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Contains fulltext : 251784.pdf (Publisher’s version ) (Closed access) BACKGROUND: Concerns have been raised regarding the risks of SARS-CoV-2 breakthrough infections in vaccinated patients with immune-mediated inflammatory diseases treated with immunosuppressants, but clinical data on breakthrough infections are still scarce. The primary objective of this study was to compare the incidence and severity of SARS-CoV-2 breakthrough infections between patients with immune-mediated inflammatory diseases using immunosuppressants, and controls (patients with immune-mediated inflammatory diseases not taking immunosuppressants and healthy controls) who had received full COVID-19 vaccinations. The secondary objective was to explore determinants of breakthrough infections of the delta (B.1.617.2) variant of SARS-CoV-2, including humoral immune responses after vaccination. METHODS: In this substudy, we pooled data collected in two large ongoing prospective multicentre cohort studies conducted in the Netherlands (Target to-B! [T2B!] study and Amsterdam Rheumatology Center COVID [ARC-COVID] study). Both studies recruited adult patients (age ≥18 years) with immune-mediated inflammatory diseases and healthy controls. We sourced clinical data from standardised electronic case record forms, digital questionnaires, and medical files. We only included individuals who were vaccinated against SARS-CoV-2. For T2B!, participants were recruited between Feb 2 and Aug 1, 2021, and for ARC-COVID, participants were recruited between April 26, 2020, and March 1, 2021. In this study we assessed data on breakthrough infections collected between July 1 and Dec 15, 2021, a period in which the delta SARS-CoV-2 variant was the dominant variant in the Netherlands. We defined a SARS-CoV-2 breakthrough infection as a PCR-confirmed or antigen test-confirmed SARS-CoV-2 infection that occurred at least 14 days after vaccination. All breakthrough infections during this period were assumed to be due to the delta variant due to its dominance during the study period. We analysed post-vaccination serum samples for anti-receptor binding domain (RBD) antibodies to assess the humoral vaccination response (T2B! study only) and anti-nucleocapsid antibodies to identify asymptomatic breakthrough infections (ARC-COVID study only). We used multivariable logistic regression analyses to explore potential clinical and humoral determinants associated with the odds of breakthrough infections. The T2B! study is registered with the Dutch Trial Register, Trial ID NL8900, and the ARC-COVID study is registered with Dutch Trial Register, trial ID NL8513. FINDINGS: We included 3207 patients with immune-mediated inflammatory diseases who receive immunosuppressants, and 1807 controls (985 patients with immune-mediated inflammatory disease not on immunosuppressants and 822 healthy controls). Among patients receiving immunosuppressants, mean age was 53 years (SD 14), 2042 (64%) of 3207 were female and 1165 (36%) were male; among patients not receiving immunosuppressants, mean age was 54 years (SD 14), 598 (61%) of 985 were female and 387 (39%) were male; and among healthy controls, mean age was 57 years (SD 13), 549 (67%) of 822 were female and 273 (33%) were male. The cumulative incidence of PCR-test or antigen-test confirmed SARS-CoV-2 breakthrough infections was similar in patients on immunosuppressants (148 of 3207; 4·6% [95% CI 3·9-5·4]), patients not on immunosuppressants (52 of 985; 5·3% [95% CI 4·0-6·9]), and healthy controls (33 of 822; 4·0% [95% CI 2·8-5·6]). There was no difference in the odds of breakthrough infection for patients with immune-mediate inflammatory disease on immunosuppressants versus combined controls (ie, patients not on immunosuppressants and healthy controls; adjusted odds ratio 0·88 [95% CI 0·66-1·18]). Seroconversion after vaccination (odds ratio 0·58 [95% CI 0·34-0·98]; T2B! cohort only) and SARS-CoV-2 infection before vaccination (0·34 [0·18-0·56]) were associated with a lower odds of breakthrough infections. INTERPRETATION: The incidence and severity of SARS-CoV-2 breakthrough infections in patients with immune-mediated inflammatory diseases on immunosuppressants was similar to that in controls. However, caution might still be warranted for those on anti-CD20 therapy and those with traditional risk factors. FUNDING: ZonMw (the Netherlands Organization for Health Research and Development) and Reade foundation.

Summary In this Review, we discuss the possibility of drug tapering in patients with rheumatoid arthritis in remission or low disease activity, for glucocorticoids and disease-modifying antirheumatic drugs. We review international guidelines and recommendations, as well as remaining uncertainties, and provide an overview of the current literature. Three strategies of tapering are discussed: (1) tapering by discontinuation of one of the drugs in combination therapy regimens, (2) tapering by reducing the dose of one of the drugs in combination therapy regimens, and (3) tapering by dose reduction of monotherapy with disease-modifying antirheumatic drugs. We discuss the outcomes and robustness of evidence of trials and observational cohorts, and we give a trajectory for further research and drug tapering in daily practice.

