warfarin to address his cardiac thrombus and optimization of his cardiac secondary prevention therapy, and maintenance medicine recommended for the patient such as oral prednisolone.

Introduction: Rituximab is effective and safe treatment of immunobullous disorders. There are variations in doses of drugs used in different studies and uncertainties on when to use it along with use of adjuvant therapies. Efficacy and safety of this drug has not been described in Nepalese population till date. Dermatologists have hesitation in starting this drug in immunobullous diseases because of lack of data on efficacy and safety. Aim: To assess the efficacy and side effects of Rituximab therapy in treating immunobullous disorders in Nepalese patients. Materials and Methods: This was a retrospective study of patients with immunobullous diseases treated with Rituximab in Dermatological ward of Tribhuvan University Teaching Hospital, Kathmandu, Nepal from May 2018 to August 2019. Data were analysed for duration of disease and treatment received before Rituximab therapy, duration of steroid used before Rituximab, adverse effects due to prolonged steroid use, time to remission from 1st Rituximab pulse, duration of remission, relapse, duration of steroid and adjuvant drug used post 1st pulse and adverse effects associated with Rituximab. SPSS version 20 was used for data entry and descriptive statistics was used for analysis of the data. Results: Nine patients (Pemphigus Vulgaris-8 (PV-8), Bullous Pemphigoid-1 (BP-1) were treated with Rituximab. Seven were treated for refractory disease not controlled by conventional therapy and two received Rituximab as first-line therapy. The patients were under follow-up for 15-60 weeks (mean 31.89±15.62 weeks). Out of these nine patients, eight were free of lesions in one to eight weeks (mean 5.125±2 weeks) of first pulse. One patient with Oral Pemphigus had persistence of old lesions, however there were no new cutaneous lesions after first pulse. Adverse effects were seen in four patients that included infusion reaction in one and infection in three. There was relapse in one patient at last follow-up. Conclusion: Rituximab is efficacious and is safe in treating immunobullous disorders in Nepalese Population. [ABSTRACT FROM AUTHOR]

