What are the main factors affecting the outcome of tocilizumab therapy in COVID-19-induced cytokine release syndrome?

OBJECTIVE: Recommendations for the treatment of cytokine release syndrome/macrophage activation syndrome (MAS) associated with coronavirus disease-2019 (COVID-19) are still of poor quality. IL-6 is an important therapeutic target as a main mediator of cytokine storm. The aim of our study was to evaluate the tocilizumab (TCZ) efficacy and factors affecting the therapy outcome. METHODS: This retrospective study included 27 patients treated with TCZ for COVID-19-MAS. All patients in this study were treated with TCZ (intravenously, at a dose of 8 mg kg1 ) in addition to standard therapy. Clinical improvement (survival and decreased oxygen demand) on the 10-14th days and secondary infection rate were assessed. RESULTS: In our 27 treated patients, 14 (51.8%) received TCZ in the intensive care unit (ICU) and seven (25.9%) were need to invasive mechanical ventilation (IMV). Fifteen (55.6%) of these patients revealed a good clinical response (four patients discharge from the ICU and 11 patients who followed-up in nonICU beds showed a decrease in oxygen demand). TCZ was significantly less effective in patients having high Murray lung injury score, low PO2/FiO2 ratio, IMV, and ICU admission (P < .05). Severity of hypoxemia was found as a single independent risk factor in the multivariable analysis (P < .05). Secondary bacterial infections rate was significantly higher in intubated patients (P < .01) or treated in the ICU (P » .01). CONCLUSION: TCZ was showed limited efficacy for COVID-19-related MAS. The most important predictive indicator for therapy outcome was found as the severity of hypoxemia. In addition, IMV and/or ICU was associated with the poor outcome and high side effect. So, controlled trials are still needed to confirm the indications and timing of TCZ therapy.

Subclinical biventricular systolic dysfunction in patients with systemic sclerosis.

OBJECTIVE: Silent myocardial involvement is associated with poor prognosis in patients with systemic sclerosis (SSc). Here we aimed to evaluate the subclinical left ventricular (LV) and right ventricular (RV) systolic dysfunction in patients with SSc without any cardiovascular diseases, by using both strain imaging methods, speckle tracking echocardiography (STE) and real-time 3D echocardiography (RT3DE). METHODS: A total of 47 patients with SSc and 20 age- and gender-matched healthy controls (HC) were studied. Conventional echocardiography, STE-based strain imaging, and real-time 3D echocardiography (Bothell, WA, USA) were performed to assess the biventricular deformation. Clinical and serological findings were sought. RESULTS: Conventional echocardiographic LV measurements were similar between SSc and HC. Both the LV and RV longitudinal peak systolic strain/strain rates were significantly impaired in SSc, demonstrating subclinical LV and RV systolic dysfunction (p≤0.001). Systolic pulmonary artery pressure (SPAP) was negatively correlated with both the LV and RV longitudinal peak systolic strain/strain rates (LV, r=-0.554 and r=-0.642, respectively, p<0.001; and RV, r=-0.554 and r=-0.642, respectively, p=0.001). There was a trend for decreasing LV strain and increasing LEVSV in a 1-year analysis of patients with SSc. CONCLUSION: SSc is associated with myocardial systolic dysfunction. A deformation scrutiny conducted by both the STE-based strain imaging and end-systolic LV volume analysis by real-time 3D echocardiography are promising modalities that allow us for non-invasive, comprehensive investigation of subtle deterioration in the biventricular systolic function of patients with SSc.

A multicenter report of biologic agents for the treatment of secondary amyloidosis in Turkish rheumatoid arthritis and ankylosing spondylitis patients.

In this multicenter, retrospective study, we evaluated the efficacy and safety of biologic therapies, including anti-TNFs, in secondary (AA) amyloidosis patients with ankylosing spondylitis (AS) and rheumatoid arthritis (RA). In addition, the frequency of secondary amyloidosis in RA and AS patients in a single center was estimated. Fifty-one AS (39M, 12F, mean age: 46.7) and 30 RA patients (11M, 19F, mean age: 51.7) with AA amyloidosis from 16 different centers in Turkey were included. Clinical and demographical features of patients were obtained from medical charts. A composite response index (CRI) to biologic therapy-based on creatinine level, proteinuria and disease activity-was used to evaluate the efficacy of treatment. The mean annual incidence of AA amyloidosis in RA and AS patients was 0.23 and 0.42/1000 patients/year, respectively. The point prevalence in RA and AS groups was 4.59 and 7.58/1000, respectively. In RA group with AA amyloidosis, effective response was obtained in 52.2 % of patients according to CRI. RA patients with RF positivity and more initial disease activity tended to have higher response rates to therapy (p values, 0.069 and 0.056). After biologic therapy (median 17 months), two RA patients died and two developed tuberculosis. In AS group, 45.7 % of patients fulfilled the criteria of good response according to CRI. AS patients with higher CRP levels at the time of AA diagnosis and at the beginning of anti-TNF therapy had higher response rates (p values, 0.011 and 0.017). During follow-up after anti-TNF therapy (median 38 months), one patient died and tuberculosis developed in two patients. Biologic therapy seems to be effective in at least half of RA and AS patients with AA amyloidosis. Tuberculosis was the most important safety concern.