ObjectiveTo investigate the success rate of glucocorticoid (GC) discontinuation during follow-up in observational cohorts and clinical trials using temporary GC as part of initial therapy (‘bridging’) in newly diagnosed patients with rheumatoid arthritis (RA).MethodsSystematic literature searches were conducted to identify observational cohorts and clinical trials including patients with RA treated with initial GC bridging therapy, defined as discontinuation of GC within 1 year. Patient percentages still using GC were considered the reverse of successful discontinuation. Random effects meta-analyses were performed stratified by time point.ResultsThe scoping literature search for observational cohort studies could not identify studies answering the research question. The literature search for clinical trials identified 7160 abstracts, resulting in 10 included studies, with varying type and dose of GC and varying tapering schedules, of which 4 reported sufficient data on GC discontinuation or use after the bridging phase. The pooled proportion of patients who were still or again using GC was 22% (95% CI 8% to 37%, based on four trials) at 12 months and 10% at 24 months (95% CI −1 to 22, based on two trials). Heterogeneity was substantial (I²≥65%).ConclusionThe success rate of GC discontinuation after bridging as part of initial treatment of RA has been described in a limited number of studies. Reports on observational cohorts did not answer the research question. In clinical trials, protocolised discontinuation was mostly successful, although 22% of the patients who started GC bridging therapy still or again used GC at 12 months, and 10% at 24 months.

Background: Disease-specific studies have reported impaired humoral responses after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders treated with specific immunosuppressants. Disease-overarching studies, and data on recall responses and third vaccinations are scarce. Our primary objective was to investigate the effects of immunosuppressive monotherapies on the humoral immune response after SARS-CoV-2 vaccination in patients with prevalent immune-mediated inflammatory disorders.Methods: We did a cohort study in participants treated in outpatient clinics in seven university hospitals and one rheumatology treatment centre in the Netherlands as well as participants included in two national cohort studies on COVID-19-related disease severity. We included patients aged older than 18 years, diagnosed with any of the prespecified immune-mediated inflammatory disorders, who were able to understand and complete questionnaires in Dutch. Participants with immune-mediated inflammatory disorders who were not on systemic immunosuppressants and healthy participants were included as controls. Anti-receptor binding domain IgG responses and neutralisation capacity were monitored following standard vaccination regimens and a three-vaccination regimen in subgroups. Hybrid immune responses-ie, vaccination after previous SARS-CoV-2 infection-were studied as a proxy for recall responses.Findings: Between Feb 2 and Aug 1, 2021, we included 3222 participants in our cohort. Sera from 2339 participants, 1869 without and 470 participants with previous SARS-CoV-2 infection were analysed (mean age 49·9 years [SD 13·7]; 1470 [62·8%] females and 869 [37·2%] males). Humoral responses did not differ between disorders. Anti-CD20 therapy, sphingosine 1-phosphate receptor (S1P) modulators, and mycophenolate mofetil combined with corticosteroids were associated with lower relative risks for reaching seroconversion following standard vaccination (0·32 [95% CI 0·19-0·49] for anti-CD20 therapy, 0·35 [0·21-0·55] for S1P modulators, and 0·61 [0·40-0·90] for mycophenolate mofetil combined with corticosteroids). A third vaccination increased seroconversion for mycophenolate mofetil combination treatments (from 52·6% after the second vaccination to 89·5% after the third) but not significantly for anti-CD20 therapies (from 36·8% to 45·6%) and S1P modulators (from 35·5% to 48·4%). Most other immunosuppressant groups showed moderately reduced antibody titres after standard vaccination that did not increase after a third vaccination, although seroconversion rates and neutralisation capacity were unaffected. In participants with previous SARS-CoV-2 infection, SARS-CoV-2 antibodies were boosted after vaccination, regardless of immunosuppressive treatment.Interpretation: Humoral responses following vaccination are impaired by specific immunosuppressants. After standard vaccination regimens, patients with immune-mediated inflammatory disorders taking most immunosuppressants show similar seroconversion to controls, although antibody titres might be moderately reduced. As neutralisation capacity and recall responses are also preserved in these patients, this is not likely to translate to loss of (short-term) protection. In patients on immunosuppressants showing poor humoral responses after standard vaccination regimens, a third vaccination resulted in additional seroconversion in patients taking mycophenolate mofetil combination treatments, whereas the effect of a third vaccination in patients on anti-CD20 therapy and S1P modulators was limited.Funding: ZonMw (The Netherlands Organization for Health Research and Development).