Objective: Patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) have an elevated risk of cardiovascular disease (CVD). This study was undertaken to develop a clearer understanding of the association between changes in disease activity and lipid levels in AAV, which may inform CVD risk stratification in this population. Methods: Lipid levels were assessed in stored serum samples (obtained at baseline and month 6) from the Rituximab for ANCA‐Associated Vasculitis (RAVE) trial, which randomized patients to receive either rituximab or cyclophosphamide followed by azathioprine. Paired t‐tests and multivariable linear regression were used to assess changes in lipid levels. Results: Of the 142 patients with serum samples available, the mean ± SD age was 52.3 ± 14.7 years, 72 (51%) were male, 95 (67%) were proteinase 3 (PR3)–ANCA positive, 72 (51%) had received a new diagnosis of AAV, and 75 (53%) were treated with rituximab. Several lipid levels increased between baseline and month 6, including total cholesterol (+12.4 mg/dl [95% confidence interval (95% CI) +7.1, +21.0]), low‐density lipoprotein (+10.3 mg/dl [95% CI +6.1, +17.1]), and apolipoprotein B (+3.5 mg/dl [95% CI +1.0, +8.3]). These changes were observed among newly diagnosed and PR3‐ANCA–positive patients but not among those with relapsing disease or myeloperoxidase‐ANCA–positive patients. There was no difference in change in lipid levels between rituximab‐treated patients and cyclophosphamide‐treated patients. Changes in lipid levels correlated with changes in erythrocyte sedimentation rate but not with other inflammatory markers or glucocorticoid exposure. Conclusion: Lipid levels increased during remission induction among patients with newly diagnosed AAV and those who were PR3‐ANCA positive. Disease activity and ANCA type should be considered when assessing lipid profiles to stratify CVD risk in patients with AAV. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the safety and efficacy of belimumab as adjunctive therapy to maintain remission in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). Methods: In this multicenter, double‐blind, placebo‐controlled study, patients with AAV (ages ≥18 years) were randomized 1:1 to receive azathioprine (2 mg/kg/day), low‐dose oral glucocorticoids (≤10 mg/day), and either intravenous belimumab (10 mg/kg) or placebo, following remission induction with rituximab or cyclophosphamide along with glucocorticoids. The primary end point was time to first protocol‐specified event (PSE), with first PSE defined as a Birmingham Vasculitis Activity Score (BVAS) of ≥6, presence of ≥1 major BVAS item, or receipt of prohibited medications for any reason, resulting in treatment failure (adjusted for ANCA type [proteinase 3 (PR3) or myeloperoxidase (MPO)], disease stage at induction, and induction regimen). Vasculitis relapse was defined as the PSE of either a BVAS activity score of ≥6 or receipt of prohibited medications for vasculitis. Changes in treatment practice led to truncation of the study population from ~300 patients to ~100 patients. Results: The intent‐to‐treat population totaled 105 patients with AAV, of whom 52 (40 with PR3‐ANCAs, 12 with MPO‐ANCAs) received placebo and 53 (41 with PR3‐ANCAs, 12 with MPO‐ANCAs) received belimumab; 27 of the patients were in rituximab‐induced disease remission, while 78 were in cyclophosphamide‐induced disease remission at baseline. Compared with placebo, treatment with belimumab did not reduce the risk of a PSE (adjusted hazard ratio [HR] 1.07, 95% confidence interval [95% CI] 0.44–2.59; P = 0.884) or vasculitis relapse (adjusted HR 0.88, 95% CI 0.29–2.65; P = 0.821). The overall rate of PSEs was low (11 [21.2%] of 52 patients receiving placebo, 10 [18.9%] of 53 patients receiving belimumab). Vasculitis relapse in the placebo group (n = 8) occurred independent of the induction regimen, disease stage, or ANCA type. All vasculitis relapses in the belimumab group (n = 6) occurred in patients who had PR3‐ANCA–associated vasculitis with cyclophosphamide‐induced disease remission. Adverse events occurred in 49 (92.5%) of 53 patients receiving belimumab and 43 (82.7%) of 52 patients receiving placebo, with no new safety concerns. Conclusion: Belimumab plus azathioprine and glucocorticoids for the maintenance of remission in AAV did not reduce the risk of relapse. [ABSTRACT FROM AUTHOR]

Introduction: Neuromyelitis optica is a spectrum of autoimmune, inlammatory and demyelinating disorders of the central nervous system. It is recommended to institute immunosuppressive therapy after the irst attack as a preventive relapse treatment. Objective: Analyze the clinical response to treatment measured by the annualized relapse rate and progression of disability with EDSS (Expanded Disability Status Scale), as well as clinical and demographic variables in subjects with NMO in the population of a reference hospital. Material and methods: An observational, retrospective, cross-sectional and descriptive study was conducted. Clinical and demographic variables were obtained from the clinical record; as well as the EDSS relapse index and disability score of patients who have received at least one year of immunosuppressant treatment as a preventive relapse treatment, from January 2010 to June 2017. Results: 60 patients were included. With an average age at diagnosis of 38.2 years, 88.3% female and 11.7% male. 13 patients received treatment with azathioprine, 19 with cyclophosphamide and 28 with rituximab. The azatioprina group presented a relapse index of 1.2 and EDSS of 4, in the cyclophosphamide of 1.6 with EDSS of 2.8, and in that of rituximab of 1 with EDSS of 2.8. Conclusions: Patients diagnosed with optic neuromyelitis with IgG + in immunosuppressive treatment preventive relapse, present significantly higher response to treatment with rituximab, demonstrated by a lower rate of relapse and lower EDSS. [ABSTRACT FROM AUTHOR]

