Factors Associated with the Development of Anti-drug Antibodies to TNFi and the Consequences for Axial Spondyloarthritis: A Two-year Follow-up Study.

Objective: To evaluate the development of anti-drug antibodies (ADAb) against tumor necrosis factor inhibitors (TNFi) therapy during a 2-year period and search the factors linked to patients with axial spondyloarthritis (axSpA). Methods: Biologic-naive patients with axSpA were included in this observational study. Serum drug levels and ADAb were measured at weeks 12, 24, 52, and 104 of treatment by enzyme-linked immunosorbent assay (ELISA). The development of ADAb and factors related to ADAb over time were investigated using generalized estimating equations (GEE). Results: A total of 180 patients with axSpA (116 male, mean (±SD) 45.6 (±11.9) years) who started TNFi treatment (etanercept (32.2%), adalimumab (27.2%), golimumab (20.6%), infliximab (20%)) were included. In the etanercept treatment group, only 1 patient had ADAb at 12 weeks and 24 weeks. Anti-drug antibodies against TNFi drugs were present in the adalimumab group in 32.7% of patients and in the infliximab group in 21.2% of patients at 12 weeks, and the proportion of ADAb-positive patients were found to be stable throughout the follow-up for adalimumab- and infliximab-treated patients. In the golimumab group, one patient had ADAb against golimumab at 12 weeks and the proportion of ADAb-positive patients increased throughout follow-up. In longitudinal analysis, baseline age, TNFi type, longitudinal Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and ASDAS-CRP scores, serum C-eeactive protein (CRP) levels, presence of adverse events and treatment discontinuation were associated with the presence of ADAb. Conclusion: The development of ADAb against TNFi therapy is associated with younger age, high disease activity, the development of adverse events and more common treatment discontinuation in patients with axSpA during 2-year follow-up.

Frequency and the effects of spondyloarthritis-spectrum disorders on the clinical course and management of Takayasu arteritis: an observational retrospective study.

OBJECTIVES: Extravascular findings of Takayasu arteritis (TAK) often share features with the spondyloarthritis (SpA) spectrum of disorders. However, the characteristics of this overlap and its effect on the vascular manifestations of TAK are not fully known. Therefore, we aimed to investigate the frequency of SpA-related features in TAK patients. MATERIAL AND METHODS: In this observational retrospective study, 350 patients with TAK classified according to ACR 1990 criteria, from 12 tertiary rheumatology clinics, were included and evaluated for the presence of axSpA, IBD, or psoriasis. Demographic, clinical features, angiographic involvement patterns, disease activity, and treatments of TAK patients with or without SpA were analyzed. RESULTS: Mean age was 45.5 ± 13.6 years and mean follow-up period was 76.1 ± 65.9 months. Among 350 patients, 31 (8.8%) had at least one additional disease from the SpA spectrum, 8 had IBD, 8 had psoriasis, and 20 had features of axSpA. In the TAK-SpA group, TAK had significantly earlier disease onset, compared to TAK-without-SpA (p = 0.041). SpA-related symptoms generally preceded TAK symptoms. Biological treatments, mostly for active vasculitis, were higher in the TAK-SpA group (70.9%) compared to TAK-without-SpA (27.9%) (p < 0.001). Vascular involvements were similar in both. CONCLUSION: Our study confirmed that diseases in the SpA spectrum are not rare in TAK. Vascular symptoms appeared earlier in such patients, and more aggressive therapy with biological agents was required in the TAK-SpA group, suggesting an association between TAK and SpA spectrum. Key Points • The pathogenesis of Takayasu arteritis is mediated by an MHC class I alelle (HLA-B*52), similar to spondyloarthritis-disorders. • Extravascular findings of Takayasu arteritis are in the spectrum of spondyloarthritis disease. • This frequent coexistence between Takayasu arteritis and spondyloarthritic disorders suggests a relationship rather than a coincidence.

Comparison of methotrexate and azathioprine as the first-line steroid-sparing immunosuppressive agents in patients with Takayasu's arteritis.

