Characteristics of elderly patients with rheumatoid arthritis who have not responded to methotrexate therapy within 24 weeks

Objective: To describe the clinical, laboratory and pharmacokinetic features of elderly patients with rheumatoid arthritis (RA), with insufficient response to methotrexate (MTX) therapy for 24 weeks compared with patients with a good response. Material(s) and Method(s): The study included 32 patients with RA, according to the older age category according to WHO criteria, 65 (82%) women and 14 (18%) men, BMI was 27 +/- 4 kg/m2, DAS28 was 5.9 +/- 1. In each case, MTX was administered parenterally, at the rate of 10-15 mg/m2 of body surface. therapeutic drug monitoring was carried out, it was the determination of the concentrations of MTX monoglutamate (initial form) and MTX compounds: polyglutamates and 7-hydroxymethotrexate (7-OH- MT) in erythrocytes (ER) and mononuclear cells (MO) after 4, 12 and 24 weeks. We used high performance liquid chromatography with mass spectrometric detection. The MTX metabolite index was calculated (the ratio of the metabolite concentration to the initial concentration of unchanged MT). Achievement of therapy targets (good response to therapy) was established in accordance with the EULAR criteria. The lack of achievement of therapy goals corresponded to an insufficient response to therapy. Result(s): By week 24, 12 patients (36%, group 1) achieved therapy targets, 17 patients (53%, group 2) did not reach treatment targets, and in 3 more, MTX was discontinued due to Adverse reactions (ARs) and/or the development of COVID-19. A comparison was made of clinical and laboratory parameters before the start of MTX treatment and during MTX therapy. At all stages of the study the groups did not differ in terms of: sex, age, BMI, disease duration, VAS (pain), DAS28 index, creatinine, taking glucocorticoids, statins, the presence and frequency of comorbid pathology (arterial hypertension, diabetes mellitus, chronic autoimmune thyroiditis). The 7-OH- MTX( ER) metabolic index after 12 weeks of treatment was higher in group 1 (1.35 [0.8;2.1] versus 0.35 [0.19;0.73] in group 2). Metabolic indices of other MTX metabolites did not differ. ARs were less common in group 1 (in 1 (18%) versus 6 (35%) in group 2), P = 0.09. Conclusion(s): Clinical and laboratory characteristics of patients of the older age group did not differ in groups with different responses to methotrexate therapy. The 7-OH- MT( ER) metabolism index after 12 weeks of treatment was higher in the group of patients with a good response to therapy, which most likely indicates a more rapid catabolism of MTX in this group of patients.

A Literature Review on SARS-CoV-2 and Other Viruses in Thyroid Disorders: Environmental Triggers or No-Guilty Bystanders?

A growing number of findings indicate a relationship between COVID-19 infection and thyroid dysfunction. This association is also strengthened by knowledge on the potential of viral infections to trigger thyroid disorders, although the exact underlying pathogenetic process remains to be elucidated. This review aimed to describe the available data regarding the possible role of infectious agents, and in particular of SARS-CoV-2, in the development of thyroid disorders, summarizing the proposed mechanisms and levels of evidence (epidemiological, serological or direct presence of the viruses in the thyroid gland) by which the infection could be responsible for thyroid abnormalities/diseases. Novel data on the association and mechanisms involved between SARS-CoV-2 vaccines and thyroid diseases are also discussed. While demonstrating a clear causal link is challenging, numerous clues at molecular and cellular levels and the large amount of epidemiological data suggest the existence of this relationship. Further studies should be taken to further investigate the true nature and strength of this association, to help in planning future preventive and therapeutic strategies for more personal and targeted care with attention to the underlying causes of thyroid dysfunction.