Neuromyelitis optica (NMO) is an inflammatory and demyelinating disease of the central nervous system. Although the prevalence of NMO is low, the rapid and severe impairment observed in patients has led to extensive development of research in the fields of diagnostic criteria and therapy in the past 15 years. With improved understanding of the pathophysiology of NMO and the role of aquaporin-4 (AQP4) or myelin oligodendrocyte glycoprotein antibodies, numerous therapeutic approaches have been proposed and are currently undergoing evaluation. In this review, we describe the rationale for existing therapeutics and their benefit/risk ratio. We also discuss the pharmacological and clinical interest of future approaches targeting, among others, B or T cells, the blood-central nervous system barrier, complement, polynuclear cells, AQP4-antibody linkage and AQP4 activity. The numerous agents under development are the result of a major collaborative effort all over the world. After the considerable progress on diagnosis, we are now close to class I evidence for a therapeutic effect of several drugs in NMO spectrum disorders, most notably with the anti-interleukin-6 receptor antibody (satralizumab) and anti-complement-5 antibody (eculizumab). [ABSTRACT FROM AUTHOR]

Objective S100A8/A9 (calprotectin) has shown promise as a biomarker for predicting relapse in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This study was undertaken to investigate serum S100A8/A9 level as a biomarker for predicting future relapse in a large cohort of patients with severe AAV. Methods Serum levels of S100A8/A9 were measured at baseline and months 1, 2, and 6 following treatment initiation in 144 patients in the Rituximab in ANCA-Associated Vasculitis trial (cyclophosphamide/azathioprine versus rituximab [RTX] for induction of remission) in whom complete remission was attained. Results Patients were divided into 4 groups: proteinase 3 (PR3)-ANCA with relapse (n = 37), PR3-ANCA without relapse (n = 56), myeloperoxidase (MPO)-ANCA with relapse (n = 6), and MPO-ANCA without relapse (n = 45). Serum S100A8/A9 level decreased in all groups during the first 6 months of treatment. The percentage reduction from baseline to month 2 was significantly different between patients who experienced a relapse and those who did not in the PR3-ANCA group ( P = 0.046). A significantly higher risk of relapse was associated with an increase in S100A8/A9 level between baseline and month 2 ( P = 0.0043) and baseline and month 6 ( P = 0.0029). Subgroup analysis demonstrated that patients treated with RTX who had increased levels of S100A8/A9 were at greatest risk of future relapse ( P = 0.028). Conclusion An increase in serum S100A8/A9 level by month 2 or 6 compared to baseline identifies a subgroup of PR3-ANCA patients treated with RTX who are at higher risk of relapse by 18 months. Since RTX is increasingly used for remission induction in PR3-ANCA-positive patients experiencing a relapse, S100A8/A9 level may assist in identifying those patients requiring more intensive or prolonged treatment. [ABSTRACT FROM AUTHOR]

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a generic definition referring to a series of neurological and psychiatric symptoms directly related to systemic lupus erythematosus (SLE). NPSLE includes heterogeneous and rare neuropsychiatric (NP) manifestations involving both the central and peripheral nervous system. Due to the lack of a gold standard, the attribution of NP symptoms to SLE represents a clinical challenge that obligates the strict exclusion of any other potential cause. In the acute setting, management of these patients does not differ from other non-SLE subjects presenting with the same NP manifestation. Afterwards, an individualized therapeutic strategy, depending on the presenting manifestation and severity of symptoms, must be started. Clinical trials in NPSLE are scarce and most of the data are extracted from case series and case reports. High-dose glucocorticoids and intravenous cyclophosphamide remain the cornerstone for patients with severe symptoms that are thought to reflect inflammation or an underlying autoimmune process. Rituximab, intravenous immunoglobulins, or plasmapheresis may be used if response is not achieved. When patients present with mild to moderate NP manifestations, or when maintenance therapy is warranted, azathioprine and mycophenolate may be considered. When symptoms are thought to reflect a thrombotic underlying process, anticoagulation and antiplatelet agents are the mainstay of therapy, especially if antiphospholipid antibodies or antiphospholipid syndrome are present. Recent trials on SLE using new biologicals, based on newly understood SLE mechanisms, have shown promising results. Based on what we currently know about its pathogenesis, it is tempting to speculate how these new therapies may affect the management of NPSLE patients. This article provides a comprehensive and critical review of the literature on the epidemiology, pathophysiology, diagnosis, and management of NPSLE. We describe the most common pharmacological treatments used in NPSLE, based on both a literature search and our expert opinion. The extent to which new drugs in the advanced development of SLE, or the blockade of new targets, may impact future treatment of NPSLE will also be discussed. [ABSTRACT FROM AUTHOR]

