Rheumatological aspects of pathogenesis and treatment of COVID-19 infection.

Contemporary rheumatology is a field dealing with the phenomena of autoimmune states and inflammation. Rheumatic diseases cover a wide spectrum of diseases of the musculoskeletal system, connective tissue and vessels. The occurrence of an immune, autoimmune and autoinflammatory response is often linked to different kinds of infections. Which aspects of the coronavirus infection relate to rheumatological therapy and practice? In order to answer this question one needs to look at the pathogenesis of the SARS-CoV-2 infection. Antimalarial drugs may block antigen presentation of the viral peptides from antigen presenting cells, as they may alter the lysosomal proteases that mediate the viral entry in the cells and have demonstrated efficacy in improving the infection. Anti-IL-6 may interfere with cytokine storm in severe cases and use of tocilizumab has had good results in a small cohort. Baricitinib not only plays a role in inhibiting the synthesis of cytokines but it also has a function in suppressing receptor-mediated endocytosis. The constantly new and tested concepts in the treatment of COVID testify to the growing knowledge about the virus, but also to the need for more targeted therapy. Treatment regimens have been developed for both patients with COVID-19 and those with symptomatic SARS-CoV infection and rheumatic disease. This article is an attempt to discuss the management of COVID-19 and coexisting rheumatic disease.

Coincidence of Guillain-Barré syndrome presenting with Landry's acute flaccid paralysis and transverse myelitis.

Transverse myelitis is one of the causes of acute transverse myelopathy; three main categories are described in the differential diagnosis of transverse myelitis: demyelination (multiple sclerosis, neuromyelitis optica), infections (herpes zoster and herpes simplex virus), and some autoimmune connective tissue disorders (systemic lupus erythematosus, vasculitis). The authors present a clinical case of a 33-year-old patient with transverse myelitis occurring in the course of acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barré syndrome). The patient's medical history was notable. The patient was diagnosed with thrombotic thrombocytopenic purpura (Moschcowitz syndrome) and leukocytoclastic vasculitis when he was 12 years old.

Severe mononeuritis multiplex in a patient with eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic vasculitis characterised by bronchial asthma, hypereosinophilia, and systemic vasculitis. History of asthma with blood eosinophilia and multiorgan involvement are the important clues to suspect EGPA. In the original paper by Churg and Strauss cardiac, gastrointestinal tract, renal, and neurological involvement were noted more frequently. The pattern of neurological involvement may be mononeuritis multiplex, and symmetrical and asymmetrical polyneuropathy. Mononeuritis multiplex was present in 78.1% while cranial nerves were involved in only 4.1% of cases. Glucocorticosteroids and immunosuppressants, especially cyclophosphamide, have considerably improved the prognosis and overall survival rates in patients with systemic vasculitis, including eosinophilic granulomatosis with polyangiitis. The authors present a clinical case of eosinophilic granulomatosis with polyangiitis with severe mononeuritis multiplex. The case reflects the successful application of a cyclophosphamide regime as a remission inducer.

Spondylodiscitis developing in a young man - diagnostic and therapeutic difficulties.

Infectious spondylodiscitis is characterized by vertebral osteomyelitis, spondylitis, and discitis. Patients present with persistent low back pain, fever, or neurological findings. Diagnosis is made with a combination of clinical, radiological, and laboratory findings. Magnetic resonance tomography (MRI) has high sensitivity and specificity in diagnosis and differentiation of the type of spondylodiscitis and may reveal signs of spondylodiscitis even in very early stages. Infectious spondylodiscitis responds to antimicrobial therapy well if diagnosed early before development of neurological deficit and requirement of surgical intervention. We present a clinical case of spondylodiscitis developing in a young immunocompetent man without any predisposing factors.

Organising pneumonia - the first manifestation of rheumatoid arthritis.

Organising pneumonia (OP) is a distinct type of interstitial lung disease, because it can also be seen in association with several conditions such as infections, drugs, and connective tissue diseases. An association of OP with rheumatoid arthritis (RA) has also been described. Joint manifestations of RA usually precede lung involvements by several years; however, in less than 10% of cases of RA, interstitial lung disease may be the initial feature of RA. Organising pneumonia as the initial manifestation or developed simultaneously of RA is extremely rare, and its clinical features remain unknown. We present a 56-year-old woman with OP as the first manifestation of RA.

Two clinical cases of granulomatosis with polyangiitis with isolated otitis media and mastoiditis.

Granulomatosis with polyangiitis (GPA) is characterised by granulomatous necrotising inflammatory lesions of the upper and lower respiratory tract, often associated with pauci-immune glomerulonephritis. The diagnosis of granulomatosis with polyangiitis is made according to the classification criteria of the ACR criteria for granulomatosis with polyangiitis. We present two cases of granulomatosis with polyangiitis limited/localised form. The common feature between two clinical cases were not sufficient criteria for a definite diagnosis at the beginning. In both cases the clinical presence was otitis media with acute mastoiditis, peripheral facial nerve palsy, and severe headache. Early diagnosis and treatment of patients with granulomatosis with polyangiitis define favourable prognosis. On the other hand, the treatment of granulomatosis with polyangiitis (corticosteroids and immunosuppressive therapy) has various side effects, and the "ex juvantibus" therapy is hazardous.

Women's health and fertility, family planning and pregnancy in immune-mediated rheumatic diseases: a report from a south-eastern European Expert Meeting.

