Role for antimalarials in the management of COVID-19.

PURPOSE OF REVIEW: The current review highlights recent insights into direct antiviral effects by antimalarials against severe acute respiratory syndrome (SARS)-CoV-2 and other viruses and their potential indirect effects on the host by avoiding exaggerated immune responses (reduced cytokine release, Toll-like receptor response, antigen presentation related to lysosomal processing). RECENT FINDINGS: Currently, there is a large debate on the use of antimalarials for prophylaxis and treatment of SARS-CoV-2-induced disease based on preclinical in-vitro data, small case series and extrapolation from earlier studies of their effect on intracellular pathogens, including many viruses. Hydroxychloroquine (HCQ) or chloroquine have not demonstrated robust efficacy in prior randomized controlled studies against several other viruses. In-vitro data indicate a reduced viral replication of SARS-CoV-2. Especially immunomodulatory effects of antimalarials might also contribute to a clinical efficacy. For SARS-CoV-2 various large studies will provide answers as to whether antimalarials have a place in prophylaxis or treatment of the acute virus infection with SARS-CoV-2 but compelling data are missing so far. SUMMARY: In-vitro data provide a theoretical framework for an efficacy of antimalarials in SARS-CoV-2-induced disease but clinical proof is currently missing.

ERN ReCONNET points to consider for treating patients living with autoimmune rheumatic diseases with antiviral therapies and anti-SARS-CoV-2 antibody products.

Recent studies have shown that people who are immunocompromised may inadvertently play a role in spurring the mutations of the virus that create new variants. This is because some immunocompromised individuals remain at risk of getting COVID-19 despite vaccination, experience more severe disease, are susceptible to being chronically infected and remain contagious for longer if they become infected and considering that immunocompromised individuals represent approximately 2% of the overall population, this aspect should be carefully considered. So far, some autoimmune rheumatic disease (ARD) patients with COVID-19 have been treated with antiviral therapies or anti-SARS-CoV-2 antibody products. However, there is no homogeneous approach to these treatment strategies. This issue was addressed within the European Reference Network (ERN) on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ReCONNET) in a discussion among experts and patient's representatives in the context of the rare and complex connective tissue diseases (rCTDs) covered by the Network. ERN ReCONNET is one of the 24 ERNs launched by the European Commission in 2017 with the aim of tackling low prevalence and rare diseases that require highly specialised treatment and promoting concentration of knowledge and resources through virtual networks involving healthcare providers (HCPs) across the European Union (EU). Considering the urgent need to provide guidance not only to the rCTDs community, but also to the whole ARDs community, a multidisciplinary Task Force, including expert clinicians and European Patient Advocacy Group (ePAG) Advocates, was created in the framework of ERN ReCONNET with the aim of developing overarching principles (OP) and points-to-consider (PtC) on a homogenous approach to treat immunocompromised patients with ARDs (with a particular focus on CTDs) affected by COVID-19 using antiviral therapies and anti-SARS-CoV-2 antibody products. The present work reports the final OP and PtC agreed by the Task Force.

Improvement of humoral immunity by repeated dose-intensified COVID-19 vaccinations in primary non- to low-responders and B cell deficient rheumatic disease patients.

OBJECTIVE: To determine whether repeated, dose-intensified mRNA vaccinations against COVID-19 increase humoral immunity in previously low-responding patients with autoimmune rheumatic diseases (AIRD), including rituximab-treated and B cell depleted patients. METHODS: Of 308 AIRD patients receiving basic immunization, 98 had a low serological response against SARS-CoV-2 with a neutralizing capacity of < 70% using surrogate neutralization assay. 38 patients received a third vaccination with 30 µg BNT162b2 16 weeks after second vaccination. If neutralizing serum capacity was below 70% four weeks after the last vaccination, then the fourth vaccination (n = 19) and the fifth (n = 4) vaccination with 100 µg mRNA-1273 took place eight weeks after the last vaccination. RESULTS: Each of the three booster vaccinations resulted in a significant increase of mean serum neutralizing capacity (3rd: Δ = 42%, p < 0.001; 4th: Δ = 19%, p = 0.049 and 5th: Δ = 51%, p = 0.043) and produced a significant proportion of high-responders (3rd: 34%; 4th: 32% and 5th: 75%). Low B cell counts (p = 0.047), lower previous antibody response (p < 0.001) and rituximab therapy (p = 0.021) were negatively associated with successful response to the third but not to the fourth vaccination. Remarkably, substantial increases in neutralization capacity of up to 99% were observed after repeated vaccinations in B cell depleted patients. CONCLUSION: AIRD patients with low humoral response benefited from up to three repeated dose-intensified mRNA booster vaccinations - despite low B cell count and previous rituximab therapy. Each additional vaccination substantially reduced the number of low-responding, vulnerable patients.