Lung involvement in rheumatologic diseases has a broad spectrum of clinical and radiological presentations, from acute and inflammatory predominance to chronic and fibrotic lung disorders. Therapy has to be guided by the type of rheumatologic disease, the kind of lung involvement and the risk associated with the clinical state of the patient and prognostic factors. Although several therapeutic approaches have been used, the best treatment is still not certain; clinical trials are mandatory, which would require a better knowledge of the pulmonary pathogenesis of immunologic diseases. The following review is focused on the therapeutic options for those rheumatologic disorders that could present as a predominant interstitial lung disease which may confer a bad or life-threatening prognosis. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Until now, treatment of primary autoimmune hemolytic anemia of the warm type (wAIHA) is primarily based on immunosuppression. However, many patients do not respond adequately to treatment, and treated patients may develop severe side effects due to uncontrolled, mixed and/or long-lasting immunosuppression. Unfortunately, the newly used therapeutic monoclonal antibodies are unspecific and remain frequently ineffective. Thus, development of a specific therapy for AIHA is necessary. The ideal therapy would be the identification and elimination of the causative origin of autoimmunization and/or the correction or reprogramming of the dysregulated immune components. Blood transfusion is the most rapidly effective measure for patients who develop or may develop hypoxic anemia. Although some effort has been made to guide physicians on how to adequately treat patients with AIHA, a number of individual aspects should be considered prior to treatment. Based on my serological and clinical experience and the analysis of evidence-based studies, we remain far from any optimized therapeutic measures for all AIHA patients. Today, the old standard therapy using controlled steroid administration, with or without azathioprine or cyclophosphamide, is, when complemented with erythropoiesis-stimulating agents, still the most effective therapy in wAIHA. Rituximab or other monoclonal antibodies may be used instead of splenectomy in therapy-refractory patients. [ABSTRACT FROM AUTHOR]

Objective Nonsevere relapses are more common than severe relapses in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but their clinical course and treatment outcomes remain largely unexamined. We undertook this study to analyze the outcomes of patients with nonsevere relapses in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial who were treated with prednisone according to a prespecified protocol. Methods RAVE was a randomized, double-blind, placebo-controlled trial comparing rituximab (RTX) to cyclophosphamide (CYC) followed by azathioprine (AZA) for induction of remission. Patients who experienced nonsevere relapses between months 1 and 18 were treated with a prednisone increase without a concomitant change in their nonglucocorticoid immunosuppressants, followed by a taper. Results Forty-four patients with a first nonsevere relapse were analyzed. In comparison to the 71 patients who maintained relapse-free remission over 18 months, these patients were more likely to have proteinase 3-ANCAs, diagnoses of granulomatosis with polyangiitis (Wegener's), and a history of relapsing disease at baseline. A prednisone increase led to remission in 35 patients (80%). However, only 13 patients (30%) were able to maintain second remissions through the followup period (mean 12.5 months); 31 patients (70%) had a second disease relapse, 14 of them with severe disease. The mean time to second relapse was 9.4 months (4.7 months in the group treated with RTX versus 13.7 months in the group treated with CYC/AZA; P < 0.01). Patients who experienced nonsevere relapses received more glucocorticoids than those who maintained remission (6.7 grams versus 3.8 grams; P < 0.01). Conclusion Treatment of nonsevere relapses in AAV with an increase in glucocorticoids is effective in restoring temporary remission in the majority of patients, but recurrent relapses within a relatively short interval remain common. Alternative treatment approaches are needed for this important subset of patients. [ABSTRACT FROM AUTHOR]

