Helicobacter canis bacteraemia in a rheumatoid arthritis patient treated with tofacitinib: case report and literature review.

BACKGROUND: Non-Helicobacter pylori species (NHPS) are newly emerging bacteria that naturally inhabit birds and mammals apart from humans and rarely cause diseases in humans. In recent years, a rise in the number of cases associated with NHPS infections in humans has been observed. Among them, infections with Helicobacter (H.) canis are sporadic and challenging to recognise clinically. To date, ten cases of H. canis infections in mainly immunocompromised humans have been reported in the literature. Transmission pathway is most likely zoonotic via the faecal-oral route during close contacts with dogs and cats or may result from a contaminated sheep milk intake. No clear guidelines for successful antibiotic regimen are known. Important additional risk factor for infection might be biologic agents and Janus kinase inhibitors (JAKi) used in the treatment of rheumatoid arthritis (RA) and other conditions. Herein we present the first case of H. canis bacteraemia in a RA patient treated with novel JAKi tofacitinib. CASE PRESENTATION: A 65-year-old female patient with RA and rituximab-induced hypogammaglobulinemia treated with tofacitinib, methotrexate, and methylprednisolone came to a planned visit in our outpatient rheumatology clinic. She presented with a history of back pain that significantly worsened 2 days before visit. She had numbness and tingling sensation in both legs and muscle weakness. Neurological examination was within a normal range. The patient was afebrile, had no chills, and was haemodynamically stable. She was in close contact with her pet dogs. Laboratory examination showed increased markers of inflammation. She was found to have H. canis bacteraemia with underlying multilevel degenerative lumbar spinal stenosis. Identification of H. canis was performed by MALDI-TOF MS and 16 S rRNA gene sequence analysis of isolate from subcultured positive aerobic blood culture bottles. Antimicrobial susceptibility testing showed low minimum inhibitory concentrations to amoxicillin-clavulanate, cefotaxime, ceftriaxone, meropenem, and gentamicin. She was treated with combined antibiotic regimen (ceftriaxone, doxycycline) for 14 days, which resulted in total remission of the infection. CONCLUSIONS: Clinicians should recognise H. canis infection risk in patients with recent pet exposure and predisposing factors such as immunodeficiency disorders or diseases that demand immunosuppressive drug therapy. A minimum of two weeks of antibiotic therapy is suggested.

Survival of Patients With Idiopathic Inflammatory Myopathies in Slovenia.

Background: Idiopathic inflammatory myopathies (IIMs) are rare systemic diseases associated with significant morbidity and mortality. The aim of our study was to estimate for the first time the survival of IIM patients in Slovenia. Methods: We included IIM patients diagnosed between January 2005 and December 2020 and followed at two secondary/tertiary rheumatology centers in the country. To study survival/mortality the censor date of April 14 2021 was set. Kaplan-Meier analysis and standardized mortality ratio (SMR) were plotted using data of age and sex matched Slovenian population as a reference. Cox proportional hazards regression analysis was used to study prognostic factors for IIM mortality. Results: During the 16-year observation period, we identified 217 new IIM patients. During follow up 65 (30.0%) patients died. In the first year following IIM diagnosis the SMR was nearly 7-fold higher compared to the matched general population [SMR 6.88 (95%CI 4.41-10.24)] and remained higher also during the following 4 years. However, when excluding IIM patients with cancer, the survival outcome was, except in the first year after IIM diagnosis [SMR 5.55 (95%CI 3.10-9.15)], comparable to matched general population. In addition to cancer [HR 3.71 (95% CI 2.18-6.04)], cardiac involvement [HR 2.18 (95% CI 1.07-4.45)], fever [HR 2.13 (95% CI 1.13-4.03)], and older age [HR 1.07 (95% CI 1.04-1.09)] were extracted as prognostic factors associated with death. Conclusion: The survival of patients with IIM patients was substantially worse compared to matched general population. Cancer was the leading cause of death in our cohort.

Accelerated atherosclerosis in premenopausal women with rheumatoid arthritis - 15-year follow-up.

Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increased mortality and morbidity due to the higher cardiovascular risk in these patients. Traditional risk factors are not the only answer for the accelerated atherosclerosis. In a long-term prospective study, we investigated the relationship between asymptomatic atherosclerosis and traditional risk factors and inflammatory markers in patients with RA and matched healthy controls. We studied the laboratory test results, the concentrations of inflammatory mediators, matrix metalloproteases (MMP), and inflammation markers in a total of 70 (60 at follow-up) premenopausal healthy women with RA and 40 (34 at follow-up) matched controls. We used the B-mode ultrasound imaging of carotid arteries for the detection of asymptomatic atherosclerosis. Correlation with different factors was evaluated. Statistically significant higher values of inflammatory markers such as selective adhesion molecules ICAM and VCAM, interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and MMP-3 in the patients group were found in the follow-up study. More plaques were found in the patients group (42.4% vs. 12.9%; p=0.005), as compared with the controls group. The patients had also higher values of cIMT (p=0.001). Using bivariate regression analysis only VCAM was found as a prognostic factor for plaque occurrence (r= 0. 341, p=0.016), but not for cIMT (r= -0.130, p=0.327) in premenopausal female patients with RA after the follow-up. Therefore, asymptomatic atherosclerosis is accelerated in premenopausal women with RA. The results of our follow-up study showed the association between inflammation and accelerated atherosclerosis. Furthermore, VCAM was found to have a statistically significant correlation with plaque occurrence in these patients.

[Spectral Domain Optical Coherence Tomographic Findings in Systemic Lupus erythematosus in Patients Treated with Chloroquine]. / Ergebnisse spektraler optischer Kohärenztomografie bei den mit Chloroquin behandelten Patienten mit systemischem Lupus erythematodes.

PURPOSE: To recognise possible retinal changes in patients with SLE treated with chloroquine phosphate, as depending on the duration of treatment. METHODS: The study included 41 patients (82 eyes) who received treatment for SLE with chloroquine or hydroxychloroquine phosphate and had not previously been diagnosed with retinal pathology. Participants were divided into two groups according to the duration of treatment. The first group included 18 patients (36 eyes) treated for up to five years and the second group consisted of 23 patients (46 eyes) treated from five to twenty years. We performed a thorough eye exam, including best-corrected visual acuity, colour vision, visual field examination, dilated fundus examination, autofluorescence imaging, color fundus photography and spectral domain optical coherence tomography. RESULTS: Mean duration of treatment in the first group was 2.79 ± 1.37 years, and in the second group 8.67 ± 2.26 years. The difference in central retinal thickness between the two groups was not statistically significant (p > 0.05). Comparison of parafoveal thickness between the two groups was statistically non-significant in all quadrants (p > 0.05). Visual field examination, autofluorescence images and colour fundus photographs were without noteworthy pathology. CONCLUSION: Our results indicate that there were no significant changes in retinal structure between groups that depended on the duration of treatment. Hence, we can conclude that a yearly follow-up of these patients is sufficient to discover possible preclinical maculopathy.

Opportunities and challenges in rheumatology research in Central Europe.

The Central European Congress of Rheumatology (CECR) has been organized by seven Central European countries: Austria, Croatia, Czech Republic, Hungary, Poland, Slovakia, and Slovenia. These countries have lots of similarities, but also differences, with respect to rheumatology research. In this paper, based on questionnaires, we wish to demonstrate achievements and difficulties in rheumatology research performed in our region.

STAT5 phosphorylation in CD4 T cells from patients with SLE is related to changes in their subsets and follow-up disease severity.

Activation of the STAT5 signaling pathway up-regulates antiapoptotic protein Bcl2 and drives proliferation of autoreactive conventional CD4 T cells (Tcons). In systemic lupus erythematosus (SLE), an increased T cell Bcl2 content and perturbed homeostasis of CD45RA-FOXP3hi activated regulatory T cells (aTregs) were described. We assessed Tcon/Treg subsets and phosphorylation of STAT5 (pSTAT5) in blood T cells from patients with SLE by using conventional and imaging flow cytometry. Forty-one patients with SLE, 33 healthy controls, and 29 patients with rheumatoid arthritis were included. Long-term monitoring was performed in 39 patients with SLE, which were followed longitudinally for up to 1000 d. Significantly increased Bcl2 protein content in T cells from patients with SLE was associated with IL-7-dependent STAT5 activation, expressed as increased basal levels and nuclear localization of pSTAT5. pSTAT5 levels were significantly increased in the FOXP3 low-expressing CD4+ T cell subsets but not in the aTreg subset, which was significantly decreased in patients with SLE. In contrast to aTreg, SLE Tcon displayed significantly increased pSTAT5 and Bcl2 levels. Moreover, the percentage of Tcon-expressing proliferation marker Ki-67 was significantly increased in patients with SLE and was positively correlated with CD4 T cell pSTAT5 levels. Finally, a subgroup of patients characterized by an increased Tcon-pSTAT5/aTreg-pSTAT5 ratio experienced a more aggressive-relapsing disease course and displayed higher time-adjusted cumulative CD4 T cell pSTAT5 levels during follow-up, which were positively correlated with time-adjusted cumulative disease activity. Our results indicate that imbalanced STAT5 phosphorylation, which is related to Bcl2 and Ki-67 expression, may confer survival and proliferative advantage to Tcon over aTreg and could represent a possible marker of SLE disease severity.

