Outcomes of COVID-19 re-infections: a single-center cohort of 167 patients with systemic rheumatic diseases.

Data on COVID-19 re-infections in patients with systemic rheumatic diseases (SRDs) are lacking. We aimed to describe the course and outcomes of COVID-19 re-infections in these patients versus controls. In this single-center retrospective study, we included 167 consecutive SRD patients with at least one COVID-19 re-infection (mean age 47.3 years, females 70.7%). SRD patients were compared in terms of patient-perceived COVID-19 re-infection severity and hospitalizations/deaths with 167 age/sex-matched non-SRD controls. Logistic regression analysis was performed to assess potential milder re-infection versus primary infection severity, adjusting for study group, demographics (age, sex), vaccination status, body mass index, smoking, and comorbidities. 23 and 7 out of 167 re-infected SRD patients experienced two and three re-infections, respectively, which were comparable to the re-infection rates in controls (two: 32; and three: 2) who also had comparable COVID-19 vaccination history (89% and 95% vaccinated, respectively). In the initial infection, patients with SRDs were hospitalized (7.2% versus 1.8%, p = 0.017), and had received antiviral treatment (16.1% versus 4.7%, p < 0.001) more frequently than controls. However, hospitalizations (1.8% vs 0.6%) and antiviral treatment (7.8% vs 3.5%) did not differ (p > 0.05) between patients and controls at the first re-infection, as well as during the second and third re-infection; no deaths were recorded. Perceived severity of re-infections was also comparable between patients and controls (p = 0.847) and among those on biologic DMARDs or not (p = 0.482). In multivariable analysis, neither SRDs presence nor demographics or comorbidities were associated with COVID-19 re-infection severity. COVID-19 re-infection severity (patient-perceived/hospitalizations/deaths) did not differ between SRDs and controls.

Progression of subclinical atherosclerosis in ankylosing spondylitis: a 10-year prospective study.

Chronic systemic inflammation contributes to increased CVD burden in Ankylosing Spondylitis (AS). Since long-term follow-up data on subclinical atherosclerosis acceleration are lacking, we examined its progression in contemporary AS patients during 10 years. Fifty-three (89% male, aged 50.4 (36.3-55.9) years,) non-diabetic, CVD-free AS patients and 53 age-sex-matched non-diabetic, control individuals were re-evaluated after 9.2-10.2 years by ultrasonography for carotid/femoral atheromatosis, pulse wave velocity (PWV) and intima-media thickness (IMT), performed by the same operator/protocol. New atheromatic plaque formation, PWV deterioration, and IMT increase were associated only with classical CVD risk factors, as reflected by the heartSCORE (age, gender, smoking status, blood pressure and cholesterol levels) by multivariate analysis, rather than disease presence. However, among AS patients, despite remission/low disease activity at follow-up end in 79%, atheromatosis progression was associated by multivariate analysis with higher BASDAI scores (p = 0.028), independently of biologic therapies administered in 2/3 of them. Moreover, in AS patients, but not in controls, PWV values at baseline were associated with plaque progression during the 10-year follow-up after taking into account baseline heartSCORE and plaque burden status (p = 0.033). Despite comparable prevalence of both hypertension and hypercholesterolemia at baseline between patients and controls, a lower percentage of AS patients had achieved "adequate" CVD risk factor control at follow-up end (11% vs 25% respectively, p = 0.076). Classical CVD risk factors and residual disease activity account for the progression of subclinical atherosclerosis in AS, pointing to the unmet needs in the contemporary management of these patients.

IL-6 blockade for Behçet's disease: review on 31 anti-TNF naive and 45 anti-TNF experienced patients.