Until recently, standard of care for patients with generalized or severe antineutrophil cytoplasmic antibody (ANCA)- associated vasculitis (AAV) has consisted of an induction regimen with cyclophosphamide (CYC) and corticosteroids followed by maintenance treatment with azathioprine. This regimen is associated with significant toxicity resulting in considerable morbidity and mortality whereas relapses are still not infrequent. In two controlled trials, the Rituximab in ANCAassociated Vasculitis study (RAVE) and the RITUXVAS trial of the European Vasculitis Study Group (EUVAS), rituximab (RTX) proved non-inferior to CYC for induction of remission. In addition, outcome at 18 months for the RAVE trial and 12 months for the RITUXVAS trial showed that RTX without maintenance treatment was as efficacious as CYC followed by azathioprine maintenance. To prevent relapses, which occur particularly in patients positive for PR3-ANCA, 500 mg RTX given every 6 months was shown to be superior to azathioprine in a French study. Thus, RTX is a new and promising therapeutic armamentarium for AAV although long-term safety has still to be established. [ABSTRACT FROM AUTHOR]

Since activation of the immune system and a perivascular infiltrate of inflammatory cells are key features of SSc, immunosuppression has long been considered to be an anchor treatment. Non-selective immunosuppression remains central to the treatment of interstitial lung disease (ILD) and skin involvement, with CYC most widely used to obtain remission. The use of MTX as a first-line agent may be considered in the presence of skin involvement without ILD. More recently, MMF has shown encouraging results in observational studies, but still needs more formal evaluation to verify if it can be considered an alternative drug to CYC or a maintenance agent such as AZA. Rituximab has provided promising results in small open-label studies and other novel therapies targeting specific molecular and cellular targets are under evaluation. Patients with rapidly progressing diffuse cutaneous SSc should be evaluated for haematopoietic stem cell transplantation. [ABSTRACT FROM PUBLISHER]

Immunoglobulin G4-related disease ( IgG4- RD) is a recently described entity with protean manifestations. We describe a novel case of IgG4- RD with hypergammaglobulinemic hyperviscosity responsive to fludarabine and rituximab. A 33-year-old Asian man developed bilateral lacrimal gland and submandibular salivary gland swelling with cervical lymphadenopathy. Biopsies of the affected tissues revealed reactive follicular hyperplasia. Seven years later, he presented with bilateral retinal hemorrhages due to hyperviscosity syndrome from profound polyclonal increase in IgG, including marked IgG4 elevation. Despite plasmapheresis, overproduction of IgG continued and he was refractory to systemic steroids, azathioprine, interferon alpha, and cyclophosphamide. IgG4- RD was suspected following a myocardial infarction and detection of aneurysmal coronary arteries indicating large vessel vasculitis. Review of the cervical lymph node and lacrimal gland biopsies with immunohistochemical staining for IgG4-positive plasma cells confirmed IgG4- RD. B-cell depletion with rituximab produced a partial response, but clinical symptoms and elevated protein levels persisted. Fludarabine was added to rituximab to suppress T-cell activity, and this resulted in an excellent clinical and biochemical response. Combination therapy with fludarabine and rituximab in IgG4- RD has not previously been reported and can be considered in patients with severe refractory disease. [ABSTRACT FROM AUTHOR]