BACKGROUND: Immunosuppressive (IS) agents are recommended for the first-line treatment of patients with active Takayasu's arteritis (TAK) together with glucocorticoids (GCs). However, there is limited data comparing the efficacy and outcomes of different IS agents for this purpose. OBJECTIVES: In this study, we aimed to compare the outcomes of two most frequently used first-line IS agents, namely methotrexate (MTX) and azathioprine (AZA) in TAK patients. METHODS: TAK patients who received any IS agent in addition to GCs as the initial therapy were included in this multicentre, retrospective cohort study. Clinical, laboratory and imaging data of the patients were assessed. In addition, a matched analysis (cc match) using variables 'age', 'gender' and 'diffuse aortic involvement' was performed between patients who received MTX or AZA as the first-line IS treatment. RESULTS: We recruited 301 patients (F/M: 260/41, mean age: 42.2 ± 13.3 years) from 10 tertiary centres. As the first-line IS agent, 204 (67.8 %) patients received MTX, and 77 (25.6 %) received AZA. Less frequently used IS agents included cyclophosphamide in 17 (5.6 %), leflunomide in 2 (0.5 %) and mycophenolate mofetil in one patient. The remission, relapse, radiographic progression and adverse effect rates were similar between patients who received MTX and AZA as the first-line IS agent. Vascular surgery rate was significantly higher in the AZA group (23% vs. 9 %, p = 0.001), whereas the frequency of patients receiving ≤5 mg/day GCs at the end of the follow-up was significantly higher in the MTX group (76% vs 62 %, p = 0.034). Similarly, the rate of vascular surgery was higher in AZA group in matched analysis. Drug survival was similar between MTX and AZA groups (median 48 months, MTX vs AZA: 32% vs 42 %, p = 0.34). IS therapy was discontinued in 18 (12 MTX, 6 AZA) patients during the follow-up period due to remission. Among those patients, two patients had a relapse at 2 and 6 months, while 16 patients were still on remission at the end of a mean 69.4 (±50.9) months of follow-up. CONCLUSIONS: Remission, relapse, radiographic progression and drug survival rates of AZA and MTX were similar for patients with TAK receiving an IS agent as the first-line f therapy. The rate of vascular surgery was higher and the rate of GC dose reduction was lower with AZA compared to MTX at the end of the follow-up.

Ocular manifestations of granulomatosis with polyangiitis: report from a tertiary eye care center.

PURPOSE: To report demographic characteristics and ophthalmological manifestations of patients with granulomatosis with polyangiitis (GPA) in a tertiary eye care center in Turkey. METHODS: Medical records of patients with GPA-related ocular manifestations evaluated between 2013 and 2023 were included. Demographic and clinical characteristics of the patients including nature of systemic involvement, ophthalmologic symptoms and signs, laboratory investigations and treatment modality were reviewed. RESULTS: Twelve eyes of 10 patients (5 female/5 male) were included. The mean age was 57.2 ± 12.2 (35-71) years. Five (50%) patients were already diagnosed with GPA. Ocular involvement was the first manifestation of GPA in 3 patients. The remaining 2 patients had simultaneous systemic and ocular symptoms at presentation. Conjunctival hyperemia (9 eyes) and pain (7 eyes) were the most frequent presenting symptoms followed by blurred vision (3 eyes). The frequencies of ocular manifestations were as follows:episcleritis (3 eyes), isolated peripheral ulcerative keratitis (PUK) (3 eyes), scleritis (3 eyes), simultaneous PUK and scleritis (2 eyes) and periorbital mass (1 eye). CONCLUSION: Ophthalmological manifestations can be the initial findings in GPA. Since GPA can affect different structures of the eye, it sometimes might be challenging for ophthalmologists. Therefore, it is crucial for ophthalmologists to be well-informed about GPA-related ocular findings and to have a high index of suspicion for GPA. Although PUK associated with scleritis is highly suggestive for GPA, isolated cases of PUK or scleritis can be seen in GPA. Therefore, it is important to adopt a multidisciplinary approach, consider GPA in differential diagnosis, and benefit from accurate diagnostic tests.

Low relapse rate in patients with giant cell arteritis in a multi-centre retrospective Turkish Registry.

