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Annals of the Rheumatic Diseases Jan 2024To update the EULAR recommendations for the management of systemic lupus erythematosus (SLE) based on emerging new evidence.
OBJECTIVES
To update the EULAR recommendations for the management of systemic lupus erythematosus (SLE) based on emerging new evidence.
METHODS
An international Task Force formed the questions for the systematic literature reviews (January 2018-December 2022), followed by formulation and finalisation of the statements after a series of meetings. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned, and participants finally provided their level of agreement with each item.
RESULTS
The Task Force agreed on 5 overarching principles and 13 recommendations, concerning the use of hydroxychloroquine (HCQ), glucocorticoids (GC), immunosuppressive drugs (ISDs) (including methotrexate, mycophenolate, azathioprine, cyclophosphamide (CYC)), calcineurin inhibitors (CNIs, cyclosporine, tacrolimus, voclosporin) and biologics (belimumab, anifrolumab, rituximab). Advice is also provided on treatment strategies and targets of therapy, assessment of response, combination and sequential therapies, and tapering of therapy. HCQ is recommended for all patients with lupus at a target dose 5 mg/kg real body weight/day, considering the individual's risk for flares and retinal toxicity. GC are used as 'bridging therapy' during periods of disease activity; for maintenance treatment, they should be minimised to equal or less than 5 mg/day (prednisone equivalent) and, when possible, withdrawn. Prompt initiation of ISDs (methotrexate, azathioprine, mycophenolate) and/or biological agents (anifrolumab, belimumab) should be considered to control the disease and facilitate GC tapering/discontinuation. CYC and rituximab should be considered in organ-threatening and refractory disease, respectively. For active lupus nephritis, GC, mycophenolate or low-dose intravenous CYC are recommended as anchor drugs, and add-on therapy with belimumab or CNIs (voclosporin or tacrolimus) should be considered. Updated specific recommendations are also provided for cutaneous, neuropsychiatric and haematological disease, SLE-associated antiphospholipid syndrome, kidney protection, as well as preventative measures for infections, osteoporosis, cardiovascular disease.
CONCLUSION
The updated recommendations provide consensus guidance on the management of SLE, combining evidence and expert opinion.
Topics: Humans; Azathioprine; Tacrolimus; Rituximab; Methotrexate; Lupus Erythematosus, Systemic; Immunosuppressive Agents; Cyclophosphamide; Hydroxychloroquine; Glucocorticoids; Enzyme Inhibitors
PubMed: 37827694
DOI: 10.1136/ard-2023-224762 -
Annals of the Rheumatic Diseases Jan 2024Since the publication of the EULAR recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in 2016, several...
BACKGROUND
Since the publication of the EULAR recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in 2016, several randomised clinical trials have been published that have the potential to change clinical care and support the need for an update.
METHODS
Using EULAR standardised operating procedures, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 16 countries. We modified existing recommendations and created new recommendations.
RESULTS
Four overarching principles and 17 recommendations were formulated. We recommend biopsies and ANCA testing to assist in establishing a diagnosis of AAV. For remission induction in life-threatening or organ-threatening AAV, we recommend a combination of high-dose glucocorticoids (GCs) in combination with either rituximab or cyclophosphamide. We recommend tapering of the GC dose to a target of 5 mg prednisolone equivalent/day within 4-5 months. Avacopan may be considered as part of a strategy to reduce exposure to GC in granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Plasma exchange may be considered in patients with rapidly progressive glomerulonephritis. For remission maintenance of GPA/MPA, we recommend rituximab. In patients with relapsing or refractory eosinophilic GPA, we recommend the use of mepolizumab. Azathioprine and methotrexate are alternatives to biologics for remission maintenance in AAV.
CONCLUSIONS
In the light of recent advancements, these recommendations provide updated guidance on AAV management. As substantial data gaps still exist, informed decision-making between physicians and patients remains of key relevance.