Interdisciplinary Approach Is Essential for Sufficient Diagnosis and Therapy in Igg4-Related Disease Involving Multiple Organs

Introduction: IgG4-related disease (IgG4-RD) is a systemic, chronic inflammatory syndrome, with enlargement of involved organs, elevated serum levels of IgG4, dense lymphoplasmocytic infiltrates, rich in IgG4-positive plasma cells, and fibrosis in involved organs. The most frequently involved organs are the pancreato-hepatobiliary tract, salivary and lacrimal glands, the retroperitoneum, kidneys, lungs, and aorta. Often multiple organ systems are involved. As an initial treatment, glucocorticoids are recommended. In patients with relapse along with glucocorticoid dose reduction, various immunosuppressive agents have been reported. Aims & Methods: We reviewed 98 patients (2019-now) who were treated in the special outpatient unit for IgG4-RD at the University Hospital of Essen and identified 10 patients with IgG4-RD involving multiple organ systems. Result(s): The first patient is a 65-year-old male diagnosed with an IgG4- RD involving parotitis, lymphadenitis, sialadenitis with orbitopathy and elevated IgG4 serum level (7400 mg/l). Clinically response to therapy with steroids was documented. The second patient is a 63-year-old man with an IgG4-positive pancreatitis, sialadentis, lymphadenopathy, and elevated IgG4 serum level (3960 mg/l). Immunosuppression with tacrolimus leaded to clinical benefit. As the third patient, we report a 48-year-old man with IgG4-related inflammatory condition in pancreas and kidneys with high IgG4 serum levels. The patient was successfully treated with azathioprine and prednisolone. As the fourth patient, we demonstrate a 34-year-old man with IgG4-related autoimmune hepatitis, lymphadenitis, and pancreatitis. After treatment with tacrolimus in combination with rituximab, a significant decrease of IgG4-level was detected. The fifth patient, a 65-year-old man, was diagnosed with IgG4-related fibro- inflammatory pseudotumors in the liver, esophagitis, and lymphadenopathy combined with high serum levels of IgG4 (12000 mg/l). Clinically response to therapy with steroids and azathioprine was reported. As the sixth patient we demonstrate a 29-year-old male with IgG4-related lymphadenopathy, recurrent myocarditis, and pancreatitis. The patient has symptom-free episodes under low-dose prednisolone. We also found an IgG4-RD with multiple organ involvement in our seventh patient. A 54-year-old man with IgG4-related cholangitis, pancreatitis, prostatitis, and very high serum level of IgG4 (26700 mg/l) were treated with steroids and azathioprine. As our eight case, we present a 23-year-old man with congenital hepatic fibrosis, after living-donor liver transplantation, who developed an IgG4- related disease with high IgG4 serum levels (45300 mg/l) after infection with SARS-CoV-2. Pathologically enlarged lymph nodes were detected. In a biopsy of retroperitoneal lymph nodes, IgG4-positive plasma cells were detectable. Intestinal biopsies have shown numerous positive plasma cells in the IgG4-staining (40 IgG4 positive plasma cells/HPF). Treatment with rituximab is planned. The ninth patient is a 56-year-old woman with lymphadenitis and cholangitis, who clinically responded to a treatment with budesonide. As the last patient we present a 59-year-old man with an IgG4-related aortitis, cardiac fibrosis, cholangitis, hepatitis, exocrine pancreatic insufficiency and Hashimoto's thyroiditis responding very sufficient to rituximab. Conclusion(s): An interdisciplinary approach is essential for a sufficient diagnosis and therapy in IgG4-RD involving multiple organs. This collective is extremely heterogeneous, and treatment is often based on individual concepts.

Two Cases of Autoimmune Thyroid Disorders after COVID Vaccination in Dialysis Patients.

SARS-CoV-2 infection and vaccination have been associated with autoimmune thyroid dysfunctions. Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) and molecular mimicry have been referred to as potential causes. Such a case has not been reported in immunocompromised end-stage renal disease (ESRD) patients. Herein we present two dialysis patients with no previous history of thyroid disease who developed immune mediated thyroid disorders after BNT162b mRNA vaccine against SARS-CoV-2. The first patient is a 29-year-old man on hemodialysis diagnosed with Grave's disease four months post-vaccination and the second one is a 67-year-old female on peritoneal dialysis who developed Hashimoto's thyroiditis two months post-vaccination. Grave's disease is uncommon in dialysis patients, whereas Hashimoto's thyroiditis has a higher incidence in this population. Time proximity in both cases suggests potential causality. To our knowledge, this is the first report of de novo immune-mediated thyroid disorders in dialysis patients following vaccination against SARS-CoV-2.

