Evaluation of the frequency and intensity of COVID-19 in patients with ankylosing spondylitis under anti-TNF therapy.

BACKGROUND: Dear Editor, After the coronavirus disease 2019 (COVID-19) pandemic affected the whole world, rheumatologists began to think about how COVID-19 will progress in patients with inflammatory conditions. High cytokine levels play a role in the pathophysiology of COVID-19 infection. Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine known to have a key role in the pathogenesis of chronic immune-mediated diseases. AntiTNF therapy may cause an increase in active tuberculosis, other granulomatous diseases, and serious infections [1]. According to many studies, rheumatological diseases have not been identified as a risk factor for severe COVID-19 infection [2]. Should significantly increased cytokine levels during COVID-19 infection make us consider anticytokine therapies that may be used in the treatment of patients with COVID-19 a risk? We aimed to explore whether the frequency of COVID-19 infection increased, the effect of comorbidities on the frequency of infection, and whether the severity of the disease and need for intensive care support increased in patients who used anti-TNF agents. We performed a retrospective case-control study between March and December 2020 in Sakarya University Training and Research Hospital. Retrospectively, we evaluated whether there was a difference in the frequency and severity of COVID-19 in our patients diagnosed with ankylosing spondylitis (AS), 77 of whom were using anti-TNF and 49 of whom didn't use anti-TNF. Hospitalization and intensive care unit (ICU) requirements were evaluated as endpoints. In the anti-TNF group, patients used adalimumab, etanercept, certolizumab, infliximab, and golimumab. Patients were questioned at an outpatient clinic in person or by phone. Seventy-seven patients with AS using anti-TNF agents (58 males, 19 females) and 49 patients with AS (38 males, 11 females) not using anti-TNF agents were included in the study (p = 0.943). Mean age of patients using antiTNF agents was 41.53 ± 10.38, and mean age of patients not using anti-TNF agents was 42.94 ± 10.86 (p = 0.468). Thirty-three (42.9%) patients were smokers in the antiTNF group, while 23 (46.9%) patients were smokers in the group not using TNFi (p = 0.791). There was 12 pack-year smoking in the anti-TNF group, and 14 pack-year smoking in not using TNFi (p = 0.623). The frequency of diabetes mellitus (DM), hypertension (HT), amiloidosis, familial mediterranean fever (FMF), coronary artery disease (CAD), chronic obstructive pulmonary disease (COPD) was similar in both groups (p = 0.403, p = 0.999, p = 0.521, p = 0.999, p = 0.999, respectively). Six patients using TNFi and 3 patients not using TNFi recovered from COVID-19 infection. However, this result was not statistically significant (p = 0.999). One patient using anti-TNF was hospitalized but with no need for admission to the ICU (p = 0.999). All 9 patients recovering from COVID-19 were male (p = 0.113). There were 2 (22.2%) smokers in the SARS-CoV-2 positive group and 54 (46.2%) smokers in SARS-CoV-2 negative group (p = 0.297). There was 37.5 pack-year smoking in SARS-CoV-2 positive group, and 12 pack-year smoking in SARS-CoV-2 negative group (p = 0.151). Nobody has comorbidities (DM, HT, amiloidosis, FMF, CAD, COPD) in SARS-CoV-2 positive group. There were patients with DM (5.1%), HT (15.4%), amiloidosis (1.7%), FMF (1.7%), CAD (0.9%) and COPD (0.9%) in SARS-CoV-2 negative group (p = 0.999, p = 0.356, p = 0.999, p = 0.999, p = 0.999, p = 0.999, respectively). Having comorbidities was not detected to be associated with frequency of COVID-19. 31 (40.3%) patients were using adalimumab, 25 (32.5%) patients were using etanercept, 13 patients were using (16.9%) certolizumab, 6 (7.8%) patients were using golimumab, and 2 patients (2.6%) were using infliximab in TNF group. Six patients using anti-TNF (2 adalimumab, 1 etanercept, 1 golimumab,2 infliximab) and 3 nonuser patients recovered from COVID-19 (p = 0.999). No statistically significant difference was found between SARS-CoV-2 positive and negative patients in terms of the types of anti TNF they used. Patients were called in March 2020, and they were advised to terminate their anti-TNF therapy, when the COVID-19 pandemic began. Among those who used antiTNF, 2 (33.3%) people who had COVID-19 and 38 (53.5%) people who did not have COVID-19 interrupted treatment (p = 0.419). Anti-TNF users who did not have COVID-19 stopped taking the treatment for an average of 3 months (min 2-max 4 months) starting from March 2020, and the patients who had COVID-19 (p = 0.102) stopped taking the treatment for 1.5 months (min 1-max 2 months). Duration of interrupting TNFi was not significant for the risk of COVID-19. Comorbidities, older age, and the presence of active disease have been associated with worse outcomes in previous studies [3]. In our study, the anti-TNF using and the nonuser groups were similar according to age, sex, and comorbidities. Although comorbidities in COVID-19 are associated with severe disease in the literature, we did not find a significant difference in our study. This result is probably related to our insufficient number of patients. As a result, we found that the use of anti-TNF did not increase the frequency and severity of COVID-19. In a recently published multicenter study, it was stated that the use of biological DMARDs in patients with inflammatory rheumatic diseases was not significantly associated with a worse outcome of COVID-19. But unlike our study, having no comorbidities was associated with a decreased risk of a worse outcome [4]. There are currently studies investigating the therapeutic utility of infliximab and adalimumab in hospitalized COVID-19 patients [5]. The results of these studies are very important. The usability of TNFi in treatment and at which stage of the disease anti-TNF agents can be used are wondered. We will see the course of the disease all over the world after the administration of the COVID-19 vaccines, but we still need more information about effective and safe treatment. RESULTS: The authors declare that there is no conflict of interest. DISCUSSION: The authors did not receive support from any organization for this work.

