FAVOURABLE COURSE of COVID-19 in PATIENTS with FAMILIAL MEDITERRANEAN FEVER USING BIOLOGIC AGENTS

Background: Serious infections are more frequently seen in patients with infam-matory rheumatic diseases, being treated with immunosuppressive or biologic disease-modifying antirheumatic drugs (b-DMARDs). Potential harmful effects of immunosuppressive drugs as well as b-DMARDs were a major concern during the early phases of the Coronavirus disease 2019 (COVID-19) pandemic, and preliminary data documented the worse outcome of COVID-19 associated with B cell depleting treatments (1). On the other hand, limited information has been shared about the course of COVID-19 in patients with monogenic autoinfamma-tory disorders using IL-1 inhibitors. Objectives: We herein aimed to evaluate the course of COVID-19 in adult patients with the most common form of infammasomopathy, Familial Mediterranean Fever (FMF), who were on biologic agents. Methods: In this cross-sectionally study, FMF patients were evaluated by screening their clinical and electronic records in our database in October 2021. The FMF patients with a record of PCR-confrmed COVID-19 were investigated in more detail in our hospital. Characteristics of FMF fndings as well as clinical and laboratory fndings associated with COVID-19 were recorded from the outpatient follow-up cards. Results: We identified 184 FMF patients using biologic agents, and their baseline characteristics are summarized in Table 1. Among them, 36 had PCR-confirmed COVID-19;32 of them were currently on b-DMARD along with colchicine (31 anti-IL-1, 1 anti-TNF), and 4 of them had a previous history of b-DMARD treatment. Data about the course of COVID-19 could be reached in 34 patients. Four (11%) patients had an asymptomatic course. Remaining patients with symptomatic COVID-19 had the following symptoms: cough (50%), headache (47.2%), fever (44.4%), loss of taste and smell (41.6%), myalgia (0.6%), dyspnoea (27.8%), diarrhea (25%) abdominal pain (5.6%). Thorax computed tomography was performed in 10 patients, and findings of pneumonia were documented in 6 (16.7%). The mean values of the laboratory parameters were as follows: C-reactive protein 99.48 ± 112.66 mg/L;ferritin 316 ± 208.3;D-Dimer 2445 ± 3917, Lactate Dehydroge-nase 253 ± 61, troponin T 26 ± 20, procalcitonin 0.348 ± 0.53. Lymphopenia was detected in 5 (13.9%) patients;mean lymphocyte count was 1080 ± 363. Data about the treatment could be reached in 34 patients. Antiviral therapy was prescribed in 25 (69.4%) patients (favipiravir, n=22;and oseltamivir, n=3). Antibiotics were given to 6 (16.7%) patients, and 6 (16.7%) received hydroxychloroquine. Parenteral steroids were administered to 2 patients during the hospitalization. Six (16.7%) patients required hospitalization, and 2 (5.6%) required oxygen support, non-invasive mechanical ventilation, and one of them followed in the intensive care unit. Twenty-two patients were on anakinra treatment, and none of them required additional dose. Only 1 patient, a 61-year-old male patient with a history of lung lobectomy and renal transplantation, received tocilizumab due to macrophage activation syndrome, and he later died of sepsis. This patient was on anakinra until 2 years before, and it was discontinued due to an allergic reaction. Only 4 patients had a history of vaccination before COVID-19, and none of them developed pneumonia and required hospitalization. Six patients had FMF attacks after recovering from COVID-19. None of the patients developed thromboembo-lism and secondary bacterial infections. Conclusion: This survey identified 36 biologic b-DMARD receiving FMF patients, who had COVID-19. All but 1 patient had complete recovery, and b-DMARD usage did not negatively affect the COVID-19 course. None of the patients currently on anti-IL-1 or anti-TNF had a worse outcome. Based on these observations, it can be suggested that refractory FMF patients can continue their b-DMARD treatments when they had COVID-19.