Response rate of initial conventional treatments, disease course, and related factors of patients with adult-onset Still's disease: Data from a large multicenter cohort.

BACKGROUND: Adult-onset Still's disease (AOSD) is a rare condition, and treatment choices are frequently dependent on expert opinions. The objectives of the present study were to assess treatment modalities, disease course, and the factors influencing the outcome of patients with AOSD. METHODS: A multicenter study was used to reach sufficient patient numbers. The diagnosis of AOSD was based on the Yamaguchi criteria. The data collected included patient age, gender, age at the time of diagnosis, delay time for the diagnosis, typical AOSD rash, arthralgia, arthritis, myalgia, sore throat, lymphadenopathy, hepatomegaly, splenomegaly, pleuritis, pericarditis, and other rare findings. The laboratory findings of the patients were also recorded. The drugs initiated after the establishment of a diagnosis and the induction of remission with the first treatment was recorded. Disease patterns and related factors were also investigated. A multivariate analysis was performed to assess the factors related to remission. RESULTS: The initial data of 356 patients (210 females; 59%) from 19 centers were evaluated. The median age at onset was 32 (16-88) years, and the median follow-up time was 22 months (0-180). Fever (95.8%), arthralgia (94.9%), typical AOSD rash (66.9%), arthritis (64.6%), sore throat (63.5%), and myalgia (52.8%) were the most frequent clinical features. It was found that 254 of the 306 patients (83.0%) displayed remission with the initial treatment, including corticosteroids plus methotrexate with or without other disease-modifying antirheumatic drugs. The multivariate analysis revealed that the male sex, delayed diagnosis of more than 6 months, failure to achieve remission with initial treatment, and arthritis involving wrist/elbow joints were related to the chronic disease course. CONCLUSION: Induction of remission with initial treatment was achieved in the majority of AOSD patients. Failure to achieve remission with initial treatment as well as a delayed diagnosis implicated a chronic disease course in AOSD.

Assessment of the New 2012 EULAR/ACR Clinical Classification Criteria for Polymyalgia Rheumatica: A Prospective Multicenter Study.

OBJECTIVE: To assess the performance of the new 2012 provisional European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) polymyalgia rheumatica (PMR) clinical classification criteria in discriminating PMR from other mimicking conditions compared with the previous 5 diagnostic criteria in a multicenter prospective study. METHODS: Patients older than 50 years, presenting with new-onset bilateral shoulder pain with elevated acute-phase reactants (APR), were assessed for the fulfillment of the new and old classification/diagnostic criteria sets for PMR. At the end of the 1-year followup, 133 patients were diagnosed with PMR (expert opinion) and 142 with non-PMR conditions [69 rheumatoid arthritis (RA)]. Discriminating capacity, sensitivity, and specificity of the criteria sets were estimated. RESULTS: Discriminating capacity of the new clinical criteria for PMR from non-PMR conditions and RA as estimated by area under the curve (AUC) were good with AUC of 0.736 and 0.781, respectively. The new criteria had a sensitivity of 89.5% and a specificity of 57.7% when tested against all non-PMR cases. When tested against all RA, seropositive RA, seronegative RA, and non-RA control patients, specificity changed to 66.7%, 100%, 20.7%, and 49.3%, respectively. Except for the Bird criteria, the 4 previous criteria had lower sensitivity and higher specificity (ranging from 83%-93%) compared with the new clinical criteria in discriminating PMR from all other controls. CONCLUSION: The new 2012 EULAR/ACR clinical classification criteria for PMR is highly sensitive; however, its ability to discriminate PMR from other inflammatory/noninflammatory shoulder conditions, especially from seronegative RA, is not adequate. Imaging and other modifications such as cutoff values for APR might increase the specificity of the criteria.

Investigation of the association between Rho/Rho-kinase gene polymorphisms and systemic sclerosis.