Topics: Humans; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Azathioprine; Cyclophosphamide; Granulomatosis with Polyangiitis; Microscopic Polyangiitis; Remission Induction; Rituximab; Practice Guidelines as Topic
PubMed: 36927642
DOI: 10.1136/ard-2022-223764 -
JAMA May 2024Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by inflammation and immune-mediated injury to multiple organ systems, including the... (Review)
Review
IMPORTANCE
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by inflammation and immune-mediated injury to multiple organ systems, including the mucocutaneous, musculoskeletal, hematologic, and kidney systems. Approximately 3.4 million people worldwide have received a diagnosis of SLE.
OBSERVATIONS
Approximately 90% of people with SLE are female. Although there are no uniformly accepted diagnostic criteria for SLE, the 2019 European Alliance of Associations for Rheumatology (formerly the European League Against Rheumatism)/American College of Rheumatology classification criteria developed for scientific study are an estimated 96.1% sensitive and 93.4% specific for SLE. These classification criteria include both clinical factors, such as fever, cytopenia, rash, arthritis, and proteinuria, which may be indicative of lupus nephritis; and immunologic measures, such as SLE-specific autoantibodies and low complement levels. Approximately 40% of people with SLE develop lupus nephritis, and an estimated 10% of people with lupus nephritis develop end-stage kidney disease after 10 years. The primary goal of treatment is to achieve disease remission or quiescence, defined by minimal symptoms, low levels of autoimmune inflammatory markers, and minimal systemic glucocorticoid requirement while the patient is treated with maintenance doses of immunomodulatory or immunosuppressive medications. Treatment goals include reducing disease exacerbations, hospitalizations, and organ damage due to the disease or treatment toxicity. Hydroxychloroquine is standard of care for SLE and has been associated with a significant reduction in mortality. Treatments in addition to hydroxychloroquine are individualized, with immunosuppressive agents, such as azathioprine, mycophenolate mofetil, and cyclophosphamide, typically used for treating moderate to severe disease. Three SLE medications were recently approved by the Food and Drug Administration: belimumab (for active SLE in 2011 and for lupus nephritis in 2020), voclosporin (for lupus nephritis), and anifrolumab (for active SLE).
CONCLUSIONS AND RELEVANCE
Systemic lupus erythematosus is associated with immune-mediated damage to multiple organs and increased mortality. Hydroxychloroquine is first-line therapy and reduces disease activity, morbidity, and mortality. When needed, additional immunosuppressive and biologic therapies include azathioprine, mycophenolate mofetil, cyclophosphamide, belimumab, voclosporin, and anifrolumab.
Topics: Female; Humans; Male; Autoantibodies; Biological Products; Black or African American; Hydroxychloroquine; Immunomodulating Agents; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Race Factors; Sex Factors; White
PubMed: 38587826
DOI: 10.1001/jama.2024.2315 -
Nephrology, Dialysis, Transplantation :... May 2024Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are characterized by small-vessel necrotizing inflammation, and prior to the advent of... (Review)
Review
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are characterized by small-vessel necrotizing inflammation, and prior to the advent of immunosuppressive therapy frequently had a fatal outcome. Treatment has transformed AAV into a relapsing/remitting disease with increased drug-related toxicities and organ damage. The use of glucocorticoids, cyclophosphamide and immunosuppressives (including azathioprine, mycophenolate and methotrexate) was optimized through a sequence of clinical trials establishing a standard of care against which subsequent targeted therapies could be developed. Improved understanding of pathophysiology has supported the development of B-cell depletion and complement inhibition in granulomatosis with polyangiitis and microscopic polyangiitis, and interleukin 5 inhibition for eosinophilic granulomatosis with polyangiitis, leading to the approval of newer agents for these conditions. There has been an increased attention on minimizing the adverse effects of treatment and on understanding the epidemiology of comorbidities in AAV. This review will focus on recent evidence from clinical trials, especially with respect to glucocorticoids, avacopan, plasma exchange, rituximab and mepolizumab, and their interpretation in the 2022 management recommendations by the European League of Associations of Rheumatology.