FREQUENCY and SEVERITY of COVID-19 in PATIENTS with VARIOUS RHEUMATIC DISEASES TREATED REGULARLY with COLCHICINE or HYDROXYCHLOROQUINE

Background: Several anti-inflammatory drugs which were targeted different mechanisms and investigated for both prevention and treatment for COVID-19. Objectives: The current study aimed to investigate whether patients regularly using colchicine or hydroxychloroquine (HCQ) have an advantage of protection from COVID-19 or developing less severe disease. Methods: Patients who were taking colchicine or HCQ regularly for a rheumatic disease including Familial Mediterranean Fever, Behçet's syndrome, Systemic Lupus Erythematosus, Rheumatoid Arthritis and Sjogren's syndrome as well as their healthy household contacts as the control group were included into the study. The clinical data regarding COVID-19 were collected using a standard form, and serum samples were analyzed for anti-SARS-COV-2 nucleocapsid IgG. Patients treated with any biologic or immunosuppressive treatments were not included into the study. Results: A total of 635 regular colchicine users with their 643 household contacts and 317 regular HCQ users with their 333 household contacts were analyzed. Anti-SARS-Cov2 IgG was positive in 43 (6.8%) regular colchicine users and 35 (5.4%) household contacts (OR=1.3;95% CI:0.8-2;p=0.3) (Table 1). COVID-19 related symptoms were described by 29 (67.4%) of the patients and 17 (48.6%) household contacts (OR=2.2;95% CI:0.9-5.5;p=0.09), and hospital admission was observed in five (11.6%) and one (2.9%) of these subjects (OR=4.5;95% CI:0.5-40.2;p=0.1), respectively (Figure 1). Seropositive subjects were observed in 22 (6.9%) regular HCQ users and 24 (7.2%) household contacts (OR=1.1;CI:0.6-1.9;p=0.8) (Table 1). COVID-19-related symptoms occurred in 16 (72.7%) of the 22 patients and 12 (50%) of 24 household contacts (OR=2.7;95% CI:0.8-9.1;p=0.1). Three patients (13.6%) were admitted to hospital, while one household contact (4.2%) was hospitalized (OR=3.6;95% CI:0.3-37.8;p=0.2) (Figure 1). Disease-specific analyses disclosed that there was no significant difference in terms of COVID-19 frequency and severity between a particular disease subset and household contacts (Table 1). Univariate logistic regression analysis showed no effect of age and gender on the SARS-CoV-2 seroprevalence rate among regular colchicine or HCQ users and household contacts (p=0.2 and p=0.7, respectively for colchi-cine users versus contacts, p=0.7 and p=0.3, respectively for HCQ users versus contacts). Conclusion: Being on a regular treatment of colchicine or HCQ was not resulted in the prevention of COVID-19 or amelioration of its manifestations.

Favourable short-term course of COVID-19 in patients with familial mediterranean fever using biologic agents