[Autoimmune encephalitis in pediatric population]

Autoimmune encephalitis can be defined as central nervous system inflammation, secondary to multiple causes, where we can possibly identify the formation of auto-antibody against neurotransmitter receptors or neuronal surface proteins. Approximately 50% of patients are seropositive;the auto-antibody against N-methyl-D-aspartate receptor (NMDAR) are the most common. In the pediatric population, the clinical presentation is characterized by movement disorders and seizures, psychiatric manifestations are more commonly found in young adults. An early intervention is associated with a better prognosis in these patients. In contrast to the seropositive group, seronegative autoimmune encephalitis is linked with less movement alterations and is related with a worse cognitive outcome. Much remains to be discovered about possible etiologies, molecular processes, detection, and interaction of yet undescribed antibodies,as well as increasing our knowledge about clinical manifestations in early disease and new diagnostic techniques that could improve the diagnosis of autoimmune encephalitis. The main goal of this document is to review the updates of the molecular field about the antibody against GluK2 and its clinical presentation in pediatric population;COVID-19 as a possible cause of autoimmune encephalitis;recognize the importance of psychiatric manifestation in early disease, especially catatonia as a marker of severity;additionally consider new imaging diagnostic method such as positron emission tomography (PET), which has shown to be more sensible than MRI (goal standard).

SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARSCoV- 2) VACCINE-INDUCED THYROID DYSFUNCTION: A TALE OF TWO PATIENTS

Introduction SARS-CoV-2 vaccine has been the main pillar in battling the coronavirus disease 2019 (COVID-19) pandemic. However, the current vast scale of SARS-CoV-2 vaccination programme has led to inevitable reports of various adverse reactions, one of which include thyroid dysfunction. CASES We describe two patients who manifested hyperthyroidism following BNT162b2 mRNA-based COVID-19 vaccine boosters. Patient 1, a previously euthyroid 46-year-old female, has an eight-year history of type 1 diabetes mellitus. She developed palpitations of increasing severity about two weeks after her COVID-19 booster vaccine on 20th January 2022. She had weight loss of 4 kg and experienced menstrual irregularities in the subsequent three months. Examination revealed tachycardia (112 beats per minute, regular) and bilateral fine tremors of the hands. There was no goitre or neck tenderness. Blood investigations showed overt hyperthyroidism with positive thyroid autoantibodies, consistent with Graves' disease. Treatment with carbimazole led to marked symptomatic improvement. Patient 2, a 38-year-old female with a six-year history of Hashimoto thyroiditis, was clinically and biochemically euthyroid while taking levothyroxine 100 mcg daily prior to her COVID-19 booster vaccine on 5th January 2022. Five weeks following the vaccine, her thyroid function test during her endocrine clinic appointment showed overt hyperthyroidism, which was confirmed by a second blood sample ten days later. There was neither a change in levothyroxine dose nor any additional supplement intake. She was otherwise asymptomatic. Levothyroxine was then withheld. She regained her baseline hypothyroid state two weeks later, during which levothyroxine was resumed. Conclusion SARS-CoV-2 vaccine-induced thyroid dysfunction can affect both euthyroid and hypothyroid patients. A history of recent COVID-19 vaccination should be included in the clinical evaluation of a newly diagnosed hyperthyroid patient or unexplained hyperthyroidism in a long-standing hypothyroid patient.