ObjectivesTo investigate whether patients with rheumatoid arthritis (RA) can discontinue glucocorticoids (GC) after GC ‘bridging’ in the initial treatment step and to identify factors that may affect this.MethodsData from 7 clinical trial arms (with 1653 patients) that included a GC bridging schedule, previously identified in a systematic literature search, were combined in an individual patient data meta-analysis. Outcomes were GC use (yes/no) at predefined time points (1/3/6/12/18 months after bridging had ended), cumulative GC dose and continuous (≥3 months) GC use after bridging had ended. Age, sex, ACPA status, initial GC dose, duration of bridging schedule, oral versus parenteral GC administration and initial co-treatment were univariably tested with each outcome.ResultsThe probability of using GC 1 month after bridging therapy had ended was 0.18, decreasing to 0.07 from 6 until 18 months after bridging had ended. The probability of continuous GC use after bridging had ended was 0.18 at 1 year and 0.30 at 2 years of follow-up. In oral GC bridging studies only, the probabilities of later and continuous GC use and the cumulative GC doses were higher compared to the combined analyses with also parenteral GC bridging studies included. A higher initial dose and a longer GC bridging schedule were associated with higher cumulative GC doses and more patients on GC at 18 months after bridging had ended.ConclusionsBased on these RA clinical trial arms with an initial GC bridging schedule, the probability of subsequent ongoing GC use following bridging is low.

With the arrival of SARS-CoV-2, it was asked whether our patients with immune-mediated inflammatory disorders, or who had an organ transplantation (IMDT patients) and/or use immunosuppressive medication (imed) are more susceptible to SARS-CoV-2 infection and/or a severe COVID-19 disease course. In the earliest reports on COVID-19, such patients were rarely described. Most reports were retrospectively collected, in various case series or cohorts without a control group.1–3 The Infection and Immunomodulation Inventory Initiative cohort study was started 10 March 2020 to prospectively register self-reported periods of illness with COVID-19-like symptoms (CLS) (see questionnaire in online supplemental table 1) and compare these between IMIDT patients with and without imed and controls as selected from the hospital database of the Leiden University Medical Center in March 2020. Patients were defined as being in outpatient care at the outpatient clinic for rheumatology, gastroenterology, pulmonology and/or nephrology and having an autoinflammatory or autoimmune disease or having had a solid organ transplantation with or without imed (verified from the medical records after participant’s informed consent). Controls were persons who had visited these outpatient clinics in the previous …

Backgrounds: Patients with an immune mediated inflammatory disorder or post solid organ transplantation (IMIDT), are at risk for infectious complications especially if they are treated with immunosuppressive drugs (imeds). There is still great uncertainty whether these IMIDT patients are more susceptible to COVID-19 than controls, and/or should be advised to avoid taking their immunosuppressive treatment. Methods: A Dutch prospective cohort study in patients with IMIDT and controls (healthy or no IMIDT) who were identified based on the hospital registration database. Participants prospectively registered COVID-like symptoms (CLS) over time, and filled in health questionnaires. Findings: Of the 8670 individuals approached, 2110 with IMIDT and 1067 controls agreed to participate. In March and April, 454 (22%) of IMIDT patients and 242 (23%) of controls recorded to have CLS, mostly mild, with a duration of (median, IQR) seven days (3-14) in the IMIDT group and six days (4-11) in the control group, with fever occurring in 178 (26%) of reported CLS episodes. Six (3%) of the IMIDT patients without imed and 11(5%) of the IMIDT patients with imed were hospitalized versus 2(1%) of the control group with CLS. In May and June, fewer episodes overall were recorded. Being female (OR 1·45 95%CI 1·15;1·82), wearing a face mask (OR 1·42 95%CI 1·13-1·77) and having a lung disease (OR 1·50 95%CI 1·20;1·88) were independently associated with a higher risk, but higher age (OR 0·96 95%CI 0·96;0·97) and having an IMIDT with immunosuppressive medication use (OR 0·68 95%CI 0·51;0·91) with a lower risk of experiencing CLS. Interpretation: Between March and July 2020, IMIDT patients, whether or not taking imeds, did not show an increased risk of reported COVID-like symptoms compared to controls. Continuing immunosuppressant drugs as long as not ill, while following the Dutch COVID rules, appears to be safe. Funding: This study was not funded. Declaration of Interests: All authors declare that they have no competing interests. Ethics Approval Statement: The study protocols of IENIMINI cohort study was approved by the Medical Ethics Committee Leiden Delft Den Haag (LDD).