Rapid improvement in severe long COVID following perispinal etanercept.

BACKGROUND: This study aimed to describe the neurological improvements in a patient with severe long COVID brain dysfunction following perispinal etanercept administration. Perispinal administration of etanercept, a novel method designed to enhance its brain delivery via carriage in the cerebrospinal venous system, has previously been shown to reduce chronic neurological dysfunction after stroke. Etanercept is a recombinant biologic that is capable of ameliorating two components of neuroinflammation: microglial activation and the excess bioactivity of tumor necrosis factor (TNF), a proinflammatory cytokine that is a key neuromodulator in the brain. Optimal synaptic and brain network function require physiological levels of TNF. Neuroinflammation, including brain microglial activation and excess central TNF, can be a consequence of stroke or peripheral infection, including infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19. METHODS: Standardized, validated measures, including the Montreal Cognitive Assessment, Beck Depression Index-II (BDI-II), Fatigue Assessment Scale, Controlled Oral Word Association Test, Trail Making Tests, Timed Finger-to-Nose Test, 20 m Self-Paced Walk Test, 5 Times Sit-to-Stand Test and Grip Strength measured with a Jamar Dynamometer were used to quantitate changes in cognition, depression, fatigue and neurological function after a single 25 mg perispinal etanercept dose in a patient with severe long COVID of 12 months duration. RESULTS: Following perispinal etanercept administration there was immediate neurological improvement. At 24 h, there were remarkable reductions in chronic post-COVID-19 fatigue and depression, and significant measurable improvements in cognition, executive function, phonemic verbal fluency, balance, gait, upper limb coordination and grip strength. Cognition, depression and fatigue were examined at 29 days; each remained substantially improved. CONCLUSION: Perispinal etanercept is a promising treatment for the chronic neurologic dysfunction that may persist after resolution of acute COVID-19, including chronic cognitive dysfunction, fatigue, and depression. These results suggest that long COVID brain neuroinflammation is a potentially reversible pathology and viable treatment target. In view of the increasing unmet medical need, clinical trials of perispinal etanercept for long COVID are urgently necessary. The robust results of the present case suggest that perispinal etanercept clinical trials studying long COVID populations with severe fatigue, depression and cognitive dysfunction may have improved ability to detect a treatment effect. Positron emission tomographic methods that image brain microglial activation and measurements of cerebrospinal fluid proinflammatory cytokines may be useful for patient selection and correlation with treatment effects, as well as provide insight into the underlying pathophysiology.

Chronic cerebral aspects of long COVID, post-stroke syndromes and similar states share their pathogenesis and perispinal etanercept treatment logic.