Background: COVID-19 runs a variable course resulting in acute respiratory distress syndrome and death in a subset of patients. The entry of SARS-CoV-2 into the cell stimulates innate immunity including NLRP3 inflammasome and lead to development of adaptive immunity later. Hyperinflammatory response with the release of proinflammatory cytokines including IL-1β and IL-6 results in cytokine storm in some patients with a worse outcome. Colchicine acts on NLRP3 inflammasome and inhibits and IL-1 mediated inflammatory attacks in gout and familial Mediterranean fever (FMF) patients. Patients with inadequate response to colchicine may benefit from anti-IL-1 biologic agents such as anakinra and canakinumab. Recently, favourable effects of anakinra have been observed in COVID-19 patients with findings of cytokine storm. Objectives: We aimed to evaluate the impact of COVID-19 among refractory FMF patients followed-up in tertiary referral with the treatment of biologic agents and also document the course of COVID-19 in these patients. Methods: We searched out database of FMF patients to identify those using biologic agents (anti-IL-1, anti-IL-6 or anti-TNF) for colchicine-refractory FMF. We interviewed the patients using a standard questionnaire by phone call for symptomatic COVID-19 and evaluated those patients who described findings of COVID-19 further by their hospital records or inviting them to the hospital for additional investigations. Results: We identified 183 patients and contacted 106 of them by phone in May-October 2020. A history of symptomatic COVID-19 was documented in 7 FMF patients who were on a biologic agent. Six were on anti-IL-1 and one was on anti-TNF, and one of the patients was not taking his biologic agents for 1 year. All of 7 patients had a favourable outcome. All but 1 patient followed at home and none of them developed findings of cytokine storm, thromboembolism and secondary bacterial infection. Hospitalized patient did not require intensive care unit (ICU) support or mechanical ventilation, and he was not given additional anti-inflammatory medications. Conclusion: This series of refractory FMF patients with potentially higher inflammatory characteristics showed COVID-19 did not result in a worse outcome in those patients during the first phase of the pandemic, and none developed findings of cytokine storm. Observations in these patients supports further that biologic agents blocking IL-1 and possibly TNF may contribute to the uneventful course of COVID-19 by preventing the development of hyperinflammatory response. Data collection from a larger group of patients, especially those with amyloidosis, will clarify the protective effects of colchicine and contribution of anti-IL-1 treatments on the favourable disease course during the second phase of the pandemic.

Preliminary criteria for macrophage activation syndrome associated with coronavirus disease-19

Background: COVID-19 runs a severe disease associated with acute respiratory distress syndrome in a subset of patients, and a hyperinflammatory response developing in the second week contributes to the worse outcome. Inflammatory features are mostly compatible with macrophage activation syndrome (MAS) observed in other viral infections despite resulting in milder changes. Early detection and treatment of MAS may be associated with a better outcome. However, available criteria for MAS associated with other causes have not been helpful. Objectives: To identify distinct features of MAS associated with COVID-19 using a large database enabling to assess of dynamic changes. Methods: PCR-confirmed hospitalized COVID-19 patients followed between March and September 2020 constituted the discovery set. Patients considered to have findings of MAS by experienced physicians and given anakinra or tocilizumab were classified as the MAS group and the remaining patients as the non-MAS group. The MAS group was then re-grouped as the cases with exact-MAS and borderline-MAS cases by the study group. Clinical and laboratory data including the Ct values of the PCR test were obtained from the database, and dynamic changes were evaluated especially for the first 14 days of the hospitalization. The second set of 162 patients followed between September-December 2020 were used as the replication group to test the preliminary criteria. In the second set, hospitalization rules were changed, and all patients required oxygen support and received dexamethasone 6mg/day or equivalent glucocorticoids. Daily changes were calculated for the laboratory items in MAS, borderline, and non-MAS groups to see the days differentiating the groups, and ROC curves and lower and upper limits (10-90%) of the selected parameters were calculated to determine the cutoff values. Results: A total of 769 PCR-confirmed hospitalized patients were analysed, and 77 of them were classified as MAS and 83 as borderline MAS patients. There was no statistically significant difference in the baseline viral loads of MAS patients compared to the non-MAS group according to the Ct values. Daily dynamic changes in the MAS group differed from the non-MAS group especially around the 6th day of hospitalization, and more than a twofold increase in ferritin and a 1.5-fold increase in D-dimer levels compared to the baseline values help to define the MAS group. Twelve items selected for the criteria are given in Table 1 below. The total score of 45 provided 79.6% sensitivity for the MAS (including borderline cases) and 81.3% specificity around days 5 and 6 in the discovery set, and a score of 60 increased the specificity to 94.9% despite a decrease in sensitivity to 40.8%. The same set provided a similar sensitivity (80.3%) in the replication, but a lower specificity (47.4-66% on days 6 to 9) due to a group of control patients with findings of MAS possibly masked by glucocorticoids. Conclusion: This study defined a set of preliminary criteria using the most relevant items of MAS according to the dynamic changes in the parameters in a group of COVID-19 patients. A score of 45 would be helpful to define a possible MAS group with reasonable sensitivity and specificity to start necessary treatments as early as possible.