Pausing methotrexate prevents impairment of Omicron BA.1 and BA.2 neutralisation after COVID-19 booster vaccination.

OBJECTIVE: The level of neutralising capacity against Omicron BA.1 and BA.2 after third COVID-19 vaccination in patients on paused or continuous methotrexate (MTX) therapy is unclear. METHODS: In this observational cohort study, neutralising serum activity against SARS-CoV-2 wild-type (Wu01) and variant of concern Omicron BA.1 and BA.2 were assessed by pseudovirus neutralisation assay before, 4 and 12 weeks after mRNA booster immunisation in 50 rheumatic patients on MTX, 26 of whom paused the medication. 44 non-immunosuppressed persons (NIP) served as control group. RESULTS: While the neutralising serum activity against SARS-CoV-2 Wu01 and Omicron variants increased 67-73 fold in the NIP after booster vaccination, the serum activity in patients receiving MTX increased only 20-23 fold. Patients who continued MTX treatment during vaccination had significantly lower neutralisation against all variants at weeks 4 and 12 compared with patients who paused MTX and the control group, except for BA.2 at week 12. Patients who paused MTX reached comparably high neutralising capacities as NIP, except for Wu01 at week 12. The duration of the MTX pause after-not before-was associated with a significantly higher neutralisation capacity against all three variants, with an optimal duration at 10 days after vaccination. CONCLUSION: Patients pausing MTX after COVID-19 booster showed a similar vaccine response to NIP. Patients who continued MTX demonstrated an impaired response indicating a potentially beneficial second booster vaccination. Our data also suggest that a 1 week MTX break is sufficient if the last administration of MTX occurs 1-3 days before vaccination.

A systematic literature review informing the consensus statement on efficacy and safety of pharmacological treatment with interleukin-6 pathway inhibition with biological DMARDs in immune-mediated inflammatory diseases.

OBJECTIVES: Informing an international task force updating the consensus statement on efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) selectively targeting interleukin-6 (IL-6) pathway in the context of immune-mediated inflammatory diseases. METHODS: A systematic literature research of all publications on IL-6 axis inhibition with bDMARDs published between January 2012 and December 2020 was performed using MEDLINE, EMBASE and Cochrane CENTRAL databases. Efficacy and safety outcomes were assessed in clinical trials including their long-term extensions and observational studies. Meeting abstracts from ACR, EULAR conferences and results on clinicaltrials.gov were taken into consideration. RESULTS: 187 articles fulfilled the inclusion criteria. Evidence for positive effect of IL-6 inhibition was available in various inflammatory diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still's disease, cytokine release syndrome due to chimeric antigen receptor T cell therapy and systemic sclerosis-associated interstitial lung disease. Newcomers like satralizumab and anti-IL-6 ligand antibody siltuximab have expanded therapeutic approaches for Castleman's disease and neuromyelitis optica, respectively. IL-6 inhibition did not provide therapeutic benefits in psoriatic arthritis, ankylosing spondylitis and certain connective tissue diseases. In COVID-19, tocilizumab (TCZ) has proven to be therapeutic in advanced disease. Safety outcomes did not differ from other bDMARDs, except higher risks of diverticulitis and lower gastrointestinal perforations. Inconsistent results were observed in several studies investigating the risk for infections when comparing TCZ to TNF-inhibitors. CONCLUSION: IL-6 inhibition is effective for treatment of several inflammatory diseases with a safety profile that is widely comparable to other bDMARDs.

Safety Profile of Upadacitinib up to 3 Years in Psoriatic Arthritis: An Integrated Analysis of Two Pivotal Phase 3 Trials.