Topics: Humans; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Immunosuppressive Agents; Glucocorticoids; Standard of Care
PubMed: 37947275
DOI: 10.1093/ndt/gfad237 -
Therapeutic Advances in Neurological... 2023Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and congenital myasthenic syndromes (CMS) represent an etiologically heterogeneous group of (very) rare... (Review)
Review
Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and congenital myasthenic syndromes (CMS) represent an etiologically heterogeneous group of (very) rare chronic diseases. MG and LEMS have an autoimmune-mediated etiology, while CMS are genetic disorders. A (strain dependent) muscle weakness due to neuromuscular transmission disorder is a common feature. Generalized MG requires increasingly differentiated therapeutic strategies that consider the enormous therapeutic developments of recent years. To include the newest therapy recommendations, a comprehensive update of the available German-language guideline 'Diagnostics and therapy of myasthenic syndromes' has been published by the German Neurological society with the aid of an interdisciplinary expert panel. This paper is an adapted translation of the updated and partly newly developed treatment guideline. It defines the rapid achievement of complete disease control in myasthenic patients as a central treatment goal. The use of standard therapies, as well as modern immunotherapeutics, is subject to a staged regimen that takes into account autoantibody status and disease activity. With the advent of modern, fast-acting immunomodulators, disease activity assessment has become pivotal and requires evaluation of the clinical course, including severity and required therapies. Applying MG-specific scores and classifications such as Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Foundation of America allows differentiation between mild/moderate and (highly) active (including refractory) disease. Therapy decisions must consider age, thymic pathology, antibody status, and disease activity. Glucocorticosteroids and the classical immunosuppressants (primarily azathioprine) are the basic immunotherapeutics to treat mild/moderate to (highly) active generalized MG/young MG and ocular MG. Thymectomy is indicated as a treatment for thymoma-associated MG and generalized MG with acetylcholine receptor antibody (AChR-Ab)-positive status. In (highly) active generalized MG, complement inhibitors (currently eculizumab and ravulizumab) or neonatal Fc receptor modulators (currently efgartigimod) are recommended for AChR-Ab-positive status and rituximab for muscle-specific receptor tyrosine kinase (MuSK)-Ab-positive status. Specific treatment for myasthenic crises requires plasmapheresis, immunoadsorption, or IVIG. Specific aspects of ocular, juvenile, and congenital myasthenia are highlighted. The guideline will be further developed based on new study results for other immunomodulators and biomarkers that aid the accurate measurement of disease activity.
PubMed: 38152089
DOI: 10.1177/17562864231213240 -
Journal of the European Academy of... Apr 2024Alopecia areata is an autoimmune form of non-scarring hair loss. It is usually characterized by limited areas of hair loss. However, the disease may progress to complete... (Review)
Review
Alopecia areata is an autoimmune form of non-scarring hair loss. It is usually characterized by limited areas of hair loss. However, the disease may progress to complete scalp and body hair loss (alopecia totalis, alopecia universalis). In patients with alopecia areata hair loss significantly impacts the quality of life. Children and adolescents with alopecia areata often experience bullying, including physical aggression. The disease severity evaluation tools used in clinical practice are: the Severity of Alopecia Tool (SALT) score and the Alopecia Areata Scale (AAS). A SALT score equal to or greater than 20 constitutes a commonly accepted indication for systemic therapy in alopecia areata. When using the AAS, moderate to severe alopecia areata should be considered a medical indication for systemic treatment. Currently, the only two EMA-approved medications for alopecia areata are baricitinib (JAK 1/2 inhibitor) for adults and ritlecitinib (JAK 3/TEC inhibitor) for individuals aged 12 and older. Both are EMA-approved for patients with severe alopecia areata. Other systemic medications used off-label in alopecia areata include glucocorticosteroids, cyclosporine, methotrexate and azathioprine. Oral minoxidil is considered an adjuvant therapy with limited data confirming its possible efficacy. This consensus statement is to outline a systemic treatment algorithm for alopecia areata, indications for systemic treatment, available therapeutic options, their efficacy and safety, as well as the duration of the therapy.
Topics: Adult; Adolescent; Child; Humans; Alopecia Areata; Quality of Life; Alopecia; Minoxidil; Azathioprine; Janus Kinase Inhibitors
PubMed: 38169088
DOI: 10.1111/jdv.19768 -
JAMA Jun 2023Autoimmune disorders can affect various organs and if refractory, can be life threatening. Recently, CD19-targeting-chimeric antigen receptor (CAR) T cells were...
