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Journal of the European Academy of... Sep 2022The evidence- and consensus-based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four...
The evidence- and consensus-based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty-nine experts (including clinicians and patient representatives) from 12 European countries participated. This first part of the guideline includes general information on its scope and purpose, the health questions covered, target users and a methods section. It also provides guidance on which patients should be treated with systemic therapies, as well as recommendations and detailed information on each systemic drug. The systemic treatment options discussed in the guideline comprise conventional immunosuppressive drugs (azathioprine, ciclosporin, glucocorticosteroids, methotrexate and mycophenolate mofetil), biologics (dupilumab, lebrikizumab, nemolizumab, omalizumab and tralokinumab) and janus kinase inhibitors (abrocitinib, baricitinib and upadacitinib). Part two of the guideline will address avoidance of provocation factors, dietary interventions, immunotherapy, complementary medicine, educational interventions, occupational and psychodermatological aspects, patient perspective and considerations for paediatric, adolescent, pregnant and breastfeeding patients.
Topics: Adolescent; Azathioprine; Child; Cyclosporine; Dermatitis, Atopic; Eczema; Humans; Immunosuppressive Agents; Mycophenolic Acid
PubMed: 35980214
DOI: 10.1111/jdv.18345 -
Nature Reviews. Rheumatology Apr 2023Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease with multi-organ involvement, fibrosis and vasculopathy. Treatment in SSc, including early... (Review)
Review
Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease with multi-organ involvement, fibrosis and vasculopathy. Treatment in SSc, including early diffuse cutaneous SSc (dcSSc) and the use of organ-specific therapies, has improved, as evident from randomized clinical trials. Treatments for early dcSSc include immunosuppressive agents such as mycophenolate mofetil, methotrexate, cyclophosphamide, rituximab and tocilizumab. Patients with rapidly progressive early dcSSc might be eligible for autologous haematopoietic stem cell transplantation, which can improve survival. Morbidity from interstitial lung disease and pulmonary arterial hypertension is improving with the use of proven therapies. Mycophenolate mofetil has surpassed cyclophosphamide as the initial treatment for SSc-interstitial lung disease. Nintedanib and possibly perfinidone can be considered in SSc pulmonary fibrosis. Pulmonary arterial hypertension is frequently treated with initial combination therapy (for example, with phosphodiesterase 5 inhibitors and endothelin receptor antagonists) and, if necessary, the addition of a prostacyclin analogue. Raynaud phenomenon and digital ulcers are treated with dihydropyridine calcium channel blockers (especially nifedipine), then phosphodiesterase 5 inhibitors or intravenous iloprost. Bosentan can reduce the development of new digital ulcers. Trial data for other manifestations are mostly lacking. Research is needed to develop targeted and highly effective treatments, best practices for organ-specific screening and early intervention, and sensitive outcome measurements.
Topics: Humans; Mycophenolic Acid; Pulmonary Arterial Hypertension; Phosphodiesterase 5 Inhibitors; Scleroderma, Systemic; Cyclophosphamide; Lung Diseases, Interstitial
PubMed: 36849541
DOI: 10.1038/s41584-023-00909-5 -
The European Respiratory Journal Jun 2023Standard of care for interstitial lung disease (ILD) with a nonspecific interstitial pneumonia (NSIP) pattern proposes mycophenolate mofetil (MMF) as one of the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Standard of care for interstitial lung disease (ILD) with a nonspecific interstitial pneumonia (NSIP) pattern proposes mycophenolate mofetil (MMF) as one of the first-step therapies while rituximab is used as rescue therapy.
METHODS
In a randomised, double-blind, two-parallel group, placebo-controlled trial (NCT02990286), patients with connective tissue disease-associated ILD or idiopathic interstitial pneumonia (with or without autoimmune features) and a NSIP pattern (defined on NSIP pathological pattern or on integration of clinicobiological data and a NSIP-like high-resolution computed tomography pattern) were randomly assigned in a 1:1 ratio to receive rituximab (1000 mg) or placebo on day 1 and day 15 in addition to MMF (2 g daily) for 6 months. The primary end-point was the change in percent predicted forced vital capacity (FVC) from baseline to 6 months analysed by a linear mixed model for repeated measures analysis. Secondary end-points included progression-free survival (PFS) up to 6 months and safety.
