Impact of biologic therapies on risk of adverse cardiovascular events in patients with Ankylosing Spondylitis or Psoriatic Arthritis: A systematic literature review.

BACKGROUND: Recent evidence highlights increased mortality and morbidity due to cardiovascular disease (CVD), especially within the two major forms of Spondyloarthropathies (SpAs), Ankylosing Spondylitis (AS) and Psoriatic Arthritis (PsA). Healthcare professionals and patients in these populations should be alerted regarding the high risk of cardiovascular (CV) events and thus, customize the treatment strategy accordingly. OBJECTIVE: This systematic literature review aimed to determine the effects of biological therapies on serious CV events in AS and PsA. METHODS: Screening for the study was carried out using PubMed and Scopus databases from the database's inception to the 17th of July 2021. The literature search strategy for this review is based on the Population, Intervention, Comparator, Outcomes (PICOs) framework. Randomized controlled trials (RCTs) of biologic therapies for the treatment of AS and/or PsA were included. The primary outcome measure was the number of serious CV events reported during the placebo-controlled phase. RESULTS: 4,422 articles were generated from keywords, eligibility criteria, and databases. Following the screening, we retained 13 studies for analysis: 3 in AS and 10 in PsA. Meta-analysis of results was not feasible due to the small number of the identified studies, the heterogeneity of the biologic treatment and the included populations, as well as the infrequently reported requested endpoint. According to our review, biologic treatments are safe options as for CV risk in patients with PsA or AS. CONCLUSION: Further and more extensive trials in AS/PsA patients at high risk of CV events are needed before firm conclusions can be drawn.

High 3-year golimumab survival in patients with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis: real world data from 328 patients.

OBJECTIVES: Our primary objective was to study the long-term survival on drug (SOD) of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) treated with golimumab (GLM) in real life settings. METHODS: This was a retrospective, observational study of all patients treated with GLM in 4 Academic Centres in Greece during a 4-year period (09/2010-06/2014). SOD was analysed using Kaplan-Meier survival analysis, while Cox regression analysis estimating hazard ratios (HRs) for different baseline variables associated with drug discontinuation was performed for each disease. RESULTS: 328 patients (RA: 166, PsA: 82, AS: 80) were included. The estimated SOD at 2 and 3 years was 68% and 62% overall and was better for AS (79% and 76%) compared to RA (69% and 60%, p=0.067) and PsA (58% and 53%, p=0.001) patients; no difference was noted between RA and PsA patients (p=0.204). There was no difference in SOD between biologic-naïve and experienced nor between non-biologic co-treated or GLM monotherapy treated patients. Seropositivity (rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies) was associated with a lower risk for GLM discontinuation by multivariate analysis (HR=0.5, 95% CI=0.0.25-1.1, p=0.05) in RA patients. During 606 patient-years of follow-up, 11 (3.3%) patients discontinued GLM due to adverse events (AE), accounting for 11% of treatment discontinuations. The rates of serious AEs and serious infections were 2.3 and 1.0/100-patient-years, respectively. CONCLUSIONS: In this real-life study, GLM showed a high 3-year SOD in patients with inflammatory arthritides with a low rate of discontinuation due to AEs.

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.

Anti-TNFα treatment for recalcitrant ulcerative necrobiosis lipoidica diabeticorum: A case report and review of the literature.

INTRODUCTION: Necrobiosis lipoidica diabeticorum (NLD) is a rare degenerative connective tissue disorder associated with diabetes mellitus, which usually presents with red papules or plaques with raised edges and occasional ulceration. Ulcerating NLD is notoriously difficult to treat. We present a young patient with ulcerative NLD who was successfully treated with the anti-TNFα agent infliximab. Case presentation is followed by a review of therapeutic TNFα blockade in NLD. CASE PRESENTATION: A 17-year old woman with type 1 diabetes since the age of 8, presented with a long-standing and extensively ulcerated and infected NLD lesion on her left shin. After achieving better glycemic control and treating her for infection of the wound, several NLD treatments failed to help, including corticosteroids and hyperbaric oxygen. She was treated successfully with 4 monthly sessions of 5mg/kg body weight intravenous infliximab, achieving complete resolution of ulceration. DISCUSSION: A multitude of available treatments have been suggested for NLD over the past decades, based on two axes, one through wound healing and the other through immunosuppression. Anti-TNFα agents are relatively new drugs that brought a revolution in chronic inflammatory diseases and have been on the rise as novel potential treatments for NLD. Three out of the five available anti-TNFα agents have been safely tested so far, both topically and systematically, with mostly favorable results. CONCLUSION: Intravenous infliximab was successful in the treatment of recalcitrant ulcerating NLD in our patient. Taken together with an increasing number of similar reports revealing a pathogenetic role of TNFα in NLD, we suggest that anti-TNFα agents are promising drugs in the management of this condition.

Interrelated reduction of chemerin and plasminogen activator inhibitor-1 serum levels in rheumatoid arthritis after interleukin-6 receptor blockade.