IMPORTANCE
Autoimmune disorders can affect various organs and if refractory, can be life threatening. Recently, CD19-targeting-chimeric antigen receptor (CAR) T cells were efficacious as an immune suppressive agent in 6 patients with refractory systemic lupus erythematosus and in 1 patient with antisynthetase syndrome.
OBJECTIVE
To test the safety and efficacy of CD19-targeting CAR T cells in a patient with severe antisynthetase syndrome, a complex autoimmune disorder with evidence for B- and T-cell involvement.
DESIGN, SETTING, AND PARTICIPANTS
This case report describes a patient with antisynthetase syndrome with progressive myositis and interstitial lung disease refractory to available therapies (including rituximab and azathioprine), who was treated with CD19-targeting CAR T cells in June 2022 at University Hospital Tübingen in Tübingen, Germany, with the last follow-up in February 2023. Mycophenolate mofetil was added to the treatment to cotarget CD8+ T cells, hypothesized to contribute to disease activity.
EXPOSURE
Prior to treatment with CD19-targeting CAR T cells, the patient received conditioning therapy with fludarabine (25 mg/m2 [5 days before until 3 days before]) and cyclophosphamide (1000 mg/m2 [3 days before]) followed by infusion of CAR T cells (1.23×106/kg [manufactured by transduction of autologous T cells with a CD19 lentiviral vector and amplification in the CliniMACS Prodigy system]) and mycophenolate mofetil (2 g/d) 35 days after CD19-targeting CAR T-cell infusion.
MAIN OUTCOMES AND MEASURES
The patient's response to therapy was followed by magnetic resonance imaging of the thigh muscle, Physician Global Assessment, functional muscle and pulmonary tests, and peripheral blood quantification of anti-Jo-1 antibody levels, lymphocyte subsets, immunoglobulins, and serological muscle enzymes.
RESULTS
Rapid clinical improvement was observed after CD19-targeting CAR T-cell infusion. Eight months after treatment, the patient's scores on the Physician Global Assessment and muscle and pulmonary function tests improved, and there were no detectable signs of myositis on magnetic resonance imaging. Serological muscle enzymes (alanine aminotransferase, aspartate aminotransferase, creatinine kinase, and lactate dehydrogenase), CD8+ T-cell subsets, and inflammatory cytokine secretion in the peripheral blood mononuclear cells (interferon gamma, interleukin 1 [IL-1], IL-6, and IL-13) were all normalized. Further, there was a reduction in anti-Jo-1 antibody levels and a partial recovery of IgA (to 67% of normal value), IgG (to 87%), and IgM (to 58%).
CONCLUSIONS AND RELEVANCE
CD19-targeting CAR T cells directed against B cells and plasmablasts deeply reset B-cell immunity. Together with mycophenolate mofetil, CD19-targeting CAR T cells may break pathologic B-cell, as well as T-cell responses, inducing remission in refractory antisynthetase syndrome.
Topics: Humans; Antigens, CD19; Leukocytes, Mononuclear; Lung Diseases, Interstitial; Mycophenolic Acid; Myositis; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Cyclophosphamide; Immunosuppressive Agents
PubMed: 37367976
DOI: 10.1001/jama.2023.8753 -
Annals of the Rheumatic Diseases Jul 2023Following induction of remission with rituximab in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) relapse rates are high, especially in patients with... (Randomized Controlled Trial)
Randomized Controlled Trial
Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomised controlled trial.
OBJECTIVE
Following induction of remission with rituximab in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) relapse rates are high, especially in patients with history of relapse. Relapses are associated with increased exposure to immunosuppressive medications, the accrual of damage and increased morbidity and mortality. The RITAZAREM trial compared the efficacy of repeat-dose rituximab to daily oral azathioprine for prevention of relapse in patients with relapsing AAV in whom remission was reinduced with rituximab.
METHODS
RITAZAREM was an international randomised controlled, open-label, superiority trial that recruited 188 patients at the time of an AAV relapse from 29 centres in seven countries between April 2013 and November 2016. All patients received rituximab and glucocorticoids to reinduce remission. Patients achieving remission by 4 months were randomised to receive rituximab intravenously (1000 mg every 4 months, through month 20) (85 patients) or azathioprine (2 mg/kg/day, tapered after month 24) (85 patients) and followed for a minimum of 36 months. The primary outcome was time to disease relapse (either major or minor relapse).
