Adaptations to the current ECCO/ESPGHAN guidelines on the management of paediatric acute severe colitis in the context of the COVID-19 pandemic: a RAND appropriateness panel.

OBJECTIVE: Paediatric acute severe colitis (ASC) management during the novel SARS-CoV-2/COVID-19 pandemic is challenging due to reliance on immunosuppression and the potential for surgery. We aimed to provide COVID-19-specific guidance using the European Crohn's and Colitis Organisation/European Society for Paediatric Gastroenterology, Hepatology and Nutrition guidelines for comparison. DESIGN: We convened a RAND appropriateness panel comprising 14 paediatric gastroenterologists and paediatric experts in surgery, rheumatology, respiratory and infectious diseases. Panellists rated the appropriateness of interventions for ASC in the context of the COVID-19 pandemic. Results were discussed at a moderated meeting prior to a second survey. RESULTS: Panellists recommended patients with ASC have a SARS-CoV-2 swab and expedited biological screening on admission and should be isolated. A positive swab should trigger discussion with a COVID-19 specialist. Sigmoidoscopy was recommended prior to escalation to second-line therapy or colectomy. Methylprednisolone was considered appropriate first-line management in all, including those with symptomatic COVID-19. Thromboprophylaxis was also recommended in all. In patients requiring second-line therapy, infliximab was considered appropriate irrespective of SARS-CoV-2 status. Delaying colectomy due to SARS-CoV-2 infection was considered inappropriate. Corticosteroid tapering over 8-10 weeks was deemed appropriate for all. After successful corticosteroid rescue, thiopurine maintenance was rated appropriate in patients with negative SARS-CoV-2 swab and asymptomatic patients with positive swab but uncertain in symptomatic COVID-19. CONCLUSION: Our COVID-19-specific adaptations to paediatric ASC guidelines using a RAND panel generally support existing recommendations, particularly the use of corticosteroids and escalation to infliximab, irrespective of SARS-CoV-2 status. Consideration of routine prophylactic anticoagulation was recommended.

Infections after kidney transplantation: A comparison of mTOR-Is and CNIs as basic immunosuppressants. A systematic review and meta-analysis.

BACKGROUND: Side effects of the immunosuppressive therapy after solid organ transplantation are well known. Recently, significant benefits were shown for mTOR-Is with respect to certain viral infections in comparison with CNIs. However, reported total incidences of infections under mTOR-Is vs CNIs are usually not different. This raises the question to additional differences between these immunosuppressants regarding development and incidence of infections. METHODS: The current literature was searched for prospective randomized controlled trials in renal transplantation. There were 954 trials screened of which 19 could be included (9861 pts.). The 1-year incidence of infections, patient and graft survival were assessed in meta-analyses. RESULTS: Meta-analysis on 1-year incidence of infections showed a significant benefit of an mTOR-I based therapy when combined with a CNI vs CNI-based therapy alone (OR 0.76). There was no difference between mTOR-I w/o CNI and CNI therapy (OR 0.97). For pneumonia, a significant disadvantage was seen only for mTOR-I monotherapy compared to CNI's (OR 2.09). The incidence of CMV infections was significantly reduced under mTOR-I therapy (combination with CNI: OR 0.30; mTOR w/o CNI: OR: 0.46). There was no significant difference between mTOR-I and CNI therapy with respect to patient survival (mTOR-I w/o CNI vs CNI: OR 1.22; mTOR-I with CNI vs CNI: OR 0.86). Graft survival was negatively affected by mTOR-I monotherapy (OR 1.52) but not when combined with a CNI (OR 0.97). CONCLUSION: Following renal transplantation the incidence of infections is lower when mTOR-Is are combined with a CNI compared to a standard CNI therapy. Pneumonia occurs more often under mTOR-I w/o CNI.

Do disease-modifying drugs (DMD) have a positive impact on the occurrence of secondary progressive multiple sclerosis? Yes.