The chronic neurological aspects of traumatic brain injury, post-stroke syndromes, long COVID-19, persistent Lyme disease, and influenza encephalopathy having close pathophysiological parallels that warrant being investigated in an integrated manner. A mechanism, common to all, for this persistence of the range of symptoms common to these conditions is described. While TNF maintains cerebral homeostasis, its excessive production through either pathogen-associated molecular patterns or damage-associated molecular patterns activity associates with the persistence of the symptoms common across both infectious and non-infectious conditions. The case is made that this shared chronicity arises from a positive feedback loop causing the persistence of the activation of microglia by the TNF that these cells generate. Lowering this excess TNF is the logical way to reducing this persistent, TNF-maintained, microglial activation. While too large to negotiate the blood-brain barrier effectively, the specific anti-TNF biological, etanercept, shows promise when administered by the perispinal route, which allows it to bypass this obstruction.

Adamantiades-Behçet's disease therapy: current treatment options and recommendations with regard to the COVID-19 pandemic.

Adamantiades-Behçet's disease (ABD) is a chronic, idiopathic, relapsing immune-mediate disease that may involve multiple organs. It is characterized by recurrent oral and genital ulcers, skin lesions, ocular, gastrointestinal, vascular, neurological and joint involvement. It can lead to significant morbidity and mortality. Due to its heterogeneity in clinical findings and physiopathology, its treatment can be various as ABD manifestations in different organs may differently respond to the same drug. The cornerstone of therapy for inducing remission is systemic corticosteroid, whereas immunomodulatory and immunosuppressive agents such as colchicine, azathioprine, cyclosporine-A, interferon-alpha, and cyclophosphamide are used as steroid-sparing agents and to prevent relapses. For aggressive, refractory or frequently relapsing cases, tumor necrosis factor (TNF) alpha inhibitors (infliximab, adalimumab, etanercept) have been reported beneficial. Herein, we describe our experience of 7 patients treated with TNF-alpha inhibitors with recommendations regarding treatment choice during the COVID-19 era.

Infection with SARS-CoV-2 causes flares in patients with juvenile idiopathic arthritis in remission or inactive disease on medication.

BACKGROUND: Flares of juvenile idiopathic arthritis (JIA) have been described in the context of various infections. Flares of rheumatic diseases in adults have been described following infection with SARS-CoV-2 in several cohorts. So far, the effect of infection with SARS-CoV-2 on the course of JIA is unknown. METHODS: The database of the German Center for Pediatric and Adolescent Rheumatology was searched for patients with confirmed infection with SARS-CoV-2 and subsequent disease flare, admitted from July 2020 until June 2021. cJADAS-27, ESR and C-reactive protein, as well as uveitis activity, medication at the time of flare and treatment of flare was extracted. Patient cases were described individually. RESULTS: Out of 988 patients admitted, five patients with remission off medication (n = 2) or inactive disease on medication (n = 3) were identified, with flare symptoms up to four weeks after infection with SARS-CoV-2. CONCLUSIONS: Flares can occur after infection with SARS-CoV-2 in patients with JIA in remission or inactive disease on medication. Treating physicians need to be aware of this fact, especially when counseling patients with rheumatic diseases about the respective dangers of COVID-19 and vaccination against SARS-CoV-2.

Broader Insights into Understanding Tumor Necrosis Factor and Neurodegenerative Disease Pathogenesis Infer New Therapeutic Approaches.

Proinflammatory cytokines such as tumor necrosis factor (TNF), with its now appreciated key roles in neurophysiology as well as neuropathophysiology, are sufficiently well-documented to be useful tools for enquiry into the natural history of neurodegenerative diseases. We review the broader literature on TNF to rationalize why abruptly-acquired neurodegenerative states do not exhibit the remorseless clinical progression seen in those states with gradual onsets. We propose that the three typically non-worsening neurodegenerative syndromes, post-stroke, post-traumatic brain injury (TBI), and post cardiac arrest, usually become and remain static because of excess cerebral TNF induced by the initial dramatic peak keeping microglia chronically activated through an autocrine loop of microglial activation through excess cerebral TNF. The existence of this autocrine loop rationalizes post-damage repair with perispinal etanercept and proposes a treatment for cerebral aspects of COVID-19 chronicity. Another insufficiently considered aspect of cerebral proinflammatory cytokines is the fitness of the endogenous cerebral anti-TNF system provided by norepinephrine (NE), generated and distributed throughout the brain from the locus coeruleus (LC). We propose that an intact LC, and therefore an intact NE-mediated endogenous anti-cerebral TNF system, plus the DAMP (damage or danger-associated molecular pattern) input having diminished, is what allows post-stroke, post-TBI, and post cardiac arrest patients a strong long-term survival advantage over Alzheimer's disease and Parkinson's disease sufferers. In contrast, Alzheimer's disease and Parkinson's disease patients remorselessly worsen, being handicapped by sustained, accumulating, DAMP and PAMP (pathogen-associated molecular patterns) input, as well as loss of the LC-origin, NE-mediated, endogenous anti-cerebral TNF system. Adrenergic receptor agonists may counter this.

