Experience of Baricitinib in a Real-World Population with Efficacy and Side Effects: A South London Regional Analysis

Background/Aims Baricitinib is the most common Janus Kinase inhibitor (JAKi) used in the treatment of rheumatological conditions. Whilst randomised controlled trials have demonstrated the efficacy and safety profile of baricitinib, real-world data on the experience of JAKi use in clinical practice is lacking. The aim of this analysis was to evaluate baricitinib use in a real-world patient population in South London. Methods We looked at two rheumatology departments in South London (St George's Hospital;a tertiary teaching centre and Kingston Hospital;a district general hospital). All patients prescribed baricitinib between January 2017 to June 2022 were included. A retrospective assessment of electronic patient notes was performed to evaluate disease activity (determined by DAS-28 scores at baseline, 3-6 months and presently);adverse effects including side effects, rates of and reasons for discontinuation;and prescribing practice, including previous use of other biological disease modifying anti-rheumatic drugs (bDMARDs). Baseline data including age, gender, co-morbidities and rheumatological diagnoses were also included. Results 233 patients were included in this evaluation, with seropositive rheumatoid arthritis being the most common diagnosis (58%) and with a significant female population (87%). Baricitinib improved average DAS-28 scores from 5.75 (range 3.57-8.3) at baseline to 3.23 (range 0.28-7.49) at 3-6 months post-baricitinib, with the most recent DAS-28 score of 2.90 (range 0.56-6.77). Rates of adverse effects were low as shown in Table 1. Baricitinib was discontinued in 60/233 patients, with average duration to discontinuation of 9.5 months. The most common reasons for discontinuation were: ineffective disease control (28/60), recurrent bacterial infection (5/60), deranged liver function (3/60) and venous thromboembolism (2/60). Eight patients died whilst taking baricitinib. Where documented, the causes of death were Covid-19 (4/8) and malignancy (1/8). 110 out of 233 patients had received other bDMARDs before starting baricitinib. Documented reasons for baricitinib choice over tumour necrosis factor inhibitors (TNFi) included: previous lack of response to TNFi (89/233), contra-indication to TNFi (11/233) and preference of oral route (10/ 233). Conclusion Our real-world study of JAKi use shows that baricitinib is efficacious in the treatment of rheumatological conditions. Moreover, baricitinib is well tolerated, with low rates of adverse effects and subsequent discontinuation. (Table Presented).