MEDULLARY THYROID CANCER IN COMBINATION WITH AUTOIMMUNE THYROIDITIS AFTER COVID-19

Background. Coronavirus disease 2019 (COVID-19) is a pandemic of the new millennium. COVID-19 can cause both pulmonary and systemic inflammation, and can rapidly progress to multiple organ failure. Data on the relationship between COVID-19 and the thyroid gland have been available since March 2020. The thyroid gland and viral infection as well as associated inflammatory-immune reactions participate in a complex interaction. The most common autoimmune disease is chronic autoimmune thyroiditis (chronic lymphocytic thyroiditis, Hashimoto thyroiditis). The majority of medullary thyroid cancers present as a thyroid nodule. Cervical lymph nodes and distant metastases are often detected at the time of diagnosis. The development of autoantibodies may be part of a more complex protective antitumor mechanism, the purpose of which is to eliminate the precursors of future tumor cells. The purpose of the study was to describe a clinical case of diagnosing medullary thyroid cancer in the patient who had COVID-19. Case description. We present the case of a 43-year-old woman who had coronavirus pneumonia (COVID-19), which was accompanied by an increase in serum procalcitonin (PC) level, which required additional examination. Since 2020, she had been observed for autoimmune thyroiditis, which was manifested by a thyroid nodular of a small size. After discharge from the COVID hospital, an ultrasound examination of the thyroid gland revealed an increase in the left lobe thyroid nodule up to 15 mm. The level of calcitonin was 681 pg/ml. Fine needle aspiration (FNA) biopsy of the thyroid gland showed suspicion for medullary thyroid cancer. Thyroidectomy with central lymph node dissection (level VI) was performed. A planned histological examination of the surgical specimen confirmed medullary thyroid cancer. Conclusion. In the present clinical case, medullary thyroid cancer was detected in the patient who had COVID-19 with elevated PC level, which was the basis for a diagnostic search.

EARLY DIAGNOSIS OF EOSINOPHILIC FASCIITIS IN A 16 YEAR-OLD FEMALE

Introduction: Eosinophilic fasciitis (EF) is an uncommon scleroderma-like disorder resulting from infiltration of eosinophils and other white blood cells into the fascia. The etiology of EF is frequently idiopathic, but triggers have included trauma, medications, infection, and autoimmune conditions. Case Description: We present a case of EF in a 16-year old female with a history of Hashimoto’s thyroiditis, food allergies, and allergic rhinitis. Two weeks following her 1st dose of the Pfizer mRNA SARS-CoV-2 vaccine, she presented with generalized edema, weight gain (for 2-3 months prior), and polyarthritis. She did not have any scleroderma-like skin changes. Laboratory analysis was remarkable for eosinophilia (2130 cells/uL), elevated aldolase (15.6 U/L), and normal creatinine kinase. Lupus testing was unremarkable. MRI of bilateral thighs showed fasciitis and muscle/fascial biopsy demonstrated inflammatory myofasciitis consistent with EF. Given pending parasite studies, she received ivermectin prior to IV methylprednisolone therapy. Our patient has demonstrated significant improvement on prednisone, methotrexate, intravenous immunoglobulin, and hydroxychloroquine. Infectious work-up revealed positive Toxocara IgG levels, which prompted albendazole treatment. Discussion: Our case demonstrates an interesting perspective on the rare diagnosis of eosinophilic fasciitis. The etiology of her EF is unclear with confounding factors including her history of Hashimoto’s thyroiditis, positive Toxocara serology (IgG positive, IgM testing not available), and temporal relationship to Pfizer SARS-CoV-2 vaccine. This vaccine could have triggered an inflammatory process in the patient’s already hyper-reactive immune system. It is important to promptly recognize EF, as prolonged symptoms prior to diagnosis is associated with a poor treatment response.