INTRODUCTION: This integrated analysis describes the safety profile of upadacitinib, an oral Janus kinase inhibitor, at 15 and 30 mg once daily for up to 3 years of exposure in patients with active psoriatic arthritis (PsA) who had a prior inadequate response or intolerance to ≥ 1 non-biologic or biologic disease-modifying antirheumatic drug. METHODS: Safety data were pooled and analyzed from two randomized, placebo-controlled phase 3 trials. Both trials evaluated upadacitinib 15 mg and 30 mg once daily, and one trial also evaluated adalimumab 40 mg every other week. Treatment-emergent adverse events (TEAEs) and laboratory data were summarized for four groups: pooled placebo, pooled upadacitinib 15 mg, pooled upadacitinib 30 mg, and adalimumab. TEAEs were reported as exposure-adjusted event rates (events per 100 patient-years [E/100 PY]) up to a data cut-off of June 29, 2020. RESULTS: A total of 2257 patients received ≥ 1 dose of upadacitinib 15 mg (N = 907) or 30 mg (N = 921) for 2504.6 PY of exposure or adalimumab (N = 429) for 549.7 PY of exposure. Upper respiratory tract infection, nasopharyngitis, and increased creatine phosphokinase (CPK) were the most common TEAEs with upadacitinib. Rates of malignancies, adjudicated major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs), and deaths were similar across treatment groups. Rates of herpes zoster (HZ) and opportunistic infections (OI; excluding tuberculosis, HZ, and oral candidiasis) were higher with upadacitinib versus adalimumab. Serious infection, anemia, and CPK elevations were most frequent with upadacitinib 30 mg. Potentially clinically significant laboratory abnormalities were uncommon. CONCLUSIONS: Upadacitinib 15 mg and adalimumab had similar safety profiles with the exception of HZ and OIs, consistent with what was observed in rheumatoid arthritis. Rates of malignancies, MACEs, VTEs, and deaths were comparable among patients receiving upadacitinib and adalimumab. No new safety risks emerged with longer-term exposure to upadacitinib. TRIAL REGISTRATION NUMBERS: SELECT-PsA 1: NCT03104400; SELECT-PsA 2: NCT03104374.

Psoriatic arthritis is a disease that causes inflammation of the skin and joints. Upadacitinib and adalimumab are medicines that can be used to treat this condition. This analysis combined safety data from two studies of adults with psoriatic arthritis who took upadacitinib, adalimumab, or placebo (no medicine) for up to 3 years. The most common side effects of treatment with upadacitinib were infection and inflammation of the nose and throat and higher amounts of a protein in the blood called creatinine phosphokinase. The total number of cancer cases, heart (cardiovascular) problems, blood clots (embolisms), and deaths were similar across treatment groups, including the placebo (no medicine) group. However, more patients who took upadacitinib than adalimumab or placebo (no medicine) had a painful rash that causes blisters known as herpes zoster (shingles) and infections usually seen in people with a weakened immune system. Most patients had normal blood test results and continued their treatment. Overall, upadacitinib was well tolerated for up to 3 years in patients with psoriatic arthritis. These results agree with what has been found in studies of upadacitinib in patients with rheumatoid arthritis. Safety data of upadacitinib use over a longer time will be reported later.

Safety of vaccination against SARS-CoV-2 in people with rheumatic and musculoskeletal diseases: results from the EULAR Coronavirus Vaccine (COVAX) physician-reported registry.

OBJECTIVES: To describe the safety of vaccines against SARS-CoV-2 in people with inflammatory/autoimmune rheumatic and musculoskeletal disease (I-RMD). METHODS: Physician-reported registry of I-RMD and non-inflammatory RMD (NI-RMDs) patients vaccinated against SARS-CoV-2. From 5 February 2021 to 27 July 2021, we collected data on demographics, vaccination, RMD diagnosis, disease activity, immunomodulatory/immunosuppressive treatments, flares, adverse events (AEs) and SARS-CoV-2 breakthrough infections. Data were analysed descriptively. RESULTS: The study included 5121 participants from 30 countries, 90% with I-RMDs (n=4604, 68% female, mean age 60.5 years) and 10% with NI-RMDs (n=517, 77% female, mean age 71.4). Inflammatory joint diseases (58%), connective tissue diseases (18%) and vasculitis (12%) were the most frequent diagnostic groups; 54% received conventional synthetic disease-modifying antirheumatic drugs (DMARDs), 42% biological DMARDs and 35% immunosuppressants. Most patients received the Pfizer/BioNTech vaccine (70%), 17% AstraZeneca/Oxford and 8% Moderna. In fully vaccinated cases, breakthrough infections were reported in 0.7% of I-RMD patients and 1.1% of NI-RMD patients. I-RMD flares were reported in 4.4% of cases (0.6% severe), 1.5% resulting in medication changes. AEs were reported in 37% of cases (37% I-RMD, 40% NI-RMD), serious AEs in 0.5% (0.4% I-RMD, 1.9% NI-RMD). CONCLUSION: The safety profiles of SARS-CoV-2 vaccines in patients with I-RMD was reassuring and comparable with patients with NI-RMDs. The majority of patients tolerated their vaccination well with rare reports of I-RMD flare and very rare reports of serious AEs. These findings should provide reassurance to rheumatologists and vaccine recipients and promote confidence in SARS-CoV-2 vaccine safety in I-RMD patients.