OBJECTIVES: Glucocorticoids (GC) are widely accepted as the standard first-line treatment for giant cell arteritis (GCA). However, relapse rates are reported up to 80% on GC-only protocol arms in controlled trials of tocilizumab and abatacept in 12-24 months. Herein, we aimed to assess the real-life relapse rates retrospectively in patients with GCA from Turkey. METHODS: We assembled a retrospective cohort of patients with GCA diagnosed according to ACR 1990 criteria from tertiary rheumatology centres in Turkey. All clinical data were abstracted from medical records. Relapse was defined as any new manifestation or increased acutephase response leading to the change of the GC dose or use of a new therapeutic agent by the treating physician. RESULTS: The study included 330 (F/M: 196/134) patients with GCA. The mean age at disease onset was 68.9±9 years. The most frequent symptom was headache. Polymyalgia rheumatica was also present in 81 (24.5%) patients. Elevation of acute phase reactants (ESR>50 mm/h or CRP>5 mg/l) was absent in 25 (7.6%) patients at diagnosis. Temporal artery biopsy was available in 241 (73%) patients, and 180 of them had positive histopathological findings for GCA. For remission induction, GC pulses (250-1000 methylprednisolone mg/3-7 days) were given to 69 (20.9%) patients, with further 0.5-1 mg/kg/day prednisolone continued in the whole group. Immunosuppressives as GC-sparing agents were used in 252 (76.4%) patients. During a follow-up of a median 26.5 (6-190) months, relapses occurred in 49 (18.8%) patients. No confounding factor was observed in relapse rates. GC treatment could be stopped in only 62 (23.8%) patients. Additionally, GC-related side effects developed in 64 (24.6%) patients, and 141 (66.2%) had at least one Vasculitis Damage Index (VDI) damage item present during follow-up. CONCLUSIONS: In this first multi-centre series of GCA from Turkey, we observed that only one-fifth of patients had relapses during a mean follow-up of 26 months, with 76.4% given a GC-sparing IS agent at diagnosis. At the end of follow-up, GC-related side effects developed in one-fourth of patients. Our results suggest that patients with GCA had a low relapse rate in real-life experience of a multi-centre retrospective Turkish registry, however with a significant presence of GC-associated side effects during follow-up.

Does decision tree analysis predict oral ulcer activity-related factors in patients with Behçet's syndrome?

OBJECTIVES: The study aimed to identify the interactions among treatment protocols and oral ulcer activity related factors in patients with Behçet's syndrome (BS) using the Classification and Regression Tree (CART) algorithm. METHODS: In this cross-sectional study, 979 patients with BS were included from16 centres in Turkey, Jordan, Brazil and the United Kingdom. In the CART algorithm, activities of oral ulcer (active vs. inactive), genital ulcer (active vs. inactive), cutaneous involvement (active vs. inactive), musculoskeletal involvement (active vs. inactive), gender (male vs. female), disease severity (mucocutaneous and musculoskeletal involvement vs. major organ involvement), smoking habits (current smoker vs. non-smoker), tooth brushing habits (irregular vs. regular), were input variables. The treatment protocols regarding immunosuppressive (IS) or non-IS medications were the target variable used to split from parent nodes to purer child nodes in the study. RESULTS: In mucocutaneous and musculoskeletal involvement (n=538), the ratio of IS use was higher in patients with irregular toothbrushing (ITB) habits (27.1%) than in patients with regular toothbrushing (RTB) habits (14.2%) in oral ulcer activity. In major organ involvement (n=441), male patients with ITB habits were more likely treated with IS medications compared to those with RTB habits (91.6% vs. 77.6%, respectively). CONCLUSIONS: Male BS patients on IS who have major organ involvement and oral ulcer activity with mucocutaneous and musculoskeletal involvement have irregular toothbrushing habits. Improved oral hygiene practices should be considered to be an integral part for implementing patient empowerment strategies for BS.

Matrix Metalloproteinase-2 and -3 Levels in Patients with Behçet's Disease and Implication for the Presence of Vascular Aneurysm or Neurologic Involvement.