P.0177 Partial ornithine-transcarbamylase deficiency, autoimmunity and psychosis – a complex case report

Background: Ornithine-transcarbamylase deficiency (OTC) is the most common type of urea cycle disorder, and it is the only one with X-linked inheritance. The clinical presentations can vary from severe symptoms caused by hyperammonemia in childhood or adolescence to milder cases with late-onset in adulthood (similar to delirium or acute psychosis) [1], in the context of precipitating factors such as pregnancy, high protein intake, acute stress, infections, certain medications (valproate, steroids, haloperidol) [2]. Method: We present a case of a 31-year-old female, with no history of mental disorders, with a personal history of Hashimoto thyroiditis and urticaria, and a family history of OTC deficiency (her two-year-old niece). She was also a heterozygous carrier for the OTC deletion, reporting periods of meat avoidance and anorexia. She was single, lived alone, and complained of work-related stress, mainly as she worked from home during the COVID-19 pandemic as an IT consultant. The patient presented at our clinic in emergency for psychomotor agitation, slurred speech, complex auditory and visual hallucinations, and mystical delusional ideas. Furthermore, one week before her presentation, she started fasting because of her Christian orthodox religious beliefs (before Easter celebration), but she also complained of insomnia, fatigue, and tachycardia. The patient reported being vaccinated with the first dose of Pfizer's SARS-CoV-2 vaccine one week before the presentation. Results: Laboratory tests showed iron-deficient anemia and ketonuria;hepatic function was normal. Thyroid function was also normal, but anti thyroperoxidase antibodies were elevated. Serum ammonia levels were normal, and urinary orotic acid levels were within normal range. The result of head CT was unremarkable. Neurological examination was normal. She was started on 10 mg i.m. Haloperidol per day, but given the possibility of inducing hyperammonemia in urea cycle disorders patients, she was switched to Risperidone 6 mg/day, which was gradually reduced to 3 mg/day. Also, she was started on a protein-restricted diet. On the second and third days of admission, she was partially disoriented and somnolent but showed no signs of metabolic encephalopathy;therefore, metabolic treatment was not initiated. On the sixth day, she was almost completely recovered, with no psychotic symptoms. After the remission of psychotic symptoms, the neuropsychological evaluation showed significant cognitive deficits: executive functions (impaired performance on Tower of London task), deficits of focused and distributed attention, and decreased immediate verbal memory, even though the patient had received higher education, being at the top of her class during her studies. Given that metabolic profiles were normal, we discuss the complex interactions between autoimmune disorders, genetic factors, precipitating factors, and psychosocial factors that could have contributed to the psychotic episode. Conclusion: Clinicians should consider various factors that can influence the psychological state of a patient, paying attention to atypical factors or symptoms. Also, regarding the treatment of psychiatric symptoms in patients with urea cycle disorders with a normal metabolic profile, psychiatrists must avoid certain medications (haloperidol, valproate) that can worsen the patient's status. No conflict of interest

The magnitude of COVID-19 in children with rheumatic/ autoinflammatory diseases on immunomodulatory agents: A single center experience

Introduction: Children appear less susceptible to SARS-CoV2 infection comparing to adults;however, the burden of the disease remains unclear particularly among specific groups, including immunocompromised children. Objectives: To assess the impact of COVID-19 in children with chronic rheumatic/autoinflammatory diseases (AIRD) being treated with disease-modifying antirheumatic drugs (DMARDs). Methods: We conducted a telephone survey between May 2020 and May 2021 interviewing the parents of all children with AIRD that attend the Immunology and 2Rheumatology Unit of our center. A hospital physician inquired about AIRD characteristics, current DMAR Ds use and duration, COVID-19 main symptoms, if any, source of transmission and duration. Results: Of all 453 patients with AIRD who were currently on DMARDs, 20 children (4.4%) had tested positive for SARS-CoV2 by polymerase chain reaction of nasopharyngeal specimen, during the study period. Male/Female ratio of patients was 0.8 and the median age was 13 years old (interquartile range 5.3- 15 years). The underlying AIRD was polyarticular juvenile idiopathic arthritis (35%), followed by oligoarticular idiopathic arthritis (25%). In all cases, primary AIRD was in remission at the time of SARS-CoV2 acquisition. Comorbidities were recorded in three patients (15%), including one adolescent with chronic stable course of asthma, one case of Hashimoto thyroiditis and one child with atopic dermatitis. Six out of all patients (30%) were symptomatic, with a mild course of COVID-19. Predominant symptoms were malaise (67%), cough (67%) and fever (50%);sore throat, muscle aches and abdominal aches were also reported in 33% of cases, respectively. No hospitalizations nor flares of the underlying AIRD were recorded. No in-school transmission was documented. All patients successfully recovered after a median of three days, without experiencing any post-COVID-19 conditions, and were followed until having three serial negative molecular tests. Biologic agents were not administered during COVID-19 course, according to The American College of Rheumatology guidance. Tocilizumab and adalimumab were the most prevalent biologic DMARDs (35%) followed by etanercept (15%). None of the patients were on corticosteroids, while seven (35%) were receiving conventional DMARDs concomitantly, mainly methotrexate (86%). The six COVID-19 symptomatic children were receiving adalimumab (3/ 6), tocilizumab (1/6), canacimumab (1/6) and belimumab (1/6). Conclusion: In our small cohort of children with AIRD and DMARDs, SARS-CoV2 infection was relatively mild in all symptomatic cases without triggering any relapse of the primary AIRD. Our results may suggest a potential protective role of DMARDs in the evolution of COVID-19 among children with AIRD, particularly when the AIRD is in remission and there are no significant comorbidities.