OBJECTIVES: Despite the remarkable efficacy of anti-TNF agents in Behçet's disease (BD), unmet therapeutic needs for refractory or intolerant patients to these drugs still exist. Based on evidence implicating IL-6 in the pathogenesis of BD, we summarise the current experience on the off-label administration of the anti-IL-6 receptor antibody tocilizumab for BD refractory to disease-modifying anti-rheumatic drugs. METHODS: We searched PubMed and EMBASE for original articles published through December 2021 reporting on the use of tocilizumab for BD. RESULTS: We retrieved 25 articles fulfilling our search criteria, reporting on a total of 74 patients of whom 31 were anti- TNF naive; 2 additional anti-TNF experienced patients were included. The vast majority (72 of 76) received the standard intravenous dose of tocilizumab, whereas the total follow-up, including also post-treatment follow-up in many patients, ranged from 2 to 84 months without new safety issues. Tocilizumab was given in anti-TNF naive patients predominantly for vascular (n=16), central nervous system (n=7) and ocular involvement (n=5). On the other hand, anti-TNF experienced patients received tocilizumab predominantly for ocular (n=28), central nervous system (n=8) and mucocutaneous involvement (n=6). Tocilizumab was effective in 87% of anti-TNF naive (13 and 14 with complete and partial remission, respectively) and in 80% of anti-TNF experienced patients (17 and 19 with complete and partial remission, respectively). CONCLUSIONS: Although preliminary, evidence published so far suggests that IL-6 inhibition is a legitimate therapeutic option for BD patients with refractory ocular, CNS and vascular involvement. Controlled studies are clearly needed.

Osteoprotegerin and MTHFR gene variations in rheumatoid arthritis: association with disease susceptibility and markers of subclinical atherosclerosis.

We aimed to explore whether the rs2073618 variant (G1181C) of the osteoprotegerin (OPG) gene and the methylenetetrahydrofolate reductase (MTHFR) rs1801131 (A1298AC) and rs1801133 (C677T) gene polymorphisms contribute to rheumatoid arthritis (RA) susceptibility and RA related subclinical atherosclerosis. Overall 283 RA patients and 595 healthy controls (HC) were genotyped for common variants of the OPG and MTHFR genes using PCR based assays. Clinical and laboratory parameters were recorded following thorough chart review. Surrogate markers of subclinical atherosclerosis (Carotid/Femoral intima media thickness/plaque formation) along with traditional risk factors for atherosclerosis were assessed in all RA patients and 280HC. Increased prevalence of the CC genotype of the rs2073618 variant was detected in RA patients vs HC (42.4% vs. 33%, p-value: 0.04). RA patients with high serum titers of rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP) antibodies displayed increased prevalence of the CC genotype of the rs2073618 variant of the OPG gene compared to HC (48.6% and 47.5 vs 33.3%, p-values: 0.0029and 0.0077 respectively). Of interest, this genotype turned to be associated with higher carotid IMT scores (0.872 ± 0.264 vs 0.816 ± 0.284, p-value: 0.01) and marginally with higher rates of carotid plaque formation (66% vs 54.1%, p = 0.06). The MTHFR 1298CC genotype was more prevalent only in the anti-CCP positive group compared to HC, with no associations detected with markers of subclinical atherosclerosis, following adjustment for traditional cardiovascular (CVD) risk factors. Reduced rates of carotid/femoral plaque formation were detected among RA patients harboring the MTHFR TT genotype (52.4 vs 72.7, p-value: 0.009, respectively). This association remained significant following adjustment for classical CVD risk factors (OR [95% CI 0.364 [0.173-0.765], p-value: 0.008). Genetic variations of the osteoprotegerin and MTHFR genes seem to increase susceptibility for seropositive RA and potentially contribute to subclinical atherosclerosis linked to RA. Larger studies are needed to confirm these findings.

Anti-interleukin 6 Therapy Effect for Refractory Joint and Skin Involvement in Systemic Sclerosis: A Real-world, Single-center Experience.

OBJECTIVE: To examine the efficacy and safety of interleukin-6 inhibition by tocilizumab (TCZ) in difficult-to-treat, real-world patients with systemic sclerosis (SSc). METHODS: Twenty-one patients (20 women; 16 diffuse cutaneous SSc; mean age: 52 ± 10 yrs; 10 with early disease [< 5 yrs]; and 11 with long-standing disease [mean disease duration 6.4 ± 3.7 yrs]) with active joint and/or skin involvement refractory to corticosteroids (n = 21), methotrexate (n = 19), cyclophosphamide (n = 10), mycophenolate mofetil (n = 7), rituximab (n = 1), leflunomide (n = 2), hydroxychloroquine (n = 2), and hematopoietic stem cell transplantation (n = 2), who received weekly TCZ (162 mg subcutaneously) in an academic center, were monitored prospectively. Changes in modified Rodnan skin score (mRSS), Disease Activity Score in 28 joints (DAS28), lung function tests (LFTs), and patient-reported outcomes (PROs) were analyzed after 1 year of treatment and at end of follow-up. RESULTS: One patient discontinued TCZ after 3 months due to inefficacy. During the first year of treatment, improvement was evident in the remaining 20 patients regarding skin involvement (mean mRSS change: -6.9 ± 5.9, P < 0.001), polyarthritis (mean DAS28 change: -1.9 ± 0.8, P < 0.001), and PROs (all P < 0.001); LFT stabilization was observed in 16/20 patients. During the second year, 3 patients discontinued TCZ (cytomegalovirus infection in 1, inefficacy in 2) and 1 died. Beneficial effects were sustained in all 16 patients at end of follow-up (2.2 ± 1.1 yrs), except LFT deterioration in 3 patients. Apart from recurrent digital ulcer infection in 3 patients, TCZ was well tolerated. CONCLUSION: TCZ was effective in refractory joint and skin involvement regardless of SSc disease duration or subtype. Long-term retention rates and disease stabilization for most real-world patients suggest that TCZ might be a valuable choice for difficult-to-treat SSc.