BACKGROUND: Behçet's disease is a systemic vasculitis affecting both arteries and veins, as well as caus- ing recurrent inflammatory multiorgan disease. Vascular involvement is associated with increased mortality and morbidity. Matrix metalloproteinases are released at sites of inflammation and degrade various components of the extracellular matrix. Increased levels of metalloproteinase-9 and metal- loproteinase-2 have been previously reported in Behçet's disease. METHODS: In this cross-sectional study, metalloproteinase-2 and metalloproteinase-3 serum levels were investigated in 103 patients with Behçet's disease and 69 healthy controls, using Invitrogen immunoassay human metalloproteinase-2 and metalloproteinase-3 ELISA kits. RESULTS: Serum metalloproteinase-2 and metalloproteinase-3 levels were significantly higher in the Behçet's disease group compared to healthy controls. Besides, serum metalloproteinase-3 levels were significantly higher in subgroups of Behçet's disease with aneurysmal vascular involvement and with neurological involvement. However, metalloproteinase-2 and metalloproteinase-3 serum levels did not show a positive correlation with disease activity. CONCLUSION: Metalloproteinase-2 and -3 may contribute to the complex pathogenesis of Behçet's dis- ease. More importantly, the detection of very high serum levels of metalloproteinase-3 may predict the formation of an aneurysm, or possibly the presence of neurological involvement in Behçet's dis- ease and may lead the clinician to make an earlier diagnosis of these complications in young male patients with high risk.

Quality of life, disease activity and preferences for administration routes in rheumatoid arthritis: a multicentre, prospective, observational study.

Objective: We aimed to evaluate quality of life (QoL), disease activity, compliance to treatment, patient and physician preferences for route of administration (RoA), status of health and pain in RA patients starting advanced treatments or needing a switch, and the factors associated with patient preferences. Methods: A multicentre, prospective, observational and 1-year follow-up study was conducted, between 2015 and 2020, in adult RA patients using advanced treatments for the first time or needing a switch in their current treatments. All the data collected were entered into electronic case report forms. DAS in 28 joints with ESR [DAS28-4(ESR)], EuroQol 5-Dimensional Questionnaire (EQ-5D), HAQ Disability Index (HAQ-DI), Compliance Questionnaire for Rheumatology (CQR-19), Work Productivity and Activity Impairment Instrument (WPAI) and Patient Global Assessment-Visual Analogue Scale (PGA-VAS) questionnaires were used for longitudinal assessments. Results: Four hundred and fifty-nine patients were enrolled. Three hundred and eight patients (67.1%) attended the final study visit at 12 months and were included for comparative analyses. Irrespective of RoA, the disease activity and QoL improved significantly at 12 months, whereas compliance worsened. At baseline and 12 months, EQ-5D and DAS28-4(ESR) scores were significantly correlated (P < 0.001). The WPAI scores changed significantly in favour of better outcomes over 12 months after initiation of advanced treatment or switching (P < 0.001). A higher proportion of patients preferred an oral RoA, in comparison to physicians (53.6% vs 31.4%; P < 0.001). Patient and physician RoA preferences were independent of gender, age, disease duration, advanced treatment type and the EQ-5D-3L, DAS28-4(ESR), HAQ-DI, PGA-VAS and CQR-19 scores at baseline. Conclusion: The oral route was more frequently preferred by patients compared with physicians, although patients' preference rates showed a slight increase towards the end of the treatment, which might be an important factor for RA outcomes. Better control of disease activity and QoL were achieved at 12 months, regardless of RoA.

Sex-specific analysis in Behçet's disease reveals higher genetic risk in male patients.

OBJECTIVES: Behçet's disease tends to be more severe in men than women. This study was undertaken to investigate sex-specific genetic effects in Behçet's disease. METHODS: A total of 1762 male and 1216 female patients with Behçet's disease from six diverse populations were studied, with the majority of patients of Turkish origin. Genotyping was performed using an Infinium ImmunoArray-24 BeadChip, or extracted from available genotyping data. Following imputation and extensive quality control measures, genome-wide association analysis was performed comparing male to female patients in the Turkish cohort, followed by a meta-analysis of significant results in all six populations. In addition, a weighted genetic risk score for Behçet's disease was calculated and compared between male and female patients. RESULTS: Genetic association analysis comparing male to female patients with Behçet's disease from Turkey revealed an association with male sex in HLA-B/MICA within the HLA region with a GWAS level of significance (rs2848712, OR = 1.46, P = 1.22 × 10-8). Meta-analysis of the effect in rs2848712 across six populations confirmed these results. Genetic risk score for Behçet's disease was significantly higher in male compared to female patients from Turkey. Higher genetic risk for Behçet's disease was observed in male patients in HLA-B/MICA (rs116799036, OR = 1.45, P = 1.95 × 10-8), HLA-C (rs12525170, OR = 1.46, P = 5.66 × 10-7), and KLRC4 (rs2617170, OR = 1.20, P = 0.019). In contrast, IFNGR1 (rs4896243, OR = 0.86, P = 0.011) was shown to confer higher genetic risk in female patients. CONCLUSIONS: Male patients with Behçet's disease are characterized by higher genetic risk compared to female patients. This genetic difference, primarily derived from our Turkish cohort, is largely explained by risk within the HLA region. These data suggest that genetic factors might contribute to differences in disease presentation between men and women with Behçet's disease.