During the 20 past years, the management of multiple sclerosis (MS) has largely changed especially concerning therapeutical approach. Before 1996, treatments were restricted to corticosteroids for relapses, several symptomatic treatments and unselective immunosuppressive drugs (azathioprine, cyclophosphamide, methotrexate) with a low evidence of any efficacy. In the present review, we analyze the principal real-life cohorts of MS during several periods (before therapeutical modern area, first-generation treatment area and most recent period). Despite many methodological problems, we observe globally a delay of around 3-5 years between untreated cohorts and first-generation treatments for going to EDSS 6 which is probably the most robust score. This delay is clearly increase to at least 15 years with the most recent cohort treated first and second-line treatments confirming that early and more intensive treatment are necessary to have a long-term efficacy on disability progression and especially on severe disability represent by EDSS 6. Larger cohorts with longer follow-up is necessary to confirm these tendencies and OFSEP observatory or MS base will probably provide us the possibility to conclude in a couple of years.

Do disease-modifying drugs (DMD) have a positive impact on the occurrence of secondary progressive multiple sclerosis? Comment.

Very recent data from cohorts, such as that of the French Observatory of Multiple Sclerosis (OFSEP) and the MSBase cohort, are the subject of new statistical analyses using propensity scores that enable the matching of relapses frequency, EDSS, age, and sex ratio in patient populations for comparisons with each other, which reduces selection biases. The first data from these cohorts revealed a decline in transition to secondary progressive MS with the most effective disease-modifying drugs currently available, especially when these drugs were used early in the disease. However, these studies remain limited regarding the number of patients, the duration of follow-up, the use of imperfect methodologies, and the level of evidence remains low. The Gothenburg cohort in Sweden, which has been followed since the 1950s, found that 14% of benign non-progressive multiple sclerosis (MS) never evolved to secondary progression after more than 45 years of evolution. EDSS 7 was reached after 48 years of disease (median), and 50% evolved to secondary progressive MS after 15 years (consistent with data from the historic London, Ontario cohort). These data demonstrate that most people living with MS evolve without treatment to a significant long-term disability and that this evolution is closely linked to secondary progression (more than the relapse frequency). Benign forms appear as MS that never passes into secondary progressive MS. Recent data demonstrate that the delay until transition to secondary progression (more than 30 years in the MSBase cohort) and the delay in reaching EDSS 6 decreased since the introduction of disease-modifying drugs 20 years ago. However, randomized placebo-controlled trials do not last more than 2 or 3 years, and many biases may be involved in long-term follow-up studies: worsening patients who are lost to follow-up ("informative censoring" bias: only good responders to treatment remain primarily under the same long-term treatment and are followed); changes in the populations in the most recent studies with a lower rate of relapse and lower progression of disability at the beginning of the disease prior to initiating treatments; and environmental changes that remain largely misunderstood and may contribute to a natural evolution towards less severe disease.

Do disease-modifying drugs (DMD) have a positive impact on the occurrence of secondary progressive multiple sclerosis? No.

RR MS evolution has changed since the beginning of the availability of MS disease-modifying drugs (DMD). Before concluding a unique impact of the efficiency of DMD, careful analysis of long-term studies has to be conducted. Analysis of the literature points out a few bias in the long-term follow of MS patients under DMD: indication of DMD has changed since 20 years, diagnosis criteria are not the same (including the Will Rogers phenomen), and so far population are not homogeneous and comparable. Analysis criteria of the efficiency of the treatments are not the same, pending on the date of the publications. References concerning the long-term impact of DMD are in fact very limited. In addition, long-term efficiency of 2nd line treatments is not available. Another explanation of the change of MS evolution could be the lower evolutivity of MS patients since 2 decades. Analysis of placebo group in pivotal studies, argues to a decrease of the relapse annual rate and mean EDSS score in the more recent studies and recent MS diagnosed patients. To conclude, long-term evolution of MS patients is more favorable, influence of DMD is likely, but not unique.