Systemic sclerosis (SSc) is a disease characterized by inflammation, vascular abnormalities and fibrosis. The role of Rho/Rho-kinase pathway was demonstrated in the pathogenesis of fibrosis, inflammation and vascular abnormalities. This study was aimed to investigate the relation between SSc and Rho/Rho-kinase gene polymorphisms. The study included 339 patients with SSc and 302 healthy subjects who were apparently healthy and at similar age and gender. Genotype distributions and allele frequencies were detected by using Chi-square test or Fisher's exact Chi-square test between groups, and the haplotype analysis was applied using online program (SHEsis). Significant association was found in a polymorphism in the ROCK1 gene (rs35996865), a polymorphism in ROCK2 gene (rs10178332), a polymorphism in RhoA gene (rs2177268) and two polymorphisms in RhoC gene (rs11102522 and rs11538960) with SSc disease (p < 0.0022). In this study, association between SSc disease and Rho/Rho-kinase gene polymorphisms was investigated for the first time; significant associations between ROCK1, ROCK2, RhoA and RhoC gene polymorphisms and SSc disease were demonstrated. The results strongly suggest that this SNP may be an important risk factor for development of SSc. However, further validation of these findings in an independent cohort is necessary.

Association of TRPM Channel Gene Polymorphisms with Systemic Sclerosis.

BACKGROUND/AIM: Systemic sclerosis (SSc) is an inflammatory disease characterized by vascular abnormalities and fibrosis. The aim of the present study was to investigate the possible role of transient receptor potential melastatin (TRPM) channel genes in the susceptibility and phenotype expression of SSc. MATERIALS AND METHODS: A total of 339 patients with SSc and 302 healthy controls were studied. Genomic DNA was extracted from leukocytes of the peripheral blood, and 25 single nucleotide polymorphisms in the TRPM channel genes were analyzed by the BioMark HD dynamic array system. RESULTS: There were marked increases in the CC genotype (94.7% vs 81.8%, p<0.0001) and C allele frequencies (97.0% vs. 90.1%, p<0.0001) in the TRPM3 rs1328142, and TT genotype (19.0% vs. 7.8%, p=0.0002) in TRPM5 rs34551253 (Ala456Thr) polymorphism in SSc patients when compared to controls. TRPM3 gene rs1328142 polymorphism was also markedly associated with disease phenotype. However, no associations with the other 23 polymorphisms studied were found. CONCLUSION: This is the first study to examine the involvement of TRPM channel gene variations on the risk of SSc incidence. Our results suggest roles of TRPM3 and TRPM5 gene variants in the susceptibility to or clinical expression of SSc in the Turkish population.

The rate and significance of type 1/type 2 serum amyloid A protein gene polymorphisms in patients with ankylosing spondylitis and amyloidosis.

A relationship between the presence of amyloidosis and SAA1 genotype has been shown in recent studies of (principally) familial Mediterranean fever patients. We found that the SAA1 rs12218 polymorphism was significantly more prevalent in ankylosing spondylitis patients with amyloidosis.

Incidence of Cyclophosphamide-induced Urotoxicity and Protective Effect of Mesna in Rheumatic Diseases.

OBJECTIVE: To assess bladder toxicity of cyclophosphamide (CYC) and uroprotective effect of mesna in rheumatic diseases. METHODS: Data of 1018 patients (725 women/293 men) treated with CYC were evaluated in this retrospective study. All of the following information was obtained: the cumulative CYC dose, route of CYC administration, duration of therapy, concomitant mesna usage, and hemorrhagic cystitis. Cox proportional hazard model was used for statistics. RESULTS: We identified 17 patients (1.67%) with hemorrhagic cystitis and 2 patients (0.19%) with bladder cancer in 4224 patient-years. The median time for diagnosis to hemorrhagic cystitis was 10 months (4-48) and bladder cancer was 8 years (6-10.9). There were 583 patients (57.2%) who received mesna with intravenous CYC therapy. We observed similar incidence rate for hemorrhagic cystitis in both patient groups concomitantly treated with or without mesna [9/583 (1.5%) vs 8/425 (1.8%) respectively, p = 0.08]. Cumulative CYC dose (HR for 10-g increments 1.24, p < 0.001) was associated with hemorrhagic cystitis. CONCLUSION: Cumulative dose was the only risk factor for hemorrhagic cystitis in patients treated with CYC. No proof was obtained for the uroprotective effect of mesna in our cohort.

Behçet disease with vascular involvement: effects of different therapeutic regimens on the incidence of new relapses.