B Cell Numbers Predict Humoral and Cellular Response Upon SARS-CoV-2 Vaccination Among Patients Treated With Rituximab.

OBJECTIVE: Patients with autoimmune inflammatory rheumatic diseases receiving rituximab (RTX) therapy are at higher risk of poor COVID-19 outcomes and show substantially impaired humoral immune response to anti-SARS-CoV-2 vaccine. However, the complex relationship between antigen-specific B cells and T cells and the level of B cell repopulation necessary to achieve anti-vaccine responses remain largely unknown. METHODS: Antibody responses to SARS-CoV-2 vaccines and induction of antigen-specific B and CD4/CD8 T cell subsets were studied in 19 patients with rheumatoid arthritis (RA) or antineutrophil cytoplasmic antibody-associated vasculitis receiving RTX, 12 patients with RA receiving other therapies, and 30 healthy controls after SARS-CoV-2 vaccination with either messenger RNA or vector-based vaccines. RESULTS: A minimum of 10 B cells per microliter (0.4% of lymphocytes) in the peripheral circulation appeared to be required for RTX-treated patients to mount seroconversion to anti-S1 IgG upon SARS-CoV-2 vaccination. RTX-treated patients who lacked IgG seroconversion showed reduced receptor-binding domain-positive B cells (P = 0.0005), a lower frequency of Tfh-like cells (P = 0.0481), as well as fewer activated CD4 (P = 0.0036) and CD8 T cells (P = 0.0308) compared to RTX-treated patients who achieved IgG seroconversion. Functionally relevant B cell depletion resulted in impaired interferon-γ secretion by spike-specific CD4 T cells (P = 0.0112, r = 0.5342). In contrast, antigen-specific CD8 T cells were reduced in both RA patients and RTX-treated patients, independently of IgG formation. CONCLUSION: In RTX-treated patients, a minimum of 10 B cells per microliter in the peripheral circulation is a candidate biomarker for a high likelihood of an appropriate cellular and humoral response after SARS-CoV-2 vaccination. Mechanistically, the data emphasize the crucial role of costimulatory B cell functions for the proper induction of CD4 responses propagating vaccine-specific B cell and plasma cell differentiation.

Impaired humoral immunity to SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients and dialysis patients.

Patients with kidney failure are at increased risk for SARS-CoV-2 infection making effective vaccinations a critical need. It is not known how well mRNA vaccines induce B and plasma cell responses in dialysis patients (DP) or kidney transplant recipients (KTR) compared to healthy controls (HC). We studied humoral and B cell responses of 35 HC, 44 DP and 40 KTR. Markedly impaired anti-BNT162b2 responses were identified among KTR and DP compared to HC. In DP, the response was delayed (3-4 weeks after boost) and reduced with anti-S1 IgG and IgA positivity in 70.5% and 68.2%, respectively. In contrast, KTR did not develop IgG responses except one patient who had a prior unrecognized infection and developed anti-S1 IgG. The majority of antigen-specific B cells (RBD+) were identified in the plasmablast or post-switch memory B cell compartments in HC, whereas RBD+ B cells were enriched among pre-switch and naïve B cells from DP and KTR. The frequency and absolute number of antigen-specific circulating plasmablasts in the cohort correlated with the Ig response, a characteristic not reported for other vaccinations. In conclusion, these data indicated that immunosuppression resulted in impaired protective immunity after mRNA vaccination, including Ig induction with corresponding generation of plasmablasts and memory B cells. Thus, there is an urgent need to improve vaccination protocols in patients after kidney transplantation or on chronic dialysis.