What are the infectious risks with disease-modifying drugs for multiple sclerosis and how to reduce them? A review of literature.

Patients with multiple sclerosis taking immunosuppressive therapy may be at risk of reactivating latent pathogens, community-acquired infections, worsening asymptomatic chronic infections, and contracting de novo infections. This risk was evaluated mainly in short-term clinical trials and few studies have investigated this risk in real-life settings. In clinical practice, this infectious risk should be evaluated when a multiple sclerosis diagnosis is made in order to propose specific follow-up or immunization as soon as possible and thus avoid contraindications or risk of lowered vaccination responses. Systematic screening should also be proposed for each patient before second-line therapy to ensure the risk is in line with the treatment plan. This systematic screening must include HIV and hepatitis B and C for all patients before treatment. The immunization schedule needs to be updated and influenza vaccine could be proposed each year for patients receiving disease-modifying drugs. Prevention is preferable to treatment, reducing both infectious morbidity and mortality, as well as interruptions in multiple sclerosis therapy. Therefore, preventive approaches should be tailored to individual patient and treatment risk factors. In this review, we describe the infectious risk with immunossuppressive therapies and propose minimal screening recommendations to evaluate the risk and adapt the prevention and strategy of immunization to each case at multiple sclerosis diagnosis and at specific follow-up visits to avoid difficulties using live-attenuated vaccines or risk reduced immune responses.

Immunomodulatory Therapy Does Not Increase the Risk of Cancer in Persons With Inflammatory Bowel Disease and a History of Extracolonic Cancers.

OBJECTIVES: Immunosuppressant therapies (IMTs; thiopurines, anti-tumor necrosis factor agents) may influence the immunologic control of cancer and might facilitate the spread and recurrence of cancer. This study assesses the impact of the use of IMTs on the development of incident cancers (recurrent or new) in patients with inflammatory bowel disease (IBD) and a history of malignancy. METHODS: Patients with IBD included in the ENEIDA registry with a history of cancer without being exposed to IMTs were identified and retrospectively reviewed and compared regarding further treatment with IMTs or not by means of a log-rank test. RESULTS: Overall, 520 patients with previous extracolonic cancer naive to IMTs before the diagnosis of cancer were identified. Of these, 146 were subsequently treated with IMTs (exposed), whereas 374 were not (nonexposed). The proportion of patients with incident cancers was similar in both exposed (16%) and nonexposed (18%) patients (P = 0.53); however, there was more than a 10-year difference in the age at index cancer between these 2 groups. Cancer-free survival was 99%, 98%, and 97% at 1, 2, and 5 years in exposed patients, and 97%, 96%, and 92% at 1, 2, and 5 years in non-exposed patients, respectively (P = 0.03). No differences in incident cancer rates were observed between exposed and nonexposed patients when including only those who were exposed within the first 5 years after cancer diagnosis. DISCUSSION: In patients with IBD and a history of cancer not related to immunosuppression, the use of IMTs is not associated with an increased risk of new or recurrent cancers even when IMTs are started early after cancer diagnosis.

[Idiopathic inflammatory myopathies. A review]. / Miopatías inflamatorias idiopáticas: una mirada actualizada al diagnóstico y el manejo.

Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of acquired immune-mediated diseases, which typically involve the striated muscle with a variable involvement of the skin and other organs. Clinically, they are characterized by proximal muscle weakness, elevation of muscle enzymes, myopathic changes on electromyography and an abnormal muscle biopsy. The different IIM have been classified according to their distinctive histopathologic features in dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM) and immune-mediated necrotizing myopathy (IMNM). Several myositis-specific antibodies are associated with the different phenotypes, as well as with different risk of neoplastic disease and systemic complications. The basis for the treatment of DM, PM, and IMNM is immunosuppression. For IBM there are only symptomatic treatments. Steroids, associated or not with other immunosuppressant drugs, are the first line of treatment. Biologic drugs will allow future individualized therapies. The 10-year survival of DM, PM and IMNM is 62 to 90%. The leading causes of death are neoplastic, lung and cardiac complications. IBM does not impair survival, although it affects the quality of life.