FINDINGS
Between January 2017 and January 2019, 122 randomised patients received at least one dose of rituximab (n=63) or placebo (n=59). The least-squares mean change from baseline to 6 months in FVC (% predicted) was +1.60 (se 1.13) in the rituximab+MMF group and -2.01 (se 1.17) in the placebo+MMF group (between-group difference 3.60, 95% CI 0.41-6.80; p=0.0273). PFS was better in the rituximab+MMF group (crude hazard ratio 0.47, 95% CI 0.23-0.96; p=0.03). Serious adverse events occurred in 26 (41%) patients of the rituximab+MMF group and in 23 (39%) of the placebo+MMF group. Nine infections were reported in the rituximab+MMF group (five bacterial infections, three viral infections, one other) and four bacterial infections in the placebo+MMF group.
INTERPRETATION
Combination of rituximab and MMF was superior to MMF alone in patients with ILD and a NSIP pattern. The use of this combination must take into consideration the risk of viral infection.
Topics: Humans; Rituximab; Mycophenolic Acid; Immunosuppressive Agents; Lung; Treatment Outcome; Lung Diseases, Interstitial; Idiopathic Interstitial Pneumonias; Double-Blind Method
PubMed: 37230499
DOI: 10.1183/13993003.02071-2022 -
Paediatric Drugs Jul 2021Childhood-onset systemic lupus erythematosus (cSLE) is a prototype of a multisystemic, inflammatory, heterogeneous autoimmune condition. This disease is characterized by... (Review)
Review
Childhood-onset systemic lupus erythematosus (cSLE) is a prototype of a multisystemic, inflammatory, heterogeneous autoimmune condition. This disease is characterized by simultaneous or sequential organ and system involvement, with unpredictable flare and high levels of morbidity and mortality. Racial/ethnic background, socioeconomic status, cost of medications, difficulty accessing health care, and poor adherence seem to impact lupus outcomes and treatment response. In this article, the management of cSLE patients is updated. Regarding pathogenesis, a number of potential targets for drugs have been studied. However, most treatments in pediatric patients are off-label drugs with recommendations based on inadequately powered studies, therapeutic consensus guidelines, or case series. Management practices for cSLE patients include evaluations of disease activity and cumulative damage scores, routine non-live vaccinations, physical activity, and addressing mental health issues. Antimalarials and glucocorticoids are still the most common drugs used to treat cSLE, and hydroxychloroquine is recommended for nearly all cSLE patients. Disease-modifying antirheumatic drugs (DMARDs) should be standardized for each patient, based on disease flare and cSLE severity. Mycophenolate mofetil or intravenous cyclophosphamide is suggested as induction therapy for lupus nephritis classes III and IV. Calcineurin inhibitors (cyclosporine, tacrolimus, voclosporin) appear to be another good option for cSLE patients with lupus nephritis. Regarding B-cell-targeting biologic agents, rituximab may be used for refractory lupus nephritis patients in combination with another DMARD, and belimumab was recently approved by the US Food and Drug Administration for cSLE treatment in children aged > 5 years. New therapies targeting CD20, such as atacicept and telitacicept, seem to be promising drugs for SLE patients. Anti-interferon therapies (sifalimumab and anifrolumab) have shown beneficial results in phase II randomized control trials in adult SLE patients, as have some Janus kinase inhibitors, and these could be alternative treatments for pediatric patients with severe interferon-mediated inflammatory disease in the future. In addition, strict control of proteinuria and blood pressure is required in cSLE, especially with angiotensin-converting enzyme inhibitor and angiotensin receptor blocker use.