With current advances in medical treatment, reproductive issues have become more important for women with chronic immune-mediated diseases. Most, if not all, patients report that their disease affects their personal relationships, their decision to have children, and the size of their family. These decisions are multi-factorial, influenced mainly by concerns over the effect of pregnancy on the rheumatic disease, the impact of disease activity during pregnancy on foetal health, the patient's ability to care for the child, and the possible harmful effects medication could have on the child, both pre- and post-natally during breastfeeding. Apart from that, women's health issues tend to be overlooked in favour of the management of the underlying rheumatic disease. To this end, we convened an expert panel to review the published literature on women's health and reproductive issues and provide evidence- and eminence-based points to consider for the treating physicians. We conclude that there is a need for a change in mind-set from one which 'cautions against pregnancy' to one which 'embraces pregnancy' through the practice of individualised, pre- and post-conceptual, multi-disciplinary care.

Treg/Th17 cell balance and phytohaemagglutinin activation of T lymphocytes in peripheral blood of systemic sclerosis patients.

AIM: To investigate T-cell activation, the percentage of peripheral T regulatory cells (Tregs), Th17 cells and the circulating cytokine profile in systemic sclerosis (SSc). METHODS: We enrolled a total of 24 SSc patients and 16 healthy controls in the study and divided the patients as having diffuse cutaneous SSc (dcSSc, n = 13) or limited cutaneous SSc (lcSSc, n = 11). We performed a further subdivision of the patients regarding the stage of the disease - early, intermediate or late. Peripheral venous blood samples were collected from all subjects. We performed flow cytometric analysis of the activation capacity of T-lymphocytes upon stimulation with PHA-M and of the percentage of peripheral Tregs and Th17 cells in both patients and healthy controls. We used ELISA to quantitate serum levels of human interleukin (IL)-6, IL-10, tissue growth factor-ß1 (TGF-ß1), and IL-17A. RESULTS: We identified a decreased percentage of CD3+CD69+ cells in PHA-stimulated samples from SSc patients in comparison with healthy controls (13.35% ± 2.90% vs 37.03% ± 2.33%, P < 0.001). However, we did not establish a correlation between the down-regulated CD3+CD69+ cells and the clinical subset, nor regarding the stage of the disease. The activated CD4+CD25+ peripheral lymphocytes were represented in decreased percentage in patients when compared to controls (6.30% ± 0.68% vs 9.36% ± 1.08%, P = 0.016). Regarding the forms of the disease, dcSSc patients demonstrated lower frequency of CD4+CD25+ T cells against healthy subjects (5.95% ± 0.89% vs 9.36% ± 1.08%, P = 0.025). With regard to Th17 cells, our patients demonstrated increased percentage in comparison with controls (18.13% ± 1.55% vs 13.73% ± 1.21%, P = 0.031). We detected up-regulated Th17 cells within the lcSSc subset against controls (20.46% ± 2.41% vs 13.73% ± 1.21%, P = 0.025), nevertheless no difference was found between dcSSc and lcSSc patients. Flow cytometric analysis revealed an increased percentage of CD4+CD25-Foxp3+ in dcSSc patients compared to controls (10.94% ± 1.65% vs 6.88% ± 0.91, P = 0.032). Regarding the peripheral cytokine profile, we detected raised levels of IL-6 [2.10 (1.05-4.60) pg/mL vs 0.00 pg/mL, P < 0.001], TGF-ß1 (19.94 ± 3.35 ng/mL vs 10.03 ± 2.25 ng/mL, P = 0.02), IL-10 (2.83 ± 0.44 pg/mL vs 0.68 ± 0.51 pg/mL, P = 0.008), and IL-17A [6.30 (2.50-15.60) pg/mL vs 0 (0.00-0.05) pg/mL, P < 0.001] in patients when compared to healthy controls. Furthermore, we found increased circulating IL-10, TGF-ß, IL-6 and IL-17A in the lcSSc subset vs control subjects, as it follows: IL-10 (3.32 ± 0.59 pg/mL vs 0.68 ± 0.51 pg/mL, P = 0.003), TGF-ß1 (22.82 ± 4.99 ng/mL vs 10.03 ± 2.25 ng/mL, P = 0.031), IL-6 [2.08 (1.51-4.69) pg/mL vs 0.00 pg/mL, P < 0.001], and IL-17A [14.50 (8.55-41.65) pg/mL vs 0.00 (0.00-0.05) pg/mL, P < 0.001]. Furthermore, circulating IL-17A was higher in lcSSc as opposed to dcSSc subset (31.99 ± 13.29 pg/mL vs 7.14 ± 3.01 pg/mL, P = 0.008). Within the dcSSc subset, raised levels of IL-17A and IL-6 were detected vs healthy controls: IL-17A [2.60 (0.45-9.80) pg/mL vs 0.00 (0.00-0.05) pg/mL, P < 0.001], IL-6 [2.80 (1.03-7.23) pg/mL vs 0.00 pg/mL, P < 0.001]. Regarding the stages of the disease, TGF-ß1 serum levels were increased in early stage against late stage, independently from the SSc phenotype (30.03 ± 4.59 ng/mL vs 13.08 ± 4.50 ng/mL, P = 0.017). CONCLUSION: It is likely that the altered percentage of Th17 and CD4+CD25-FoxP3+ cells along with the peripheral cytokine profile in patients with SSc may play a key role in the pathogenesis of the disease.