Azodicarbonamide (ADCA): A reconsideration of classification as a respiratory sensitiser.

Azodicarbonamide (ADCA) is widely used by industry in the manufacture of a variety of products. ADCA has been classified as a respiratory allergen, and the purpose of this article was to consider whether this classification is appropriate based upon the available data. Here both clinical experience and relevant experimental data have been reviewed. Although there have been reports of an association between workplace exposure to ADCA and symptoms of respiratory allergy and occupational asthma, the evidence is less than persuasive, with in many instances a lack of properly controlled and executed diagnostic procedures. In addition, ADCA fails to elicit positive responses in mouse and guinea pig predictive tests for skin sensitisation; a lack of activity that is regarded as being inconsistent with respect to respiratory sensitising potential. Collectively, the data reviewed here do not provide an adequate basis for the classification of ADCA as a respiratory allergen.

The molecular mechanism of substrate engagement and immunosuppressant inhibition of calcineurin.

Ser/thr phosphatases dephosphorylate their targets with high specificity, yet the structural and sequence determinants of phosphosite recognition are poorly understood. Calcineurin (CN) is a conserved Ca(2+)/calmodulin-dependent ser/thr phosphatase and the target of immunosuppressants, FK506 and cyclosporin A (CSA). To investigate CN substrate recognition we used X-ray crystallography, biochemistry, modeling, and in vivo experiments to study A238L, a viral protein inhibitor of CN. We show that A238L competitively inhibits CN by occupying a critical substrate recognition site, while leaving the catalytic center fully accessible. Critically, the 1.7 Å structure of the A238L-CN complex reveals how CN recognizes residues in A238L that are analogous to a substrate motif, "LxVP." The structure enabled modeling of a peptide substrate bound to CN, which predicts substrate interactions beyond the catalytic center. Finally, this study establishes that "LxVP" sequences and immunosuppressants bind to the identical site on CN. Thus, FK506, CSA, and A238L all prevent "LxVP"-mediated substrate recognition by CN, highlighting the importance of this interaction for substrate dephosphorylation. Collectively, this work presents the first integrated structural model for substrate selection and dephosphorylation by CN and lays the groundwork for structure-based development of new CN inhibitors.

[Risk factors, clinical presentations, prevention, and treatment of corneal graft rejection]. / Faktory riska, klinicheskie proiavleniia, metody profilaktiki i lecheniia reaktsii ottorzheniia transplantata rogovitsy.

Corneal transplantation is the most common and successful type of allotransplantation surgery. Post-transplant immune response in keratoplasty is less pronounced than that in other transplantation procedures, which is accounted for by anatomical features of the cornea and, also, its low antigenic potential and active immunosuppression. However, the immune privilege of the cornea can be violated by neovascularization, inflammation, or trauma. Patients who require keratoplasty to restore their sight and whose immune privilege is disturbed, fall into a high-risk group and are likely to demonstrate tissue incompatibility and non-transparent engraftment. Two approaches exist as to how graft rejection can be prevented. One of them involves induction of donor-specific tolerance, the other - non-specific suppression of the recipient's immune response. To avoid tissue incompatibility, measures can be taken to restore the immune privilege of the cornea as well as to induce antigen-specific tolerance, which is considered a promising, thought yet experimental, area of modern transplantology. In clinical practice, one pays most attention to improvement of non-specific immune suppression methods based on interfering in the metabolism of immunocompetent cells. Thus, timely prescriptions and proper immunosuppressive tactics with account to possible risk factors determine the outcome in high-risk patients undergoing corneal transplantation surgery.