Inflammatory/metabolic factors and imbalance of haemostasis contribute to cardiovascular disease risk in rheumatoid arthritis (RA). Interleukin-6 (IL-6), a cytokine that plays an important role in immune responses, is implicated in its pathogenesis. In this study, the effects of the IL-6 receptor inhibitor, tocilizumab, on serum adipokines and coagulation/fibrinolysis factors in RA patients were examined. Nineteen consecutive patients (18 women, aged 48 ± 9 years) received six monthly infusions of 8 mg/kg tocilizumab for moderate or severe RA. Disease activity/severity, as well as serum levels of chemerin apelin, plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6), glucose, insulin and lipids were measured at baseline and at 1, 3 and 6 months thereafter. Chemerin and PAI-1 levels decreased significantly from baseline through 3 to 6 months (from 256 ± 79 to 174 ± 12 and 210 ± 85 ng/ml; from 73 ± 27 to 56 ± 22 and 51 ± 28 pg/ml, respectively). Other adipokines did not change, despite increases in adiposity. In multivariate models, significant independent associations were found between baseline chemerin with age, body mass index, remission of disease, HAQ-Di, CRP and PAI-1. Chemerin decrease at 6 months was significantly associated with PAI-1 and IL-6 changes at 6 months. Baseline PAI-1 associated negatively with remission of disease and total cholesterol, while PAI-1 change at 6 months associated with chemerin changes and smoking status. In conclusion, inhibition of IL-6 signaling in RA favorably alters chemerin and PAI-1 levels in an interrelated manner, despite increasing adiposity. This might represent a dual anti-inflammatory and anti-thrombotic/fibrinolytic mechanism of tocilizumab that may reduce cardiovascular event risk in RA patients.

Predictors of new atherosclerotic carotid plaque development in patients with rheumatoid arthritis: a longitudinal study.

INTRODUCTION: Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality attributed to both classical risk factors and chronic inflammation. We assessed longitudinally the factors associated with new carotid plaques in nondiabetic RA patients and apparently healthy individuals. METHODS: In our present prospective observational study, carotid plaques were identified by ultrasonography at baseline and follow-up end, separated by an average of 3.6 ± 0.2 years, in 64 patients (mean age 59.2 ± 12.0 and disease duration at baseline 7.8 ± 6.2 years, 83% women, clinical and laboratory evaluation every 3 to 6 months). In a substudy, 35 of the patients were matched 1:1 for traditional cardiovascular risk factors with 'healthy' controls and were studied in parallel. RESULTS: New atherosclerotic plaques formed in 30% of patients (first plaque in 9%) who were significantly older than the remaining patients. Tobacco use, blood pressure, body mass index, average cumulative low-density lipoprotein, high-sensitivity C-reactive protein, erythrocyte sedimentation rate level, RA stage, functional class, disease duration and treatment modalities during follow-up did not differ significantly between subgroups after application of the Bonferroni correction. RA was in clinical remission, on average, for approximately 70% of the follow-up time and was not different between subgroups. Multivariate analysis including all the above parameters revealed that age (P = 0.006), smoking (P = 0.009) and duration of low-dose corticosteroid use (P = 0.016) associated independently with new plaque formation. RA patients displayed similar numbers of newly formed carotid plaques to the tightly matched for traditional cardiovascular risk factors 'healthy' controls, although more patients than controls had carotid plaques at baseline. CONCLUSIONS: Formation of new atherosclerotic plaques in this small cohort of patients with well-controlled RA depended mainly on traditional cardiovascular risk factors and corticosteroid use, whereas an adverse effect of residual systemic inflammation was not readily detectable.

Sleep disturbances and interleukin 6 receptor inhibition in rheumatoid arthritis.

OBJECTIVE: Interleukin 6 (IL-6)-mediated interactions have been associated with sleep disturbances in healthy subjects. In this pilot study we examined whether administration of the IL-6 receptor antagonist tocilizumab in patients with rheumatoid arthritis (RA) affects sleep disturbances. METHODS: Fifteen patients (13 women) with sleep disturbances at baseline received 6 monthly infusions of tocilizumab 8 mg/kg for moderately or severely active RA. Sleep quality was assessed by Pittsburgh Sleep Quality Index (PSQI), daytime sleepiness by Epworth Sleepiness Scale, disease activity by the 28-joint Disease Activity Score-erythrocyte sedimentation rate, functional disability by Health Assessment Questionnaire Disability Index (HAQ-DI), and fatigue by the Functional Assessment of Chronic Illness Therapy (FACIT-Fatigue Scale; FFS) at baseline and first, second, third, and sixth month of treatment. Medications used before enrollment remained unchanged during followup. RESULTS: Sleep quality improved and daytime sleepiness decreased significantly at first-month assessment (p < 0.00001 and p < 0.004, respectively, by repeated measurement analysis) compared to baseline, and these changes became more evident through 6 months. Disease activity decreased, fatigue decreased, and functional status improved significantly. Changes in PSQI score over time were not associated with the corresponding changes in DAS28-ESR (r = 0.37, p = 0.17), but correlated significantly with HAQ-DI changes (r = 0.60, p = 0.02) and marginally with changes in FFS scores (r = -0.46, p = 0.08). CONCLUSION: Improvement of sleep quality after tocilizumab treatment in patients with RA does not appear to directly result from decreased disease activity, further suggesting that aberrant IL-6 regulation is associated with sleep disturbances.