Recent advances in the diagnosis and therapy of large vessel vasculitis.

Large vessel vasculitis (LVV), including Takayasu arteritis (TAK) and giant cell arteritis (GCA), causes granulomatous vascular inflammation mainly in large vessels, and is the most common primary vasculitis in adults. Vascular inflammation may evoke many clinical features including vision impairment, stroke, limb ischemia, and aortic aneurysms. The best way to diagnose LVV is to combine medical history, physical examination, various laboratory tests, and imaging modalities. Progress in imaging modalities facilitated early diagnosis and follow­up of the disease activity. Conventional angiography is no longer the gold standard for the diagnosis of TAK. Similarly, temporal artery biopsy is no longer the only tool for diagnosing cranial GCA. In selected cases, color Doppler ultrasound may be used for this purpose. Despite some similarities, TAK and GCA differ in many aspects and they are different diseases. They also have different clinical subtypes. The presence of aortitis does not always implicate the diagnosis of TAK or GCA; infectious aortitis, as well as noninfectious aortitis associated with other autoimmune rheumatic diseases should be excluded. Treatment of LVV includes glucocorticoids (GCs), conventional immunosuppressive agents, and biological drugs. Tumor necrosis factor inhibitors are ineffective in GCA but effective in TAK. On the other hand, tocilizumab may be used to treat both diseases. Promising targeted therapies evaluated in ongoing clinical trials include, for example, anti­IL­12/23 (ustekinumab), anti­IL­17 (secukinumab), anti­IL­1 (anakinra), anti­IL­23 (guselkumab), anti­cytotoxic T­lymphocyte antigen 4 (abatacept), Janus kinase inhibitors (tofacitinib and upadacitinib), anti­granulocyte / macrophage colony­stimulating factor (mavrilimumab), and endothelin receptor (bosentan) therapies.

Metabolic syndrome is associated with increased cardiovascular risk and disease damage in patients with Takayasu arteritis.

OBJECTIVE: Metabolic syndrome (MetS) is one of the preventable risk factors for cardiovascular disease (CVD). The aim of this study was to investigate the effect of MetS on CVD and cumulative organ damage in a multi-center, large cohort of patients with Takayasu arteritis (TAK). METHODS: This is a cross-sectional study involving 192 consecutive TAK patients from seven tertiary rheumatology centers in Turkey. Clinical data of TAK patients fulfilling the 1990 American College of Rheumatology classification criteria were collected from medical records. They were evaluated for risk factors of CVD, disease activity, damage, and MetS at their last visits. RESULTS: A total of 192 consecutive TAK patients were included in this study. One hundred and fifty-eight (82%) were female, the mean age was 43.3 ± 13 years, and mean disease duration was 13.5 ± 9.3 years. MetS was detected in 50 (26%) of the patients and CVD was detected in 28 (14.6%). The presence of MetS was detected as an independent risk factor for CVD (P < 0.001). In addition, the mean vasculitis damage index of the group with MetS was significantly higher than in the other patients (4.5 ± 3.3 vs 3.2 ± 2.2, respectively, P = 0.004). CONCLUSION: The presence of MetS in TAK is associated with increased CVD and disease damage. Awareness and management of MetS can improve disease prognosis in patients with TAK.

Pregnancy in Takayasu's arteritis has a high risk of hypertension-related fetomaternal complications: A retrospective study of a Turkish cohort.