Insomnia, Anxiety, and Depression Symptoms during the COVID-19 Pandemic May Depend on the Pre-Existent Health Status Rather than the Profession.

Despite the high number of studies on mental health among healthcare workers, only a few have attempted to assess the mental health of people with chronic diseases during the COVID-19 crisis. Therefore, the aim of this study is to evaluate the symptoms of insomnia, anxiety, and depression among people with chronic diseases working in healthcare and in other professions. The study participants were divided into two groups. The first group consisted of 441 healthcare workers, and the second consisted of 572 non-healthcare professionals. Correlation analysis showed a strong correlation between autoimmune diseases and an increase in GAD-7 scale, ISI score, and PHQ-9 scale. Therefore, only autoimmune diseases were included for further analyses as a predictor of insomnia, depression, and anxiety. After adjusting the results for gender, age, smoking, dyslipidemia, hypertension, and profession, the group with autoimmune diseases showed a more than a 2-fold increase in the risk of anxiety symptoms, a more than 2.5-fold increase in the risk of depressive symptoms, and a 4-fold increase in the risk of insomnia symptoms. This study shows that, during the COVID-19 pandemic, the incidence of insomnia, anxiety disorders, and depressive disorders may depend on the pre-existent health status of an individual rather than on their profession.

The Impact of the COVID-19 Pandemic on Psychological Health and Insomnia among People with Chronic Diseases.

The outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic highlighted the serious problems of health care systems but also threatened the mental and physical health of patients worldwide. The goal of this study was to assess psychological health and insomnia in people with chronic diseases in the time of elevated stress associated with the pandemic. The study involved 879 people from Zachodniopomorskie province in Poland. Each participant provided basic demographic data, data on symptoms of insomnia, depression, anxiety and information on concomitant diseases such as hypertension, diabetes mellitus, coronary heart disease, heart failure, dyslipidemia, chronic obstructive pulmonary disease, Hashimoto's disease and smoking cigarettes. Chronic diseases included in this study showed a strong correlation between Hashimoto's disease and increase scores according to the Insomnia Severity Index (ISI, r = 0.797, p < 0.001), the Generalized Anxiety Disorder scale (GAD-7, r = 0.766, p < 0.001) and the Patient Health Questionnaire (PHQ-9, r = 0.767, p < 0.001). After the results were corrected for age, gender, diagnosed hypertension, dyslipidemia and cigarette smoking, it was confirmed that the diagnosis of Hashimoto's disease was associated with an increased risk of anxiety (odds ratio (OR) = 2.225; p < 0.001), depression (OR = 2.518; p < 0.001) and insomnia (OR = 3.530; p < 0.001). Our study showed that during the SARS-CoV-2 pandemic patients with Hashimoto's disease show a higher risk of insomnia, anxiety and depression.