A case of hyperinflammatory COVID-19 that responded to tocilizumab therapy

Case report-IntroductionCoronavirus disease 19 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), has reached pandemic level and led to over 46,000 deaths in the UK. COVID-19 is primarily a respiratory illness and 10-20% of infected individuals develop severe disease with interstitial pneumonia or acute respiratory distress syndrome (ARDS). In this subgroup of patients, severe clinical manifestations are postulated to result from a hyperactive immune response. This has led to the proposal that immunomodulatory medications could be used for the treatment of COVID-19. Here, we report a case of COVID-19 that was treated with the IL-6 inhibitor, tocilizumab.Case report-Case descriptionA 54-year-old Middle Eastern woman presented to A&E with a one-week history of fever, cough, headache and ageusia. Her past medical history was significant for asthma, chronic headaches, gastro-oesophageal reflux syndrome and subarachnoid haemorrhage. On presentation, she had a low-grade temperature (37.8 °C) but her observations were otherwise normal, and her oxygen saturations were 99% on room air. Examination revealed right basal chest crackles. Bloods showed a mild lymphopenia (0.9x109/l) and a raised CRP (82mg/l) and a chest radiograph demonstrated bibasal shadowing. The patient was diagnosed with probable COVID-19 and discharged with a course of oral doxycycline and a plan for review in the ambulatory unit the following day. When reviewed the next day, her oxygen saturations had fallen to 90% on room air. At this point, her SARS-CoV-2 assay had been resulted as positive and a decision was made to admit her for oxygen therapy.The patient continued to deteriorate despite optimal supportive therapy and the addition of intravenous benzylpenicillin for possible superadded bacterial infection. On day 7 of admission, her respiratory rate was 32-38 breaths per minute, and she required 13l/min of oxygen. Her bloods revealed CRP 474mg/L, D dimer >6000 ng/ml, ferritin 224 μ g/L, neutrophils 9.5x109/l and lymphocytes 0.6 x109/l. There were no signs of superadded bacterial infection despite a thorough infection screen. Given her clinical deterioration, she was reviewed by the critical care team for consideration of transfer to higher-level care. The ward team decided to administer a single dose of the anti-IL-6 agent tocilizumab for the treatment of a cytokine storm secondary to COVID-19 infection. Within 24 hours of tocilizumab treatment, her oxygen requirements fell to 5l/min and her work of breathing significantly improved. On day 15 of admission, she was discharged with saturations of 92% on room air. Case report-DiscussionThe patient described in this case showed significant clinical deterioration with features suggestive of cytokine storm secondary to COVID-19. IL-6 is thought to be a key cytokine responsible for initiating the acute phase response and we postulate that IL-6 levels were raised in this patient. Unfortunately, we did not have the assay available to measure this. The treating clinical team decided to prescribe a single dose of tocilizumab on a compassionate use basis. This resulted in a rapid clinical improvement and the patient was subsequently discharged without the need for intensive care. In this case, we propose that tocilizumab inhibited further cytokine activation and prevented the positive feedback loop of inflammation that can otherwise result in rapid clinical deterioration.There are several interesting points to be noted from this case. In this patient, tocilizumab resulted in a rapid reduction in CRP levels. This is thought to correspond to the inhibition of IL-6 mediated release of acute phase proteins by the liver. Therefore, it should be noted that post-tocilizumab treatment, patients should be closely monitored for superadded bacterial infection as they may not mount a full immune response.Larger trials of tocilizumab for the treatment of COVID-19 are currently underway and are required to confirm the efficacy of IL-6 inhibition for COVID-19. The phase III COVACTA trial of toci izumab in COVID-19 patients did not meet its primary endpoint of improved clinical status however a trend towards shorter hospital admissions was seen. Further studies are ongoing to investigate the role of tocilizumab in other treatment settings, including in combination with an antiviral medication. Further information is required to determine which patients should receive immunomodulatory medications and at which point in their illness. Data is also needed to understand the most efficacious dosing regimen for tocilizumab and its side-effect profile in COVID-19 patients.Case report-Key learning pointsThe COVID-19 pandemic has affected millions of people worldwide and has led to an unprecedented effort from the scientific community to understand the pathophysiology of the disease and to find effective treatments. Emerging evidence suggests that SARS-CoV-2 can induce a hyperactive immune response in a subgroup of patients who develop highly elevated levels of acute phase proteins. It has been proposed that the overactive immune response is responsible for some of the severe clinical manifestations seen and this has led to the suggestion that immunomodulatory medications could be used for the treatment of COVID-19.Indeed, dexamethasone has been shown to be an effective treatment and other immunomodulatory medications including hydroxychloroquine, the IL-1 inhibitor anakinra and JAK-kinase inhibitors are currently being trialled for the treatment of COVID-19. This case highlights the clinical and biochemical features of a patient who developed features suggestive of a cytokine storm secondary to COVID-19 and who responded to treatment with the IL-6 inhibitor tocilizumab. Further work is required to understand the role of immunomodulatory medications for the management of COVID-19 infection.

Assessing antibody status for SARS-CoV-2 in people with coronavirus infection: A time course study in people with autoimmune conditions