A Multifactorial Approach in Type 2 Diabetes Over 3 Years Decelerates Progression of Subclinical Arterial Disease in Routine Clinical Practice.

The beneficial effect of multifactorial treatment of cardiovascular (CV) risk factors (RFs) in type 2 diabetes (T2D) is well established from randomized clinical trials. We prospectively evaluated the impact of such treatment in a real-world setting, on the development of subclinical arterial damage (SAD), as determined by structural/functional noninvasive biomarkers of vascular pathology (atheromatosis, carotid hypertrophy, arteriosclerosis). We prospectively studied 116 persons with T2D, treated with a multifactorial approach for CV RFs at a tertiary medical center, and 324 individuals without diabetes, for 3.2 years. The primary outcome was changes in vascular biomarkers related to SAD. At baseline, participants in the diabetes group had higher prevalence of SAD. At study end, the changes in clinical, biochemical, and lifestyle characteristics, as well as antihypertensive and lipid-lowering treatments, were comparable between the 2 groups. During follow-up, classical CV RFs (smoking, blood pressure, low-density lipoprotein-cholesterol, triglycerides) and behavioral features were significantly improved in both groups. Multivariate analysis, after adjusting for all classic CV RFs and use of antihypertensive/lipid-lowering therapies, demonstrated that all evaluated SAD biomarkers were similarly changed in the 2 groups. In conclusion, implementation of a multimodality approach of T2D treatment is feasible and efficacious in decelerating progression of SAD in routine clinical practice.

Induction of ocular Behçet's disease remission after short-term treatment with infliximab: a case series of 11 patients with a follow-up from 4 to 16 years.

OBJECTIVES: Initial recommendations on anti-TNF treatment for Behçet's disease (BD) included an intravenous infliximab infusion for acute posterior uveitis to achieve a fast-onset response. We aimed to examine the long-term outcome of our patients with acute sight-threatening BD who received successful short-term treatment with infliximab. METHODS: We performed a retrospective longitudinal outcome study including consecutive patients who responded to one infliximab infusion (5mg/kg) for BD-associated acute posterior uveitis or panuveitis, followed, or not, by one or two additional infusions. RESULTS: Twelve patients (aged 51±14 years, mean±SD, 67% men) with bilateral (n=9) or unilateral (n=3) ocular attack (relapsing in 9 patients) achieved resolution of ocular inflammation within 4 weeks after the first infusion of infliximab, given as add-on to azathioprine (n=9) or to azathioprine/cyclosporine combination. Ten of 12 patients received a second infusion at 4 weeks and 9 of them received a third infusion at 8 weeks from baseline. Except from a patient who relapsed after 6 months and responded to infliximab re-treatment, 11 patients remain ocular relapse-free during follow-up, ranging from 4 to 16 years (10±4). Five patients (45%) discontinued azathioprine being in full BD remission and remain any drug-free at end of follow-up. CONCLUSIONS: Successful short-term infliximab treatment combined with conventional immunosuppressives for BD-associated sight-threatening uveitis may lead to remission for many years thereafter. This observation may suggest that infliximab as a first-line therapy should be promptly administered to every patient with ocular BD for rapid remission of ocular inflammation and preservation of visual acuity.

Brief Report: Drug-Free Long-Term Remission in Severe Behçet's Disease Following Withdrawal of Successful Anti-Tumor Necrosis Factor Treatment.