BACKGROUND: This study aimed to examine fetomaternal outcomes in pregnant women in a large Turkish Takayasu arteritis (TAK) cohort and to evaluate the effects of pregnancy on the disease in those patients. METHODS: This is a cohort study involving 296 pregnancies of 112 TAK patients from 8 tertiary rheumatology centers in Turkey. Pregnancies were divided into 2 groups as pre-d (before disease onset) and post-d (after disease onset). In addition, post-d pregnancies were further divided into 2 subgroups according to fetomaternal complications (FMC) development status. Finally, patients were grouped into those with and without a history of pregnancy after disease onset. RESULTS: In post-d pregnancies, rates of worsening hypertension, new-onset hypertension, and preeclampsia were higher than in pre-d pregnancies (0.9% vs 16%, P < .001, 0.5% vs 5.3%, P = .012, and 0% vs 4%, P = .013, respectively). Patients with FMC were more likely to have renal artery involvement (65% vs 21%, P = .003). The patients who had post-d were younger, had longer disease duration, and had more relapses number than other patients (P < .001, P = .028, P = .016, respectively). Vasculitis Damage Index (VDI) results were similar in patients with or without post-d pregnancies. CONCLUSION: Pregnancies after disease onset were found to be associated with HT and preeclampsia/eclampsia. HT-related FMCs are increased in TAK, and patients with renal artery involvement are at higher risk. The number of relapses increases in patients who become pregnant after disease onset, but pregnancy was not an independent risk factor for relapse. Pregnancy after the onset of disease had no negative effect on VDI.

Budd-Chiari syndrome in Behçet's disease: a retrospective multicenter study.

OBJECTIVE: To compare the clinical features, laboratory findings, and prognosis of Behçet's disease (BD) patients with and without Budd-Chiari syndrome (BCS). METHODS: This multicenter retrospective study investigated 61 (M/F: 41/20) patients with BD, having coexistent BCS, and 169 (M/F:100/69) BD patients as the control group without BCS from 22 different centers of Turkey diagnosed between 1990 and 2017. RESULTS: Of the total 61 BD patients with BCS, the onset of the first symptom and the median age of diagnosis were earlier in contrast to BD patients without BCS (p = 0.005 and p = 0.007). Lower extremity deep vein and inferior vena cava (IVC) thrombosis were more common in patients with BCS (all; p < 0.01) compared to the control group. Mortality was significantly higher in BD-BCS patients with IVC thrombosis than in the controls (p = 0.004). Since most of the cases in our cohort had chronic and silent form of BCS, mortality rate was 14.8%, which was on the lower range of mortality rate reported in literature (14-47%). While all BD-BCS patients received immunosuppressive (IS) agents, only half of them received additional anticoagulant treatments. Among IS agents, interferon treatment was more frequently used in this cohort (19%), compared to other series reported in literature (2.3%). CONCLUSION: To our knowledge, this is the largest series of BD patients with BCS. Our patients had earlier disease onset and diagnosis, higher frequency of IVC thrombosis, and higher mortality rate, compared to BD patients without BCS. Mortality was significantly higher in BD-BCS patients with IVC thrombosis compared to controls. Key Points • Mortality rate is higher in BD-associated BCS patients with IVC involvement. • Chronic and silent form of BD-associated BCS has a better prognosis. • The main treatment options are corticosteroids and immunosuppressive agents, whereas anticoagulant treatment remains controversial.

Pathogenesis and treatment of cytokine storm in COVID-19.

COVID-19 is a viral infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that killed a large number of patients around the world. A hyperinflammatory state resulting in a cytokine storm and adult respiratory distress syndrome seems to be the major cause of the death. Many mechanisms have been suggested in the pathogenesis of COVID-19 associated cytokine storm (COVID-CS). Insufficient viral clearance and persistence of a strong cytokine response despite inadequate antiviral immunity seem to be the main mechanisms underlying the pathogenesis. The diagnosis of COVID-19 is based on relatively constant clinical symptoms, clinical findings, laboratory tests, and imaging techniques, while the diagnosis of COVID-CS is a rather dynamic process, based on evolving or newly emerging findings during the clinical course. Management of COVID-19 consists of using antiviral agents to inhibit SARS-CoV-2 replication and treating potential complications including the cytokine storm together with general supportive measures. COVID-CS may be treated using appropriate immunosuppressive and immunomodulatory drugs that reduce the level of inappropriate systemic inflammation, which has the potential to cause organ damage. Currently corticosteroids, IL-6 blockers, or IL-1 blockers are most widely used for treating COVID-CS.