Early effects of IL-6 receptor inhibition on bone homeostasis: a pilot study in women with rheumatoid arthritis.

OBJECTIVES: A critical role of interleukin-6 (IL-6) in bone homeostasis has been suggested in experimental studies. We examined whether inhibition of IL-6 receptor in patients with rheumatoid arthritis (RA) results in early alterations of circulating markers of bone remodelling. METHODS: Circulating levels of osteoprotegerin, receptor activator of nuclear factor-kappaB ligand (RANKL), Wnt signalling pathway inhibitors Dickkopf-1 (Dkk-1) and sclerostin, markers of bone resorption (C-terminal cross-linking telopeptide of collagen type-I (CTX), tartrate-resistant acid phosphatase isoform-5b) and bone formation (bone-specific alkaline-phosphatase, osteocalcin) were examined in 22 women with active RA before and after two monthly infusions of tocilizumab (8mg/kg each); 'healthy', non-osteopenic, 1:1 age-matched women served as controls. RESULTS: At baseline, osteoprotegerin/RANKL ratio in patients was lower than controls by 5-fold; circulating osteoprotegerin correlated negatively with corresponding 28-joint-count disease activity scores and circulating RANKL correlated positively with C-reactive protein. Also, Dkk-1, sclerostin, CTX and osteocalcin levels were higher in RA than controls. After two months, osteoprotegerin/RANKL ratio increased, Dkk-1 decreased and sclerostin increased comparing to baseline; other markers did not change significantly. Increases of osteoprotegerin/RANKL ratio were more prominent in 10 patients who achieved remission or low disease activity after tocilizumab than in 12 patients who did not. In contrast, the significant alterations of both Wnt inhibitors were comparable between these patient subgroups. CONCLUSIONS: Anti-IL-6 therapy induced suppression of the inflammatory response affects rapidly the disrupted bone homeostasis in active RA. An additional, possibly specific, effect of IL-6 receptor inhibition on bone remodelling in humans should be further examined.

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.

A single infliximab infusion vs corticosteroids for acute panuveitis attacks in Behçet's disease: a comparative 4-week study.

OBJECTIVE: To compare a single infusion of the anti-TNF antibody infliximab vs CSs for acute panuveitis attacks in Behçet's disease (BD). METHODS: A prospective, observational study of patients with panuveitis, who received either an infliximab infusion (5 mg/kg, 19 eyes) or high-dose methylprednisolone intravenously (1 g/day for 3 days, 8 eyes), or intra-vitreal triamcinolone acetonide (4 mg, 8 eyes) at attack's onset. Baseline maintenance therapy remained unchanged during the following 30 days. Visual acuity, anterior chamber cells, vitreous cells and inflammation of the posterior eye segment were assessed at baseline and at Days 1, 7, 14 and 29 (±1) post-treatment. RESULTS: While no significant differences were noted between i.v. and intra-vitreal CSs, infliximab was faster than CSs in decreasing total ocular inflammation scores and fundus inflammation scores (P = 0.01 and P < 0.0001 for treatment × time(2) interaction, respectively, using generalized estimating equation analysis). Independently of time, infliximab was superior to CSs in clearing retinal vasculitis (P < 0.003), as well as in resolution of retinitis (P = 0.008) and cystoid macular oedema (P < 0.007). Moreover, a faster regression of cystoid macular oedema was observed with infliximab compared with CSs (P < 0.03). The beneficial effects of the three treatment modalities on visual acuity were comparable from baseline to the end of follow-up. No side effects were noted with infliximab or methylprednisolone, whereas intra-vitreal triamcinolone acetonide caused ocular hypertension in four of the eight eyes, requiring surgical intervention in two. CONCLUSION: A single infusion of infliximab should always be considered, even as an adjunct therapy, for the control of acute panuveitis attacks in BD.

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.

Orbital lobular panniculitis in Weber-Christian disease: sustained response to anti-TNF treatment and review of the literature.

Weber-Christian disease is a febrile, relapsing, non-suppurative panniculitis of unknown etiology. Lobular panniculitis is the essential feature in biopsy specimens and evolves through three recognizable stages. We report a case of Weber-Christian disease with bilateral orbital involvement, at different stages, affecting the orbital fat along with enophthalmos in one orbit, and the upper preaponeurotic fat pad in the other. Weber-Christian disease was refractory to treatment with conventional immunosuppressive regimens; however, early inflammatory-but not chronic fibrotic-orbital lesions responded dramatically to anti-tumor necrosis factor (TNF) therapy. A literature review revealed five additional cases of orbital Weber-Christian disease, none treated with anti-TNF antibodies. Of these, four presented initially with proptosis, representing early stages of inflammation, and two subsequently developed enophthalmos, representing late, inactive stage of the disease. Although orbital Weber-Christian disease is rare, ophthalmologists need to be aware of this entity. Depending on the stage of inflammation, Weber-Christian disease should be included in the differential diagnosis of both proptosis and enophthalmos. Anti-TNF antibodies can successfully treat patients at the early inflammatory stage.