EULAR points to consider on pathophysiology and use of immunomodulatory therapies in COVID-19.

OBJECTIVES: Severe systemic inflammation associated with some stages of COVID-19 and in fatal cases led therapeutic agents developed or used frequently in Rheumatology being at the vanguard of experimental therapeutics strategies. The aim of this project was to elaborate EULAR Points to consider (PtCs) on COVID-19 pathophysiology and immunomodulatory therapies. METHODS: PtCs were developed in accordance with EULAR standard operating procedures for endorsed recommendations, led by an international multidisciplinary Task Force, including rheumatologists, translational immunologists, haematologists, paediatricians, patients and health professionals, based on a systemic literature review up to 15 December 2020. Overarching principles (OPs) and PtCs were formulated and consolidated by formal voting. RESULTS: Two OPs and fourteen PtCs were developed. OPs highlight the heterogeneous clinical spectrum of SARS-CoV-2 infection and the need of a multifaceted approach to target the different pathophysiological mechanisms. PtCs 1-6 encompass the pathophysiology of SARS-CoV-2 including immune response, endothelial dysfunction and biomarkers. PtCs 7-14 focus on the management of SARS-CoV-2 infection with immunomodulators. There was evidence supporting the use of glucocorticoids, especially dexamethasone, in COVID-19 cases requiring oxygen therapy. No other immunomodulator demonstrated efficacy on mortality to date, with however inconsistent results for tocilizumab. Immunomodulatory therapy was not associated with higher infection rates. CONCLUSIONS: Multifactorial pathophysiological mechanisms, including immune abnormalities, play a key role in COVID-19. The efficacy of glucocorticoids in cases requiring oxygen therapy suggests that immunomodulatory treatment might be effective in COVID-19 subsets. Involvement of rheumatologists, as systemic inflammatory diseases experts, should continue in ongoing clinical trials delineating optimal immunomodulatory therapy utilisation in COVID-19.

The impact of COVID-19 on rare and complex connective tissue diseases: the experience of ERN ReCONNET.

During the COVID-19 pandemic, the need to provide high-level care for a large number of patients with COVID-19 has affected resourcing for, and limited the routine care of, all other conditions. The impact of this health emergency is particularly relevant in the rare connective tissue diseases (rCTDs) communities, as discussed in this Perspective article by the multi-stakeholder European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ERN ReCONNET). The clinical, organizational and health economic challenges faced by health-care providers, institutions, patients and their families during the SARS-CoV-2 outbreak have demonstrated the importance of ensuring continuity of care in the management of rCTDs, including adequate diagnostics and monitoring protocols, and highlighted the need for a structured emergency strategy. The vulnerability of patients with rCTDs needs to be taken into account when planning future health policies, in preparation for not only the post-COVID era, but also any possible new health emergencies.

Digital crowdsourcing: unleashing its power in rheumatology.

The COVID-19 pandemic forces the whole rheumatic and musculoskeletal diseases community to reassemble established treatment and research standards. Digital crowdsourcing is a key tool in this pandemic to create and distil desperately needed clinical evidence and exchange of knowledge for patients and physicians alike. This viewpoint explains the concept of digital crowdsourcing and discusses examples and opportunities in rheumatology. First experiences of digital crowdsourcing in rheumatology show transparent, accessible, accelerated research results empowering patients and rheumatologists.

EULAR provisional recommendations for the management of rheumatic and musculoskeletal diseases in the context of SARS-CoV-2.

The provisional EULAR recommendations address several aspects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus, and the disease caused by SARS-CoV-2, COVID-19 and are meant for patients with rheumatic and musculoskeletal diseases (RMD) and their caregivers. A task force of 20 members was convened by EULAR that met several times by videoconferencing in April 2020. The task force finally agreed on five overarching principles and 13 recommendations covering four generic themes: (1) General measures and prevention of SARS-CoV-2 infection. (2) The management of RMD when local measures of social distancing are in effect. (3) The management of COVID-19 in the context of RMD. (4) The prevention of infections other than SARS-CoV-2. EULAR considers this set of recommendations as a 'living document' and a starting point, which will be updated as soon as promising new developments with potential impact on the care of patients with RMD become available.