Biologic treatments in Takayasu's Arteritis: A comparative study of tumor necrosis factor inhibitors and tocilizumab.

OBJECTIVE: To compare the treatment outcomes of TNF inhibitors and tocilizumab (TCZ) in patients with Takayasu arteritis. METHODS: Takayasu arteritis patients who were refractory to conventional immunosuppressive (IS) drugs and received biologic treatment were included in this multicenter retrospective cohort study. Clinical, laboratory and imaging data during follow-up were recorded. Remission, glucocorticoid (GC) sparing effect, drug survival was compared between TNF inhibitor and TCZ treatments. Also, a subgroup matched comparison was performed between groups. RESULTS: One hundred and eleven (F/M: 98/13) patients were enrolled. A total of 173 biologic treatment courses (77 infliximab, 49 TCZ, 33 adalimumab, 9 certolizumab, 3 rituximab, 1 ustekinumab and 1 anakinra) were given. Tocilizumab was chosen in 23 patients and TNF inhibitors were chosen in 88 patients as first-line biologic agent. Complete/partial remission rates between TCZ and TNF inhibitors were similar at 3rd month and at the end of the follow-up. GC dose decrease (≤4 mg) or discontinuation of GCs was achieved in a similar rate in both groups (TNF inhibitors vs TCZ: 78% vs 59%, p = 0.125). Drug survival rate was 56% in TNF inhibitors and 57% in TCZ group (p = 0.22). The use of concomitant conventional ISs did not affect the drug survival (HR =0.78, 95% CI =0.42-1.43, p = 0.42). The match analysis showed similar results between groups in terms of relapse, decrease in GC dose, surgery need and mortality. CONCLUSION: The efficacy and safety outcomes and drug survival rates seem to be similar for TNF inhibitors and tocilizumab in patients with Takayasu arteritis.

A practical approach for vaccinations including COVID-19 in autoimmune/autoinflammatory rheumatic diseases: a non-systematic review.

The COVID-19 pandemic has occupied the world agenda since December 2019. With no effective treatment yet, vaccination seems to be the most effective method of prevention. Recently developed vaccines have been approved for emergency use only and are currently applied to large populations. Considering both the underlying pathogenic mechanisms of autoimmune/autoinflammatory rheumatological diseases (AIIRDs) and the immunosuppressive drugs used in treatment, vaccination for COVID-19 deserves special attention in such patients. In this article, we aimed to give simple messages to the clinicians for COVID-19 vaccination in patients with AIIRDs based upon the current evidence regarding the use of other vaccines in this patient group. For this purpose, we conducted a "Pubmed search" using the following keywords: Influenza, Hepatitis B, Pneumococcal, and Shingles vaccines and the frequently used conventional and biologic disease-modifying antirheumatic drugs (DMARDs). Likewise, an additional search was performed for the COVID-19 immunization in patients with AIIRDs and considering such drugs. In summary, patients with AIIRDs should also be vaccinated against COVID-19, preferably when disease activity is under control and when there is no concurrent infection. Low-degree immunosuppression does not appear to decrease antibody responses to vaccines. Ideally, vaccinations should be done before the initiation of any biological DMARDs. Patients receiving rituximab should be vaccinated at least 4 weeks before or 6 months after treatment. Since tofacitinib may also reduce antibody responses, especially in combination with methotrexate, it may be appropriate to discontinue this drug before vaccination and to restart after 14 days of immunization. Key points • COVID-19 vaccinations should preferably be made during remission in patients with autoimmune/autoinflammatory rheumatological diseases. • Low-degree immunosuppression may not interfere with antibody response to vaccines. • Ideally, vaccinations should be made before the initiation of any biological DMARDs. • Timing of vaccination is especially important in the case of rituximab.

Genetic Association of a Gain-of-Function IFNGR1 Polymorphism and the Intergenic Region LNCAROD/DKK1 With Behçet's Disease.