Course of COVID-19 infection in a series of patients with systemic lupus erythematosus

Background: Infection is a remarkable cause of morbidity and mortality in patients with SLE. Objectives: We aimed to determine the clinical course of COVID-19 infection in our patients with SLE and the factors affecting this course Methods: SLE patients (2012 SLICC criteria) diagnosed with COVID-19 infection by a positive PCR test and/or typical findings of lung involvement in CT (computed tomography) imaging were included. Data regarding cumulative clinical and laboratory characteristics, histopathology results, autoantibody profiles, immunsuppressives and damage (SLICC damage index/SDI)) were retrieved from the existing database and revised. SLE Disease Activity Index (SLEDAI-2K) was determined at the time of infection. Results: Sixteen SLE patients with COVID-19 infection were identified. Most (87.5%) of these patients were female. Seventy % (n=11) had lupus nephritis. Twenty-five % had thrombotic antiphospholipid syndrome. PCR was positive in 70% (n=11) of the patients. Pulmonary parenchymal findings compatible with COVID-19 were observed in 56% (n=9) of those patients. Regarding complaints upon admission, 50% (n=8) had fever, 44% (n=7) cough, 44% (n=7) dyspnea, 19% (n=3) myalgia, 12.5% (n=2) headache, 12.5% (n=2) nausea /vomiting, 6% (n=1) diarrhea, and 6 % (n=1) had anosmia. Eight patients were hospitalized. Six of these patients needed oxygen therapy via nasal cannula. None needed a follow-up in the intensive care unit. The mean hospitalization duration was 14 ± 5 (8-25) days. Regarding disease activity at the time of infection, 9 had inactive disease with a SLEDAI-2K score of 0 whilst in 5 patients SLEDA-2K score was ≥4. The mean SLEDAI-2K score at the time of infection was 1.7 ± 2.3 (0-6). System/ organwise, 1 patient with chronic thrombocytopenia presented with a worsening platelet count accompanied by serologic activity. This patient was a non-adherent to treatment who had stopped taking mycophenolic acid months before COVID19. Three patients 2 of whom had proliferative nephritis experienced nephritic flares.1 patient who had a history of cutaneous lupus and was in remission presented with oral ulcer, leukopenia and hypocomplementemia during infection. Of 16 patients, 7 had system damage at the time of infection. The mean SDI score of the patients was 1.4±1.8. Comparison of patients with and without damage revealed no significant differences in disease activity, symptoms associated with COVID, in the need for hospitalization, hospitalization duration, and the requirement for oxygen therapy. However,CT findings compatible with COVID19, were more common in patients with damage (87% vs.33%,p=0.04) and their mean CRP levels were higher at diagnosis (65 ± 47 vs.22 ± 48 mg/l;p=0.032). All patients received similar treatment for COVID-19 except active patients who required high dose steroids (2 with active renal, 1 with thrombocytopenia and 1 with oral ulcer, leukopenia and hypocomplementemia).The patient with thrombocytopenia also received intravenous immunoglobulin and 1 with cutaneous active disease received tocilizumab as she developed macrophage activation syndrome. Six patients (37.5%) had received rituximab (RTX) in the last 6 months before COVID. No significant difference, in terms of hospitalization and need for oxygen therapy due to COVID19 was found between patients who had received RTX vs who had not. No hypogammaglobulinemia was detected in patients who received RTX despite lower levels of IgG (998 ± 184 vs 1481± 51 mg/dl, p=0.02) Conclusion: Although half of the patients in our series of COVID19 infected SLE patients required hospitalization, there were no mortalities. More patients with damage (none pulmonary) displayed CT findings compatible with COVID19 and further follow up will reveal whether they will suffer from fibrotic lung disease. Patients can experience disease flares during COVID. But it is also important to consider that some manifestations such as thrombocytopenia may also be a sign of severe infection. Immunosupressive agents may not have a negative impact on the course of infection.