Topics: Age of Onset; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Child; Disease Management; Glucocorticoids; Humans; Immunosuppressive Agents; Immunotherapy; Lupus Erythematosus, Systemic; Mycophenolic Acid; Randomized Controlled Trials as Topic
PubMed: 34244988
DOI: 10.1007/s40272-021-00457-z -
World Journal of Gastroenterology Oct 2020Gastrointestinal complications are common after renal transplantation, and they have a wide clinical spectrum, varying from diarrhoea to post-transplant inflammatory... (Review)
Review
Gastrointestinal complications are common after renal transplantation, and they have a wide clinical spectrum, varying from diarrhoea to post-transplant inflammatory bowel disease (IBD). Chronic immunosuppression may increase the risk of post-transplant infection and medication-related injury and may also be responsible for IBD in kidney transplant re-cipients despite immunosuppression. Differentiating the various forms of post-transplant colitis is challenging, since most have similar clinical and histological features. Drug-related colitis are the most frequently encountered colitis after kidney transplantation, particularly those related to the chronic use of mycophenolate mofetil, while IBDs are quite rare. This review will explore colitis after kidney transplantation, with a particular focus on different clinical and histological features, attempting to clearly identify the right treatment, thereby improving the final outcome of patients.
Topics: Colitis; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid
PubMed: 33132635
DOI: 10.3748/wjg.v26.i38.5797 -
Respiratory Research Jan 2023Systemic sclerosis (SSc) is a rare, complex, connective tissue disorder. Interstitial lung disease (ILD) is common in SSc, occurring in 35-52% of patients and accounting...
BACKGROUND
Systemic sclerosis (SSc) is a rare, complex, connective tissue disorder. Interstitial lung disease (ILD) is common in SSc, occurring in 35-52% of patients and accounting for 20-40% of mortality. Evolution of therapeutic options has resulted in a lack of consensus on how to manage this condition. This Delphi study was initiated to develop consensus recommendations based on expert physician insights regarding screening, progression, treatment criteria, monitoring of response, and the role of recent therapeutic advances with antifibrotics and immunosuppressants in patients with SSc-ILD.
METHODS
A modified Delphi process was completed by pulmonologists (n = 13) and rheumatologists (n = 12) with expertise in the management of patients with SSc-ILD. Panelists rated their agreement with each statement on a Likert scale from - 5 (complete disagreement) to + 5 (complete agreement). Consensus was predefined as a mean Likert scale score of ≤ - 2.5 or ≥ + 2.5 with a standard deviation not crossing zero.
RESULTS
Panelists recommended that all patients with SSc be screened for ILD by chest auscultation, spirometry with diffusing capacity of the lungs for carbon monoxide, high-resolution computed tomography (HRCT), and/or autoantibody testing. Treatment decisions were influenced by baseline and changes in pulmonary function tests, extent of ILD on HRCT, duration and degree of dyspnea, presence of pulmonary hypertension, and potential contribution of reflux. Treatment success was defined as stabilization or improvement of signs or symptoms of ILD and functional status. Mycophenolate mofetil was identified as the initial treatment of choice. Experts considered nintedanib a therapeutic option in patients with progressive fibrotic ILD despite immunosuppressive therapy or patients contraindicated/unable to tolerate immunotherapy. Concomitant use of nintedanib with MMF/cyclophosphamide can be considered in patients with advanced disease at initial presentation, aggressive ILD, or significant disease progression. Although limited consensus was achieved on the use of tocilizumab, the experts considered it a therapeutic option for patients with early SSc and ILD with elevated acute-phase reactants.
CONCLUSIONS
This modified Delphi study generated consensus recommendations for management of patients with SSc-ILD in a real-world setting. Findings from this study provide a management algorithm that will be helpful for treating patients with SSc-ILD and addresses a significant unmet need.