OBJECTIVE: Behçet's disease is a complex systemic inflammatory vasculitis of incompletely understood etiology. This study was undertaken to investigate genetic associations with Behçet's disease in a diverse multiethnic population. METHODS: A total of 9,444 patients and controls from 7 different populations were included in this study. Genotyping was performed using an Infinium ImmunoArray-24 v.1.0 or v.2.0 BeadChip. Analysis of expression data from stimulated monocytes, and epigenetic and chromatin interaction analyses were performed. RESULTS: We identified 2 novel genetic susceptibility loci for Behçet's disease, including a risk locus in IFNGR1 (rs4896243) (odds ratio [OR] 1.25; P = 2.42 × 10-9 ) and within the intergenic region LNCAROD/DKK1 (rs1660760) (OR 0.78; P = 2.75 × 10-8 ). The risk variants in IFNGR1 significantly increased IFNGR1 messenger RNA expression in lipopolysaccharide-stimulated monocytes. In addition, our results replicated the association (P < 5 × 10-8 ) of 6 previously identified susceptibility loci in Behçet's disease: IL10, IL23R, IL12A-AS1, CCR3, ADO, and LACC1, reinforcing the notion that these loci are strong genetic factors in Behçet's disease shared across ancestries. We also identified >30 genetic susceptibility loci with a suggestive level of association (P < 5 × 10-5 ), which will require replication. Finally, functional annotation of genetic susceptibility loci in Behçet's disease revealed their possible regulatory roles and suggested potential causal genes and molecular mechanisms that could be further investigated. CONCLUSION: We performed the largest genetic association study in Behçet's disease to date. Our findings reveal novel putative functional variants associated with the disease and replicate and extend the genetic associations in other loci across multiple ancestries.

Interleukin-1 Inhibitors and Vaccination Including COVID-19 in Inflammatory Rheumatic Diseases: A Nonsystematic Review.

Newly emerging variants of coronavirus 2 (SARS-CoV-2) raise concerns about the spread of the disease, and with the rising case numbers, the Coronavirus disease 2019 (COVID-19) remains a challenging medical emergency towards the end of the year 2021. Swiftly developed novel vaccines aid in the prevention of the spread, and it seems that a specific cure will not be at hand soon. The prognosis of COVID-19 in patients with autoimmune/autoinflammatory rheumatic diseases (AIIRD) is more severe when compared to the otherwise healthy population, and vaccination is essential. Evidence for both the efficacy and safety of COVID-19 vaccination in AIIRD under immunosuppression is accumulating, but the effect of Interleukin-1 on vaccination in general and in AIIRD patients is rarely addressed in the current literature. In light of the current literature, it seems that the level of agreement on the timing of COVID-19 vaccination is moderate in patients using IL-1 blockers, and expert opinions may vary. Generally, it may be recommended that patients under IL-1 blockade can be vaccinated without interrupting the anti-cytokine therapy, especially in patients with ongoing high disease activity to avoid disease relapses. However, in selected cases, after balancing for disease activity and risk of relapses, vaccination may be given seven days after the drug levels have returned to baseline, especially for IL-1 blocking agents with long half-lives such as canakinumab and rilonacept. This may help to ensure an ideal vaccine response in the face of the possibility that AIIRD patients may develop a more pronounced and severe COVID-19 disease course.

Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study.

Takayasu arteritis is a rare inflammatory disease of large arteries. We performed a genetic study in Takayasu arteritis comprising 6,670 individuals (1,226 affected individuals) from five different populations. We discovered HLA risk factors and four non-HLA susceptibility loci in VPS8, SVEP1, CFL2, and chr13q21 and reinforced IL12B, PTK2B, and chr21q22 as robust susceptibility loci shared across ancestries. Functional analysis proposed plausible underlying disease mechanisms and pinpointed ETS2 as a potential causal gene for chr21q22 association. We also identified >60 candidate loci with suggestive association (p < 5 × 10-5) and devised a genetic risk score for Takayasu arteritis. Takayasu arteritis was compared to hundreds of other traits, revealing the closest genetic relatedness to inflammatory bowel disease. Epigenetic patterns within risk loci suggest roles for monocytes and B cells in Takayasu arteritis. This work enhances understanding of the genetic basis and pathophysiology of Takayasu arteritis and provides clues for potential new therapeutic targets.