Increased Levels of STAT1 Protein in Blood CD4 T Cells from Systemic Lupus Erythematosus Patients Are Associated with Perturbed Homeostasis of Activated CD45RA-FOXP3hi Regulatory Subset and Follow-Up Disease Severity.

In murine systemic lupus erythematosus (SLE), aberrant regulation of interferon (IFN)-alpha-STAT1 signaling and perturbed homeostasis of CD4+FOXP3+ regulatory T cells (Tregs) were described. In the present study, STAT1 signaling and circulating Treg subsets were assessed by flow cytometry in 39 SLE patients and their potential association with disease course was examined during long-term follow-up. Levels of STAT1 protein as measured by median fluorescence intensity (MFI) were significantly increased in SLE CD4 T cells when compared with rheumatoid arthritis patients and healthy controls and were positively correlated with disease activity. The highest STAT1 MFI was found in CD45RA-FOXP3hi-activated Treg (aTreg) subset, which demonstrated the highest STAT1 phosphorylation responses among SLE CD4 T cells and significant decrease in proliferation marker Ki-67 expression after IFN-alpha stimulation. Percentage of Ki-67+ aTregs was significantly decreased in SLE patients and was negatively correlated with CD4 T cell STAT1 MFI. A subgroup of SLE patients characterized by lower aTreg counts experienced more severe relapsing disease course during 1,000 days of follow-up. Mean CD4 T cell STAT1 MFI in follow-up samples from SLE patients was negatively correlated with mean of follow-up aTreg counts. Our findings indicate that augmented STAT1 signaling may be involved in perturbed aTreg homeostasis, which could represent a possible marker of SLE disease severity.

Antiphospholipid antibodies and atherosclerosis: insights from rheumatoid arthritis--a five-year follow-up study.

OBJECTIVES: Life expectancy in rheumatoid arthritis (RA) patients is reduced by 3-10 years, probably due to cerebrovascular and cardiovascular diseases associated with atherosclerosis. In the present study, we wanted to verify if previously reported IgA anti-beta 2-glycoprotein I (2GPI) antibodies possibly represented an independent risk factor for atherosclerosis in RA patients during a longer period of follow up. METHODS: The follow-up study (after 5.5 years) comprised all initially included patients and controls (premenopausal women, non-diabetic, normotensive at the start of the study), except for two RA patients (one died and one not available). The same clinical, laboratory and ultrasound assessments were performed. RESULTS: Patients and controls were divided into three categories: Intima-media thickness (IMT) progressors, plaque progressors, IMT and plaque progressors. In controls, 55% represented IMT progressors and 5% IMT and plaque progressors. No statistically significant differences were detected comparing the progressors with delta (Δ=difference between follow-up and baseline study for each group in a time span of 5.5 years) LDL cholesterol, homocysteine and IgA anti-ß2GPI. In patients, there were 48.5% IMT progressors, 5.8% plaque progressors and 19.1% IMT and plaque progressors. The progression was statistically significant associated with the levels of Δ homocysteine and Δ apolipoprotein B but not with LDL cholesterol and IgA anti-ß2GPI. CONCLUSIONS: The follow-up study showed advanced atherosclerosis in RA patients compared to sex and age matched controls. However, we were not able to confirm our initial impression that IgA anti-ß2GPI might represent an independent risk factor for atherosclerosis.

Antiphospholipid antibodies as a possible risk factor for atherosclerosis in patients with rheumatoid arthritis.

Atherosclerosis shares many similarities with inflammatory and autoimmune diseases, among them rheumatoid arthritis (RA). Anticardiolipin antibodies (aCL) and antibodies against beta2-glycoprotein I (anti-beta2GPI) have been detected in sera of RA patients in several studies. We demonstrated aCL and anti-beta2GPI in a selected group of 70 patients with RA (premenopausal women, non-diabetic, non-hypertensive) and compared them with age- and sex-matched controls. There was a significant higher internal carotid artery intima-media thickness and number of plaques in RA patients compared to controls. aCL of IgG and IgM classes were present in 15.7% of RA patients as compared to 5% in the control group. Thirty percent of RA patients had anti-beta2GPI of IgG, IgM and IgA classes compared to 7.5% in controls. Major differences were seen in IgG and IgA classes. Our results support the idea that aCL and anti-beta2GPI represent an important risk factor for atherosclerosis in RA patients. Elevated levels of phosphatidylserine-dependent antiprothrombin antibodies did not contribute significantly to the general prevalence of antiphospholipid antibodies.