Background: With the emergence of the global coronavirus pandemic, increasing concerns have been raised about the course of SARS-CoV-2 infection in people with immune-mediated disorders. Objectives: In this study we aimed to assess the time course of proven SARSCoV-2 infection, development of humoral immunity with detectable antibodies to the virus and evaluate any changes in antibody titres over time. Methods: We recruited 114 participants in total who had potential symptoms of COVID-19 infection. Participants were recruited from rheumatology or inflammatory bowel disease (IBD) clinics from their records who attended a London Teaching hospital for care. Ethical Approval was in place for the study. Age-and gender-matched control participants without any underlying rheumatological condition/IBD were recruited as a comparator group. Clinical symptoms for COVID-19 infection were assessed using the COVID-19 Rheumatology Global Alliance assessment criteria (https://rheum-covid.org/). Information about Disease Modifying Anti-Rheumatic Drug (DMARD) drug use was also recorded. Participants' serum samples were collected for quantitative serological assessment of antibodies to SARS-CoV-2 using the Mologic Enzyme-Linked Immuno-Sorbent Assay (ELISA) IgG kit. The optical density values were plotted aganist time using a normalisation as previously described (1). A cut-off above 0 indicated positive serology. Results: A total of 114 subjects were recruited into the study. Subjects were recruited if they had suspected Covid symptoms. Of the population recruited, the total number subsequently testing positive for SARS-CoV-2 was n=59 (either on serology or PCR). The number of subjects with autoimmune conditions diagnosed with COVID-19 was 32, with 30 subjects being symptomatic (the asymptomatic 2 subjects were excluded from further analyses). Of the 30 symptomatic subjects, the average age was 56, with a female to male ratio of 19:11. The most prevalent diagnoses were RA (30%), Psoriatic Arthritis (16.7%), SLE (10%), sarcoidosis 10%), Ulcerative Colitis (10%), Crohn's disease (10%), seronegative inflammatory arthritis (6.7%), Sjogren's (3.3%) and Juvenile Idiopathic Arthritis (3.3%). The majority were on csDMARDs (60%), biologic DMARDs (20%), tacrolimus (3.3%) and the remaining 16.7% were not on DMARDs. Most subjects required treatment in hospital (56.7%), a smaller number required high dependency care (6.7%) and the rest were treated at home (36.6%). The majority required no oxygen (63.3%), with a further 30% requiring oxygen and 6.7% needed more supportive care i.e. CPAP/ventilation. We also had a matched control group (n=29) of subjects who developed SARS-CoV-2 but had no underlying autoimmune conditions. These subjects had a mean age of 55, female: male ratio 18: 11. Of these 31% had home management, 55.2% had ward level treatments and 13.8% had intensive care treatment. Of the controls, 48.3% did not require oxygen, 37.9% needed simple oxygen and 13.8% were on CPAP. A total of 35 subjects from the original study have attended for follow-up visits. Antibody titres for IgG using the Mologic ELISA detection assay were compared at two visits for the control and autoimmune group. Results showed that subjects with autoimmune conditions and those without who developed SARS-CoV-2 showed very similar antibody titres by optical density (OD) (Figure 1) and maintained antibody responses beyond 6 months in most cases. Conclusion: Serological assays can assist in the understanding of disease severity of SAR-CoV-2 infection. They can be a useful tool for patient surveillance, especially in people who are on immunomodulatory drugs and are being seen in Rheumatology services. Future work is needed to assess the duration and potential protective nature of humoral antibody responses to SARS-CoV-2.

What is the course of SARS-CoV-2 infection inpeople with autoimmune conditions onimmunomodulators in comparison to people withoutautoimmune disease?

Background/AimsThe pathogenesis and outcomes of COVID-19 in patients withautoimmune disease remains poorly understood. We aimed toevaluate clinical features and antibody mediated immunity againstsevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) insubjects with autoimmune disease, compared to those without.MethodsPatients who developed COVID-19 were identified through the auditdepartment/clinician identification. In total, there were 48 subjects withautoimmune disease and confirmed COVID-19. Of these patients, 6had sadly died. In recruited patients, clinical data regarding COVID-19symptoms, treatment and outcomes were collected. Blood was takenfor quantitative serology testing against SARS-CoV-2 using theMologic test kit. A binary logistic regression was used to compareserology results in subjects with and without autoimmune diagnoses.ResultsOur sample included 103 participants. 26 subjects with autoimmunedisease and confirmed COVID-19 were recruited, the most commondiagnoses being rheumatoid arthritis (27%), psoriatic arthritis (19%)and inflammatory bowel disease (15%). 21 of 28 participants were onimmunomodulatory medications including 16 on conventional synthetic disease modifying anti-rheumatic drugs (DMARDs), four onbiologic DMARDs and one on tacrolimus. We age- and gendermatched these subjects to 26 without autoimmune disease withconfirmed SARS-CoV-2 infection. 17 further subjects reported viralsymptoms during the COVID-19 pandemic but had negative serology.30 subjects had rheumatic conditions but denied symptoms suggestive of COVID-19. 4 of the asymptomatic patients tested positive forCOVID-19 on serology. 23 stored serum samples, obtained before2019, were all negative for antibodies against SARS-CoV-2. In patientswith confirmed COVID-19, clinical features and serology werecompared in those with and without autoimmune disease. Logisticregression showed a significant impact of COVID-19 severity onantibody titres in people with and without autoimmune disease(p = 0.003 and <0.001 respectively). In both mild and severe disease, autoimmunity had no effect on antibody titres (p = 0.253 and 0.119respectively).ConclusionPeople with and without autoimmune disease presented with similarsymptoms of COVID-19. In our sample, subjects with autoimmunedisease were less likely to be hospitalised or require respiratorysupport. Serology revealed no difference in antibody titres againstSARS-CoV-2 in participants with and without autoimmune disease.