Shrinking lung syndrome (SLS) is an uncommon feature of systemic lupus erythematosus (SLE) characterized by dyspnea, pleuritic chest pain, diaphragmatic elevation, restrictive ventilatory defect and reduced respiratory muscle strength as measured by volitional tests. We report the case of a 28-year-old woman with overlapping features of SLE and Sjögren syndrome who developed severe SLS while receiving corticosteroids and azathioprine for severe polyarthritis. She was treated with a combination of rituximab and cyclophosphamide, which led to a dramatic improvement in her clinical condition and respiratory function tests. The increase in vital capacity was one of the highest among 35 published cases of SLS. Thus, restoring a near-normal lung function is an achievable goal in SLS, and the use of rituximab, with or without concomitant cyclophosphamide, certainly deserves further study in this setting. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Progressive multifocal leukoencephalopathy (PML) is a disease of the central nervous system (CNS) with destructive infection of oligodendrocytes by JC virus. PML belongs to the opportunistic infections. It is observed in patients with HIV infection, lymphoid malignancies, after organ- and stem cell transplantations and more recently in the context of modern immune-therapies with monoclonal antibodies (mAb) like natalizumab, rituximab, infliximab and efalizumab. The natural course of PML is fatal within months. More recently, the Immune Reconstitution Inflammatory Syndrome (IRIS) has been observed in patients with HIV infection treated with combination antiretroviral therapy (cART) as well as patients in whom the PML-inducing immune therapy has been terminated. In PML-IRIS the immune system contributes to the elimination of JC virus from the CNS and if PML-IRIS emerges, PML can be survived but can lead as well to catastrophic outcomes with brain herniation and death. Therefore the management of IRIS requires special knowledge in JC virus biology and patient care. JC virus infection is possibly involved in a variety of additional neurological conditions and cancer. Much will be learned within the next years that could change our view on the understanding of JC virus and human disease. [Copyright &y& Elsevier]

The article focuses on clinical trials for treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) with Rituximab. The disease was associated with high rates of mortality till the development of biologic agents and decline in usage of immunosuppressant drugs in modern times. The efficacy of Rituximab was compared to cyclophosphamide for induction of remission in AAV in earlier trials. Subjects in cyclophosphamide section were switched to azathioprine whereas the Rituximab group was switched to placebo-azathioprine. It was observed that for induction of remission in patients with severe AAV, Rituximab was noninferior to cyclophosphamide.