OBJECTIVE: To test the hypothesis that remission of Behçet's disease (BD) in patients with severe vital organ involvement is maintained after withdrawal of successful anti-tumor necrosis factor (anti-TNF) treatment. METHODS: This single-center, retrospective, longitudinal outcomes study focused on consecutive patients with disease refractory to treatment with conventional immunosuppressant agents who responded to add-on long-term anti-TNF treatment that was subsequently discontinued. The end point was the proportion of patients remaining in complete remission for at least 3 years after withdrawal of anti-TNF treatment. RESULTS: In our BD cohort comprising 87 patients, 29 were eligible for analysis. All of these patients had disease that was refractory to conventional immunosuppressive therapy and had received successful anti-TNF treatment for a median of 2 years (interquartile range [IQR] 1.1-2.0) before treatment discontinuation. Of these patients, 12 (41%) achieved the study end point. The remaining 17 patients experienced a relapse within 1 year (IQR 0.6-1.5) after discontinuation. Re-treatment with anti-TNF was safe and effective in 14 (82%) of 17 patients; so far, 4 of these patients also achieved the study end point. Overall, 16 patients have remained in complete remission (median 6.5 years [IQR 5.5-8]). Ten of these patients are in drug-free remission (treated with anti-TNF agents, mainly for sight-threatening disease), and 6 are in azathioprine-maintained remission (treated with anti-TNF agents for ocular, intestinal, or central nervous system involvement). Notably, patients in drug-free remission were significantly younger and had a significantly shorter duration of BD when anti-TNF treatment was initiated compared to patients receiving azathioprine maintenance treatment. CONCLUSION: Drug-free, long-term remission after withdrawal of successful anti-TNF treatment is feasible in patients with severe BD. Because an anti-TNF agent-induced "cure" cannot be differentiated from spontaneous remission by natural history, prospective studies should examine whether anti-TNF agents should be used as first-line treatment for the induction of remission in every patient with vital organ involvement.

Subclinical Atherosclerosis Is Not Accelerated in Patients with Ankylosing Spondylitis with Low Disease Activity: New Data and Metaanalysis of Published Studies.

OBJECTIVE: Chronic inflammatory rheumatic diseases are associated with accelerated atherosclerosis, but data in ankylosing spondylitis (AS) are limited and the relative contribution of inflammation versus classical cardiovascular (CV) risk factors remains a matter of controversy. We addressed this in an original study and a metaanalysis of previous studies. METHODS: Atheromatic plaques in carotid and femoral arteries, carotid hypertrophy [intima-media thickness (IMT), cross-sectional area], and carotid stiffness by ultrasound, as well as aortic stiffness by pulse wave velocity, were examined in consecutive nondiabetic, CV disease (CVD)-free patients with AS. Healthy individuals carefully matched 1:1 with patients for age, sex, smoking habits, hyperlipidemia, and hypertension served as controls. A metaanalysis of original studies that examined subclinical atherosclerosis in patients with AS versus controls with comparable CVD risk factors was also performed. RESULTS: Carotid and femoral atheromatic plaques were slightly less prevalent compared with controls in a contemporary cohort consisting of 67 patients with AS (82% men), aged 47.5 ± 12.5 years (mean ± SD), with a median disease duration of 12 years and a Bath AS Disease Activity Index (BASDAI) of 1.8 (interquartile range 0.4-3.6), of whom 66% were receiving anti-tumor necrosis factor (TNF) treatment. Carotid hypertrophy and stiffness, as well as aortic stiffness, were similar between patients and their matched controls. Metaanalysis of all published studies revealed a significantly increased carotid IMT, but not plaque burden, in AS versus controls. Notably, however, increased IMT was not evident in studies involving patients with low disease activity (mean BASDAI < 4) or in those studies that included > 50% of patients treated with anti-TNF. CONCLUSION: Low AS disease activity is not associated with accelerated atherosclerosis.

Anti-cytokine biologic treatment beyond anti-TNF in Behçet's disease.

Unmet therapeutic needs in Behçet's disease have drawn recent attention to biological agents targeting cytokines other than TNF. The anti-IL-17 antibody secukinumab and the anti-IL-2 receptor antibody daclizumab were not superior to placebo for ocular Behçet's in randomised controlled trials, comprising 118 and 17 patients, respectively. The anti-IL-1 agents anakinra and canakinumab and the anti-IL-6 agent tocilizumab were given to isolated refractory disease patients, who were either anti-TNF naïve (n=9) or experienced (n=18). No new safety signals were reported. Although a potential for bias to report positive effects and underreport negative cases may exist, Anakinra was partially effective, whereas disease remission was noted after canakinumab in some anti-TNF resistant patients. Tocilizumab appeared effective for neuro-Behçet's, but not for mucocutaneous manifestations. Finally, in a pilot study of 7 patients with relapsing posterior uveitis refractory to azathioprine and/or cyclosporine, the anti-IL-1ß antibody Gevokizumab was beneficial. Collectively, it seems that IL-1 and IL-6 are promising targets in patients refractory or intolerant to other regimens including anti-TNFs. However, controlled studies are surely needed.