Vascular involvement is one of the major causes of mortality and morbidity in Behçet disease (BD). There are no controlled studies for the management of vascular BD (VBD), and according to the EULAR recommendations, only immunosuppressive (IS) agents are recommended. In this study, we aimed to investigate the therapeutic approaches chosen by Turkish physicians during the initial event and relapses of VBD and the association of different treatment options with the relapses retrospectively.Patients with BD (n = 936, female/male: 347/589, mean age: 37.6 ±â€Š10.8) classified according to ISG criteria from 15 rheumatology centers in Turkey were included. The demographic data, clinical characteristics of the first vascular event and relapses, treatment protocols, and data about complications were acquired.VBD was observed in 27.7% (n = 260) of the patients during follow-up. In 57.3% of the VBD patients, vascular involvement was the presenting sign of the disease. After the first vascular event, ISs were given to 88.8% and AC treatment to 59.8% of the patients. Median duration of AC treatment was 13 months (1-204) and ISs, 22 months (1-204). Minor hemorrhage related to AC treatment was observed in 7 (4.7%) patients. A second vascular event developed in 32.9% (n = 86) of the patients. The vascular relapse rate was similar between patients taking only ISs and AC plus IS treatments after the first vascular event (29.1% vs 22.4%, P = 0.28) and was significantly higher in group taking only ACs than taking only ISs (91.6% vs 29.1%, P < 0.001). During follow-up, a third vascular event developed in 17 (n = 6.5%) patients. The relapse rate was also similar between the patients taking only ISs and AC plus IS treatments after second vascular event (25.3% vs 20.8%, P = 0.93). When multivariate analysis was performed, development of vascular relapse negatively correlated with only IS treatments.We did not find any additional positive effect of AC treatment used in combination with ISs in the course of vascular involvement in patients with BD. Severe complications related to AC treatment were also not detected. Our results suggest that short duration of IS treatments and compliance issues of treatment are the major problems in VBD associated with vascular relapses during follow-up.

Behçet's disease: immunological relevance with arthritis of ankylosing spondylitis.

Behçet's disease (BD) is a multi-system inflammatory disorder, in which cytokine balance is polarized to Th1. In this study, the cell surface molecule expression, Th1/Th2, inflammatory cytokine levels in blood, and synovial fluid of CD3(+) T lymphocytes in BD were investigated. The study group consisted of 10 BD, 10 ankylosing spondylitis (AS) patients with peripheral arthritis, and 10 healthy subjects. Expression of cell surface molecules, intracellular IL-2, IL-5, IL-8, IL-10, IL-12, IFN-γ, and TNF-α levels in CD3(+) T lymphocytes were determined by flow cytometry in synovial and peripheral blood mononuclear cells (PBMCs). Synovial and plasma cytokine levels were measured by ELISA and CBA. In PBMCs, CD4, CD25, HLA-DR expression and intracellular IL-12, and TNF-α levels of CD3(+) T lymphocytes were statistically increased in BD patients compared to healthy subjects. Compare to AS patients, CD25 and HLA-DR surface expression and intracellular IFN-γ and TNF-α levels in T cells were significantly elevated in BD patients. In BD patients, there was an increase in IL-8 secretion; however, in AS patients, both Th1- and Th2-type cytokines were increased compare to healthy subjects. Intracellular cytokine expression did not show any difference in BD patients; however, IL-12 content of synovial fluid was significantly increased compared to AS patients. Our findings revealed that Th1 polarization occurred in both peripheral blood and synovial fluid of BD patients with arthritis. It is found no difference between synovial fluid analysis of BD and AS patients, showing the similarities in the pathogenesis of both diseases.

Extrapulmonary tuberculosis in immunocompetent adults.

Tuberculosis continues to be a significant cause of morbidity and mortality. Although tuberculosis usually attacks the lungs, other organs can also be affected, leading to extrapulmonary tuberculosis (EPT) or disseminated tuberculosis. This study retrospectively analysed the incidence, clinical sites and risk factors for EPT in 252 patients with EPT between 1 January 1991 and 30 June 2003. EPT was defined as clinical, laboratory, imaging, and/or histopathological evidence of mycobacterial infection in a site other than hilar lymph nodes or lung parenchyma. In our study group, tuberculous lymphadenitis (36.5%) was found to be the most common clinical presentation of EPT. 119 (47.2%) patients developed the severe form of EPT, according to the WHO report, and 133 (52.8%) patients developed the less severe form. A case history of pulmonary tuberculosis was found to be a risk factor for the development of EPT (p <0.05). The study showed that EPT is still a public health problem. These findings suggested that pulmonary tuberculosis may play a critical role in the development of EPT. 12-month therapy may be chosen in patients with EPT considering acceptable adverse effects without relapses.