Background Anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitis (AAV) are rare small and medium vessel vasculitides that include granulomatosis polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). This retrospective review summarises the clinical features of a cohort of patients with childhood onset AAV at a single tertiary centre in the North West of England. Methods Identification of all patients with diagnosis of ANCA-associated vasculitis diagnosed from 2014 to 2019, using department database and PEDVAS data. Clinical information was collected retrospectively using electronic patient record and case notes. Results 10 patients with AAV were identified, with GPA being the most common diagnosis (7 patients). 2 patients had MPA and 1 had EGPA. All patients with GPA fulfilled consensus EULAR/PRES criteria. The EGPA patient fulfilled ACR classification criteria.1 MPA patient fulfilled Chapel Hill Consensus Conference criteria. MPA presented in a younger age group compared to EGPA. AAV was more common in females, 8:2 female to male ratio, Table 1. All patients had pulmonary and renal involvement, with the exception of one EGPA patient having pulmonary disease with no evidence of glomerulonephritis (GN). MPA patients had significant renal disease and presented early, within 1 month of clinical symptoms. GPA patients had an average duration of symptoms of 2.5 months before presentation. GPA patients were mainly cANCA PR3 positive and MPA patients were MPO positive. The EGPA patient was not ANCA positive but had histological diagnosis of granulomatous vasculitis. 3 patients with GPA underwent plasmapheresis, with evidence of proliferative GN and pulmonary disease at presentation. One of these patients sustained pulmonary haemorrhage. The 2 patients with MPA presented with significant renal failure; one patient died 19 months after diagnosis, the other had renal transplant. All patients received cyclophosphamide and required further immunosuppression with either DMARD or biologic. Most patients remain on MMF or rituximab as maintenance therapy which appears successful in maintaining remission so far. P31 Table 1: Demographics and clinical features of patients with AAV   GPA, n = 7  MPA, n = 2  EGPA, n = 1  Gender F:M  6:1  2:0  0:1  Mean age at onset  13.2 (8.7- 15)  5.9 (2.3- 9.6)  11.8  (years)  Mean duration of follow-up (months)  23.2 (5- 36)  28.5 (19- 38)  53  Mean duration of symptoms  2.5 (1-6)  1 (1)  11  pre-presentation (months)  ENT  4  1  1  Pulmonary  7  2  1  Renal  7  2  0  Asthma  0  0  1  Eosinophilia  0  0  1  ANCA PR3 +ve  6  0  0  ANCA MPO +ve  1  2  0  ESRF  0  2  0  Death  0  1  0  Plasmapheresis  3  2  0  Cyclophosphamide  7  2  1  Azathioprine  3  1  1  MMF  3  2  1  Rituximab  4  1  1    GPA, n = 7  MPA, n = 2  EGPA, n = 1  Gender F:M  6:1  2:0  0:1  Mean age at onset  13.2 (8.7- 15)  5.9 (2.3- 9.6)  11.8  (years)  Mean duration of follow-up (months)  23.2 (5- 36)  28.5 (19- 38)  53  Mean duration of symptoms  2.5 (1-6)  1 (1)  11  pre-presentation (months)  ENT  4  1  1  Pulmonary  7  2  1  Renal  7  2  0  Asthma  0  0  1  Eosinophilia  0  0  1  ANCA PR3 +ve  6  0  0  ANCA MPO +ve  1  2  0  ESRF  0  2  0  Death  0  1  0  Plasmapheresis  3  2  0  Cyclophosphamide  7  2  1  Azathioprine  3  1  1  MMF  3  2  1  Rituximab  4  1  1  P31 Table 1: Demographics and clinical features of patients with AAV   GPA, n = 7  MPA, n = 2  EGPA, n = 1  Gender F:M  6:1  2:0  0:1  Mean age at onset  13.2 (8.7- 15)  5.9 (2.3- 9.6)  11.8  (years)  Mean duration of follow-up (months)  23.2 (5- 36)  28.5 (19- 38)  53  Mean duration of symptoms  2.5 (1-6)  1 (1)  11  pre-presentation (months)  ENT  4  1  1  Pulmonary  7  2  1  Renal  7  2  0  Asthma  0  0  1  Eosinophilia  0  0  1  ANCA PR3 +ve  6  0  0  ANCA MPO +ve  1  2  0  ESRF  0  2  0  Death  0  1  0  Plasmapheresis  3  2  0  Cyclophosphamide  7  2  1  Azathioprine  3  1  1  MMF  3  2  1  Rituximab  4  1  1    GPA, n = 7  MPA, n = 2  EGPA, n = 1  Gender F:M  6:1  2:0  0:1  Mean age at onset  13.2 (8.7- 15)  5.9 (2.3- 9.6)  11.8  (years)  Mean duration of follow-up (months)  23.2 (5- 36)  28.5 (19- 38)  53  Mean duration of symptoms  2.5 (1-6)  1 (1)  11  pre-presentation (months)  ENT  4  1  1  Pulmonary  7  2  1  Renal  7  2  0  Asthma  0  0  1  Eosinophilia  0  0  1  ANCA PR3 +ve  6  0  0  ANCA MPO +ve  1  2  0  ESRF  0  2  0  Death  0  1  0  Plasmapheresis  3  2  0  Cyclophosphamide  7  2  1  Azathioprine  3  1  1  MMF  3  2  1  Rituximab  4  1  1  Conclusion Childhood onset AAV are severe diseases with significant morbidity and mortality. Rituximab was found to be effective in induction as well as maintenance therapy in our patients. In our cohort, children had multi-system involvement at presentation. Clinicians should investigate thoroughly for ENT, pulmonary and renal complications at diagnosis. Conflicts of Interest The authors declare no conflicts of interest. [ABSTRACT FROM AUTHOR]

The article presents case study of a 8-year-old boy who was diagnosed with systemic lupus erythematosus after onset of thrombotic thrombocytopenic purpura (TTP). Topics discussed include treatment of the patient with methylprednisolone (mPSL) pulse therapy for suspected Evans syndrome; negative results of the Antinuclear antibody (ANA) and anti-double stranded DNA (dsDNA) antibody; and need for understanding immunopathological interactions between diseases and optimum therapeutic interventions.