A risk classification for immunosuppressive treatment-associated progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a rare, complex opportunistic infection of the central nervous system caused by the JC virus. This past decade, PML was increasingly recognized to be associated with the use of immunosuppressive and biologic agents. The risk for PML differs among these agents and remains difficult to quantify because of the complex pathogenesis of PML and the presence of confounding factors. This paper explores and updates the association of PML with different biologic and immunosuppressive agents and proposes an expanded classification system for the risk of PML. We identify three classes of drug that vary by PML risk, latency to infection, and underlying illness. We also review some of the most common agents with known associations to PML and explore risk mitigation strategies that aim to inform the decision-making process for clinicians and patients in the face of the changing incidence of PML and the growing landscape of immunologic agents.

Anti-TNF-α therapy in the management of severe neurosarcoidosis: a report of five cases from a single centre and literature review.

Neurologic manifestations are found in 5-15 % of patients with sarcoidosis. This granulomatous disease may affect any part of the peripheral or the central nervous system, being potentially severe and difficult to treat. Corticosteroids are the cornerstone of therapy in sarcoidosis. However, some patients become resistant or experience side effects to corticosteroids. In these patients, second line therapies including immunosuppressive drugs such as methotrexate, azathioprine, mycophenolate, cyclophosphamide and leflunomide have been used. Anti-TNF-α drugs have been proposed as a therapeutic option for those who are refractory to immunosuppressive drugs or initially in cases of severe sarcoidosis. We report on 5 patients with neurosarcoidosis treated with anti-TNF-α drugs in our center. A literature review of patients with neurosarcoidosis treated with anti-TNF-α drugs was conducted. In our series successful response to anti-TNF-α therapy was achieved. However, the high frequency of relapses following anti-TNF-α discontinuation makes necessary a close follow-up of these patients when the biologic agent is stopped.

The use of the EVITA algorithm for clinical assessment of novel agents used in prostate cancer, metastatic melanoma, and systemic lupus erythematosus.

PURPOSE: Existing health technology assessment methods can be time-consuming and complicated to use in practice. EValuation of pharmaceutical Innovations with regard to Therapeutic Advantage (EVITA) is a recently developed drug assessment strategy that provides a detailed and clinically relevant evaluation of new agents compared to standard therapies. We therefore sought to use EVITA to evaluate eight novel agents recently introduced to clinical practice or in late-stage trials for the treatment of prostate cancer, metastatic melanoma, or systemic lupus erythematosus (SLE). METHODS: Eight agents (abiraterone, enzalutamide, sipuleucel-T, Prostvac, radium 223, ipilimumab, vemurafenib, and belimumab) were selected for study using the EVITA algorithm. A comprehensive literature search was performed to find clinical trial data, which were then classified using the EVITA protocol. EVITA was also compared to results from health technology assessments (HTAs) or reimbursement decisions. RESULTS: The EVITA scores for the eight drugs ranged from 5.5 to 9: all the selected agents are therefore classed as 'recommended' and are likely to produce a therapeutic advantage. In particular, vemurafenib is likely to be highly beneficial to patients with metastatic melanoma and radium 223 to patients with metastatic prostate cancer affecting the bone. The EVITA results were generally concordant with HTAs. CONCLUSIONS: All the agents show favourable EVITA scores and are therefore recommended for clinical practice. EVITA is an easy-to-use tool that provides clinical context to the assessment of newly introduced agents and can be easily used by non-specialists.

[Immunomodulators in Therapy of Respiratory Infections].

Viral infections provoke dysbalance in the interferon system and inhibition of the cellular and phagocytic responses of the host. Long-term persistence of pathogenic viruses and bacteria induce atopy and could aggravate chronic respiratory diseases. The up-to-date classification of immunomodulators is described. High efficacy of interferon inductors, such as cycloferon and some others as auxiliary means in therapy or prophylaxis (immunorehabilitation) of viral respiratory infections in adults and children was shown.

A short story of anti-rheumatic therapy. VIII. The immunodepressants.