Adalimumab or cyclosporine as monotherapy and in combination in severe psoriatic arthritis: results from a prospective 12-month nonrandomized unblinded clinical trial.

OBJECTIVE: To assess the efficacy and safety of adalimumab or cyclosporine (CYC) as monotherapy or combination therapy for patients with active psoriatic arthritis (PsA), despite methotrexate (MTX) therapy. METHODS: A prospective 12-month, nonrandomized, unblinded clinical trial of 57, 58, and 55 patients who received CYC (2.5-3.75 mg/kg/day), adalimumab (40 mg every other week), or combination, respectively. Lowering of concomitant nonsteroidal antiinflammatory drugs (NSAID) and corticosteroids and reductions of adalimumab and/or CYC doses in responding patients were not restricted. RESULTS: Mean numbers of tender/swollen joints at baseline were 9.7/6.7 in CYC-treated, 13.0/7.8 in adalimumab-treated, and 14.5/9.4 in combination-treated patients, indicating lesser disease severity of patients assigned to the first group. The Psoriatic Arthritis Response Criteria at 12 months were met by 65% of CYC-treated (p = 0.0003 in favor of combination treatment), 85% of adalimumab-treated (p = 0.15 vs combination treatment), and 95% of combination-treated patients, while the American College of Rheumatology-50 response rates were 36%, 69%, and 87%, respectively (p < 0.0001 and p = 0.03 in favor of combination treatment). A significantly greater mean improvement in Health Assessment Questionnaire Disability Index was achieved by combination treatment (-1.11) vs CYC (-0.41) or adalimumab alone (-0.85). Combination therapy significantly improved Psoriasis Area and Severity Index-50 response rates beyond adalimumab, but not beyond the effect of CYC monotherapy. Doses of NSAID and corticosteroids were reduced in combination-treated patients; CYC doses and frequency of adalimumab injections were also reduced in 51% and 10% of them, respectively. No new safety signals were observed. CONCLUSION: The combination of adalimumab and CYC is safe and seemed to produce major improvement in both clinical and serological variables in patients with severely active PsA and inadequate response to MTX.

Anti-TNF agents for Behçet's disease: analysis of published data on 369 patients.

OBJECTIVE: Off-label use of anti-tumor necrosis factor (TNF) agents for Behçet's disease (BD) is increasing. We evaluated published data on their efficacy and safety for patients with unmet medical needs due to severe disease manifestations, including ocular, gastrointestinal, and central nervous system involvement. METHODS: Peer-reviewed articles on anti-TNF agents for BD appearing in Medline/PubMed through March 2010 were identified using the appropriate indexing terms. RESULTS: We found 88, 12, and 13 primary articles from 20 countries on infliximab, etanercept, and adalimumab, reporting on 325, 37, and 28 patients, respectively. All patients were inadequately controlled with, or intolerant to, other immunosuppressive regimens, including interferon; 20 patients received more than 1 anti-TNF agent. In the only randomized placebo-controlled trial, 4-week administration of etanercept was effective in suppressing most of the mucocutaneous manifestations. In 16 open prospective studies evaluating the effect of repetitive infliximab injections (174 patients in total, men:women = 3:1, median follow-up = 16.2 months), sustained organ-specific, clinical responses were evident in 90%, 89%, 100%, and 91% of patients with resistant mucocutaneous, ocular, gastrointestinal, and central nervous system involvement, respectively. Combination of infliximab with azathioprine and/or cyclosporine-A appeared superior to monotherapy for sustained ocular remission. However, due to the fact that necessary data were lacking, formal estimation of anti-TNF treatment effect on the disease activity indexes for different organ involvement was not possible. CONCLUSIONS: Although more controlled data are needed, there is enough published experience to suggest that TNF blockade represents an important therapeutic advancement for patients with severe and resistant, or intolerant, to standard immunosuppressive regimens BD.