RESULTS
Rituximab was superior to azathioprine in preventing relapse: HR 0.41; 95% CI 0.27 to 0.61, p<0.001. 19/85 (22%) patients in the rituximab group and 31/85 (36%) in the azathioprine group experienced at least one serious adverse event during the treatment period. There were no differences in rates of hypogammaglobulinaemia or infection between groups.
CONCLUSIONS
Following induction of remission with rituximab, fixed-interval, repeat-dose rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse.
TRIAL REGISTRATION NUMBER
NCT01697267; ClinicalTrials.gov identifier.
Topics: Humans; Azathioprine; Rituximab; Immunosuppressive Agents; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Recurrence; Remission Induction; Treatment Outcome; Cyclophosphamide; Antibodies, Antineutrophil Cytoplasmic
PubMed: 36958796
DOI: 10.1136/ard-2022-223559 -
Expert Review of Gastroenterology &... 2023Most guidelines for IBD still recommend step-by-step therapy with initially classic drugs such aminosalicylates (in ulcerative colitis) or steroids but avoid... (Review)
Review
INTRODUCTION
Most guidelines for IBD still recommend step-by-step therapy with initially classic drugs such aminosalicylates (in ulcerative colitis) or steroids but avoid prioritizing certain biological drugs and JAK inhibitors in the complicated course. This review provides an aid to pending therapy decisions.
AREAS COVERED
In this review, we analyze the evidence for Crohn's disease as well as ulcerative colitis in order to optimize and 'personalize' the choice of therapy, especially in difficult cases. The relevant publications in Pubmed were identified in a continuous literature review with the key words 'Crohn´s disease' and 'ulcerative colitis.'
EXPERT OPINION
Based on this complex data set following standard therapies steroid-refractory Crohn´s disease should preferentially be treated with combined infliximab plus azathioprine or risankizumab, in second line after their failure with ustekinumab or 7adalimumab. In steroid-refractory ulcerative colitis infliximab plus azathioprine or upadacitinib should be preferred in first line, filgotinib, tofacitinib or ustekinumab in second line. A steroid-dependent course in both diseases requires azathioprine or vedolizumab, in second line infliximab or Janus kinase inhibitors. The conclusions drawn from these complex data may be helpful for individual decision making in daily clinical practice.
Topics: Humans; Azathioprine; Colitis, Ulcerative; Crohn Disease; Infliximab; Ustekinumab; Inflammatory Bowel Diseases; Steroids; Janus Kinase Inhibitors
PubMed: 37480322
DOI: 10.1080/17474124.2023.2240699 -
Life (Basel, Switzerland) Jul 2023Systemic lupus erythematosus (SLE), the prototype of systemic autoimmune diseases is characterized by extreme heterogeneity with a variable clinical course. Renal... (Review)
Review
Systemic lupus erythematosus (SLE), the prototype of systemic autoimmune diseases is characterized by extreme heterogeneity with a variable clinical course. Renal involvement may be observed and affects the outcome. Hydroxychloroquine should be administered to every lupus patient irrespective of organ involvement. Conventional immunosuppressive therapy includes corticosteroids, methotrexate, cyclophosphamide, mycophenolate mofetil, azathioprine, cyclosporine and tacrolimus. However, despite conventional immunosuppressive treatment, flares occur and broad immunosuppression is accompanied by multiple side effects. Flare occurrence, target organ involvement, side effects of broad immunosuppression and increased knowledge of the pathogenetic mechanisms involved in SLE pathogenesis as well as the availability of biologic agents has led to the application of biologic agents in SLE management. Biologic agents targeting various pathogenetic paths have been applied. B cell targeting agents have been used successfully. Belimumab, a B cell targeting agent, has been approved for the treatment of SLE. Rituximab, an anti-CD20 targeting agent is also used in SLE. Anifrolumab, an interferon I receptor-targeting agent has beneficial effects on SLE. In conclusion, biologic treatment is applied in SLE and should be further evaluated with the aim of a good treatment response and a significant improvement in quality of life.
PubMed: 37511872
DOI: 10.3390/life13071496