The use of immunosuppressive drugs in rheumatology is fairly recent, starting just after the Second World War with the introduction of the first alkylating agents in oncohematology. When it became clear that some rheumatic diseases, particularly rheumatoid arthritis and systemic lupus erythematosus, showed an immune-mediated pathogenesis, including proliferation of immunocompetent cells, an application was soon found for immunosuppressive drugs in their treatment. This review outlines the historical milestones that led to the current use of drugs belonging to the major groups of immunosuppressants, i.e. alkylating agents (cyclophosphamide), folic acid (methotrexate) and purine (azathioprine) antagonists. We will also talk about the history of cyclosporin A, the first "selective" immunosuppressive agent, and that of some immunoactive drugs used more recently in rheumatology, such as mycophenolate mofetil, dapson and thalidomide, is briefly described.

Clinical characteristics and genetic analysis of A20 haploinsufficiency.

PURPOSE: To evaluate the clinical and genetic characteristics of 3 children with Haploinsufficiency of A20 (HA20). METHODS: The clinical and genetic testing data of 3 children with HA20 treated at Capital Institute of Pediatrics (CIP) between August 2016 and October 2019 were retrospectively analysed. RESULT: Patient 1 presented with arthritis and inflammatory bowel disease, patient 2 presented with axial spinal arthritis and lupus-like syndrome, and patient 3 presented with recurrent oral ulcers, gastrointestinal ulcers, and perianal abscesses. Regarding laboratory tests, patients were found to have elevated white blood cell (WBC) count, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). The CRP and ESR was reported to be high in all the patients. The WBC was reported to be high in patient 1 and 3. Patient 2 was positive for antinuclear antibodies, anti-Sjögren's syndrome antigen A, dsDNA, rheumatoid factor and Coombs test. Genetic testing showed that all three patients had heterozygous mutation in TNFAIP3 gene. As for the treatment, patient 1 was treated with TNFα antagonist, patient 2 was treated with TNF α antagonist and sulfasalazine, and patient 3 was treated with corticosteroids and thalidomide. Patients 1 and 2 were followed for four and 3 months, respectively. There was an improvement in joint and gastrointestinal symptoms; inflammatory indices and rheumatoid factor (RF) were normal, and dsDNA and Coombs test became negative. Patient 3 was treated at another hospital and showed gradual improvement in oral ulcers and perianal abscesses. CONCLUSION: HA20 is a single-gene auto-inflammatory disease caused by mutation in tumour necrosis factor (TNF)-α-induced protein 3 (TNFAIP3) gene. It may present as Behçet-like syndrome and resemble various other autoimmune diseases as well. Corticosteroids and immunosuppressive agents are effective treatments, and cytokine antagonists can be used in refractory cases. Whole-exome genetic testing should be proactively performed for children with early-age onset or Behçet-like syndrome to achieve early diagnosis and accurate treatment.

The Oxford IgA nephropathy clinicopathological classification is valid for children as well as adults.

To study the predictive value of biopsy lesions in IgA nephropathy in a range of patient ages we retrospectively analyzed the cohort that was used to derive a new classification system for IgA nephropathy. A total of 206 adults and 59 children with proteinuria over 0.5 g/24 h/1.73 m(2) and an eGFR of stage-3 or better were followed for a median of 69 months. At the time of biopsy, compared with adults children had a more frequent history of macroscopic hematuria, lower adjusted blood pressure, and higher eGFR but similar proteinuria. Although their outcome was similar to that of adults, children had received more immunosuppressants and achieved a lower follow-up proteinuria. Renal biopsies were scored for variables identified by an iterative process as reproducible and independent of other lesions. Compared with adults, children had significantly more mesangial and endocapillary hypercellularity, and less segmental glomerulosclerosis and tubulointerstitial damage, the four variables previously identified to predict outcome independent of clinical assessment. Despite these differences, our study found that the cross-sectional correlation between pathology and proteinuria was similar in adults and children. The predictive value of each specific lesion on the rate of decline of renal function or renal survival in IgA nephropathy was not different between children and adults.