Retention and survival rate of etanercept in psoriasis over 15 years and patient outcomes during the COVID-19 pandemic: The real-world experience of a single center.

There have been a number of investigations of the efficacy and safety of etanercept. This study was performed to obtain long-term drug survival data (ie, time to drug discontinuation) for etanercept, and the reasons for its discontinuation. The study population consisted of patients with psoriatic arthritis and psoriasis followed up by our clinic, registered in the Turkish Psoriasis Registry (PSR-TR) and treated with etanercept for at least 4 weeks between January 1, 2005, and January 31, 2020. The efficacy of etanercept was evaluated in terms of the Psoriasis Area and Severity Index (PASI) 75, PASI 90 and PASI 100 response rates at 12, 24, 36, and 48 weeks, and annually thereafter. The behaviors of the patients with respect to the use of etanercept, and the outcomes of those who continued to use it during the COVID-19 pandemic, were also investigated.

[SARS-CoV-2 infection in a patient treated by hydroxychloroquine and anti TNF α for Inflammatory Rheumatic Disease]. / Une infection par le SARS-CoV-2 chez un patient sous hydroxychloroquine et anti TNF α pour rhumatisme inflammatoire chronique.

Hydroxychloroquine is an agent used as a treatment but also considered as a prophylaxis for SARS-CoV-2 infection. We report the case of a patient who developed COVID-19 while on hydroxychloroquine for mixed connectivitis associated with spondyloarthritis. Although more work is needed before any conclusions can be drawn, this raises questions about the protective role of this drug against infection. Are they really protected against COVID-19 or will they develop pauci-symptomatic forms?

Management of childhood-onset autoinflammatory diseases during the COVID-19 pandemic.

Concerns regarding the comorbidity as a significant risk factor for Coronavirus Disease-2019 (COVID-19), gave rise to an urgent need for studies evaluating patients with chronic conditions such as autoinflammatory diseases (AIDs). We prepared a web-based survey investigating the clinical findings and contact histories among pediatric patients with AIDs. Confirmed COVID-19 cases, patients with contact history and those with symptoms which were highly suggestive of COVID-19 were called via phone or recruited to a video or face to face appointment. Data of AIDs were obtained from their medical records, retrospectively. Laboratory and screening findings were confirmed by our national health registry website. There were 404 patients (217 female) eligible for the enrollment. During pandemic, 375 (93%) were on colchicine treatment and 48 (11.8%) were receiving biologic treatment. Twenty-four out of 404 patients were admitted to hospital due to COVID-19 suspicion. Severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) was identified through rhinopharyngeal swabs in seven patients, six of whom were only on colchicine treatment. Only one patient with no finding of any severe respiratory complications was hospitalized. All of seven patients recovered completely. Among patients on biologic drugs, neither a symptom nor a positive polymerase chain reaction test for COVID 19 was detected. In conclusion, pediatric patients with AIDs, those receiving biologic treatment and/or colchicine, may not be at increased risk for neither being infected nor the severe disease course.

Olfactory and Gustatory Dysfunction in a COVID-19 Patient with Ankylosing Spondylitis Treated with Etanercept: Case Report.

The neurologic manifestations concerning coronavirus disease 2019 (COVID-19) are highly penetrated. Anosmia and ageusia are one of the common acute neurologic symptoms, which develop in the early stage of COVID-19. However, it is not reported that how immunosuppressive agents affect these symptoms. We report olfactory and gustatory dysfunctions in a patient with ankylosing spondylitis (AS) treated with etanercept during COVID-19. A 53-year-old female showing AS controlled with tumor necrosis factor-α inhibitor, etanercept, had been diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, presenting cough and rhinorrhea. One month after diagnosis, she complained about hyposmia and hypogeusia two days before the seronegative conversion of SARS-CoV-2, which were confirmed by a neurological examination. We speculate that the etanercept may have delayed the development of olfactory and gustatory dysfunction in the patient.