Topics: Humans; Consensus; Immunosuppressive Agents; Lung Diseases, Interstitial; Lung; Mycophenolic Acid; Scleroderma, Systemic
PubMed: 36624431
DOI: 10.1186/s12931-022-02292-3 -
International Journal of Molecular... Apr 2022Neuromyelitis optica spectrum disorders (NMOSD) are rare neurologic autoimmune diseases that have a poor prognosis if left untreated. For many years, generic oral... (Review)
Review
Neuromyelitis optica spectrum disorders (NMOSD) are rare neurologic autoimmune diseases that have a poor prognosis if left untreated. For many years, generic oral immunosuppressants and repurposed monoclonal antibodies that target the interleukin-6 pathway or B cells were the mainstays of drug treatment. Recently, these drug treatments have been complemented by new biologics developed and approved specifically for NMOSD. In principle, all of these drugs are effective, but treatment recommendations that take this into account are still pending. Instead, the choice of a drug may depend on other criteria such as drug safety or tolerability. In this review, we summarise current knowledge on the adverse effects of azathioprine, mycophenolate mofetil, rituximab, tocilizumab, eculizumab, satralizumab, and inebilizumab in NMOSD. Infections, cytopenias, and infusion-related reactions are most common, but the data are as heterogeneous as the manifestations are diverse. Nevertheless, knowledge of safety issues may facilitate treatment choices for individual patients.
Topics: Azathioprine; Drug-Related Side Effects and Adverse Reactions; Humans; Immunosuppressive Agents; Mycophenolic Acid; Neuromyelitis Optica; Rituximab
PubMed: 35456972
DOI: 10.3390/ijms23084154 -
Clinical Journal of the American... Aug 2021The long-term management of maintenance immunosuppression in kidney transplant recipients remains complex. The vast majority of patients are treated with the calcineurin... (Review)
Review
The long-term management of maintenance immunosuppression in kidney transplant recipients remains complex. The vast majority of patients are treated with the calcineurin inhibitor tacrolimus as the primary agent in combination with mycophenolate, with or without corticosteroids. A tacrolimus trough target 5-8 ng/ml seems to be optimal for rejection prophylaxis, but long-term tacrolimus-related side effects and nephrotoxicity support the ongoing evaluation of noncalcineurin inhibitor-based regimens. Current alternatives include belatacept or mammalian target of rapamycin inhibitors. For the former, superior kidney function at 7 years post-transplant compared with cyclosporin generated initial enthusiasm, but utilization has been hampered by high initial rejection rates. Mammalian target of rapamycin inhibitors have yielded mixed results as well, with improved kidney function tempered by higher risk of rejection, proteinuria, and adverse effects leading to higher discontinuation rates. Mammalian target of rapamycin inhibitors may play a role in the secondary prevention of squamous cell skin cancer as conversion from a calcineurin inhibitor to an mammalian target of rapamycin inhibitor resulted in a reduction of new lesion development. Early withdrawal of corticosteroids remains an attractive strategy but also is associated with a higher risk of rejection despite no difference in 5-year patient or graft survival. A major barrier to long-term graft survival is chronic alloimmunity, and regardless of agent used, managing the toxicities of immunosuppression against the risk of chronic antibody-mediated rejection remains a fragile balance.
Topics: Abatacept; Adrenal Cortex Hormones; Calcineurin Inhibitors; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; MTOR Inhibitors; Maintenance Chemotherapy; Mycophenolic Acid; Tacrolimus; Time Factors
PubMed: 33853841
DOI: 10.2215/CJN.15040920 -
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 -
Cleveland Clinic Journal of Medicine May 2023C3 glomerulopathy (C3G) is a rare kidney disease that causes kidney dysfunction as a result of dysregulation of the complement system alternate pathway (AP). C3G...
C3 glomerulopathy (C3G) is a rare kidney disease that causes kidney dysfunction as a result of dysregulation of the complement system alternate pathway (AP). C3G encompasses 2 separate disorders, C3 glomerulonephritis and dense deposit disease. The presentation and natural history is variable and kidney biopsy is needed to confirm the diagnosis. The overall prognosis is poor with high recurrence rates after transplant. A better understanding of C3G is needed as is high-quality evidence to guide therapy, which currently includes mycophenolate mofetil and steroids for moderate to severe disease, and terminal complement blockade with anti-C5 therapy in unresponsive cases.
Topics: Humans; Kidney Diseases; Kidney; Mycophenolic Acid
PubMed: 37225259
DOI: 10.3949/ccjm.90.e-s1.01