Are antiphospholipid antibodies just a common epiphenomenon or are they causative of immune-mediated coagulopathy in COVID-19?

The coronavirus disease 2019 (COVID-19) is the largest public health emergency in recent times. A significant number of patients develop a severe form of COVID-19 characterized by coagulopathy, organ failure, and elevated mortality. In addition, an unusually high frequency of antiphospholipid antibodies (aPLs) has been found in patients with COVID-19. These clinical and serological manifestations closely resemble those seen in the antiphospholipid syndrome (APS), especially in its catastrophic form, suggesting a role of aPLs in immune-associated coagulopathy. However, government bodies such as the American Society of Hematology have spoken out against the systematic search for aPLs in patients with COVID-19. In an attempt to bridge the gap on this hot topic, we conducted a comprehensive review of currently available cohort studies and case series systematically evaluating aPLs in COVID-19 patients. In this Perspective, we seek to identify both the frequency and the type of aPLs found in patients with COVID-19, as well as the potential association of these aPLs with vascular thrombosis and other distinctive characteristics of COVID-19. Furthermore, we investigated whether there is evidence that allows us to define the occurrence of aPLs in COVID-19 as an epiphenomenon, as has been observed in other systemic viral infections, or as antibodies against self-antigens bearing hallmarks that suggest a pathogenic role in immune-mediated thrombosis. Defining whether aPLs represent an epiphenomenon or they are actually involved in hemostatic abnormalities of COVID-19 is crucial both for uncovering novel mechanisms of immune-mediated thrombosis and for identifying potential prognostic biomarkers in this devastating disease.

Is Takayasu arteritis the result of a Mycobacterium tuberculosis infection? The use of TNF inhibitors may be the proof-of-concept to demonstrate that this association is epiphenomenal.

Although the association between Takayasu arteritis (TA) and latent or active Mycobacterium tuberculosis infection has been suggested for a long time, studies conducted in recent years are challenging this notion. Until recently, the possibility of a pathogenic relationship between TA and tuberculosis (TB) was considered a medical curiosity, but the advent of tumor necrosis factor (TNF) inhibitors as therapy for recalcitrant TA cases, as well as the widespread use of Bacille Calmette-Guérin (BCG) for vaccination purposes, has relocated this association as a top priority issue. In an attempt to define whether both diseases are pathogenically linked or if their association is only epiphenomenal in nature, we conduct a thorough literature search on the development of TB in patients with TA receiving TNF inhibitors. From a total of 13 studies that included 214 patients, the occurrence of TB was observed only in two individuals exposed to infliximab. This frequency of 0.93% is similar to that encountered in patients with other rheumatic diseases exposed to TNF inhibitors. Finally, we propose a novel pathogenic model that could reconcile the epidemiological, clinical, and immunological evidence that links TA and TB, while providing rationality for the use of TNF inhibitors in patients with TA.

Levels of Cytokines and MicroRNAs in Individuals With Asymptomatic Hyperuricemia and Ultrasonographic Findings of Gout: A Bench-to-Bedside Approach.

OBJECTIVE: To assess potential associations among serum cytokines and microRNA (miR) levels with ultrasound (US) findings suggestive of urate deposits in chronic asymptomatic hyperuricemia and gout. METHODS: All participants underwent musculoskeletal US and measurements of serum interleukin-1ß (IL-1ß), IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, interferon-γ, tumor necrosis factor, monocyte chemoattractant protein 1, and epithelial neutrophil-activating peptide 78, as well as miR-146a, miR-155, and miR-223 levels. RESULTS: Thirty individuals with asymptomatic hyperuricemia, 31 normouricemic controls, and 30 patients with gout were included. The frequency of synovitis and double contour sign using US was similar between asymptomatic hyperuricemia (67% and 27%, respectively) and patients with gout (77% and 27%, respectively), and each had a higher frequency than controls (45% and 0%, respectively). Serum IL-6 and IL-8 levels were similar between patients with asymptomatic hyperuricemia (mean ± SD 69.7 ± 73.4 and 18.5 ± 25.6 pg/ml, respectively) and gout (mean ± SD 75.8 ± 47.6 and 24.4 ± 31.7 pg/ml, respectively), and higher than controls (mean ± SD 28.2 ± 17.6 and 7.4 ± 6.0 pg/ml, respectively). A similar distribution was observed for miR-155 levels in asymptomatic hyperuricemia, patients with gout, and controls (mean ± SD 0.22 ± 0.18, 0.20 ± 0.14, and 0.08 ± 0.04, respectively). Associations between morphostructural abnormalities suggestive of urate deposits (regardless of clinical diagnosis) and serum markers were assessed. Subjects with urate deposits had higher IL-6 (257.2 versus 47.0 pg/ml; P = 0.005), IL-8 (73.2 versus 12.0 pg/ml; P = 0.026), and miR-155 (0.21 versus 0.16; P = 0.015) levels than those without deposition findings. CONCLUSION: In individuals with chronic asymptomatic hyperuricemia, the presence of synovitis and double contour sign by US may represent a subclinical manifestation of monosodium urate crystal nucleation, capable of triggering inflammatory pathways (IL-6 and IL-8) and mechanisms of intercellular communication (miR-155), similar to what is observed in patients with gout.

Type III Interferons in Systemic Lupus Erythematosus: Association Between Interferon λ3, Disease Activity, and Anti-Ro/SSA Antibodies.

OBJECTIVE: The aim of this study was to assess associations between serum type III (λ) interferons (IFN-λ) and disease activity in systemic lupus erythematosus (SLE). METHODS: Serum levels of IFN-λ1, IFN-λ2, and IFN-λ3 were measured in 93 SLE patients and 67 healthy individuals. The associations with overall disease activity, organ-specific damage, and SLE-related antibodies were assessed. RESULTS: Median IFN-λ1 levels were 0 pg/mL (range, 0-510 pg/mL) and 0 pg/mL (0-171 pg/mL; P = 0.814) in SLE patients and control subjects, respectively. These figures were 0 pg/mL (0-28 pg/mL) and 0 pg/mL (0-43 pg/mL; P = 0.659) for IFN-λ2, as well as 83 pg/mL (0-965 pg/mL) and 42 pg/mL (0-520 pg/mL; P = 0.002) for IFN-λ3, respectively. According to the Systemic Lupus Erythematosus Disease Activity Index categories, IFN-λ3 levels were 44 pg/mL (0-158 pg/mL) in quiescent, 117 pg/mL (0-344 pg/mL) in mild, 79 pg/mL (0-965 pg/mL) in moderate, and 78 pg/mL (0-329 pg/mL) in severe disease, with the highest levels found in patients with serosal or cutaneous involvement. In line with this, IFN-λ3 levels were inversely correlated with C3 (ρ = -0.44; 95% confidence interval, -0.62 to -0.20; P = 0.0003) and C4 (ρ = -0.40; 95% confidence interval, -0.59 to -0.15; P = 0.0001) complement proteins. In addition, higher IFN-λ3 levels were found in patients positive for anti-Ro/SSA antibodies than in those negative for that antibody (122 pg/mL [0-965 pg/mL] vs. 0 pg/mL [0-165 pg/mL]; P = 0.001). The concentration of IFN-λ3 also was higher in patients receiving glucocorticoids (104 pg/mL [0-965 pg/mL] vs. 30 pg/mL [0-165 pg/mL]; P = 0.009), and a dose-related effect was observed. CONCLUSIONS: Interferon λ3, a subtype of type III IFNs, is associated with the extent of lupus activity, in particular with active serosal and cutaneous disease. This association could be mechanistically related to anti-Ro/SSA antibodies.

Type-III interferons and rheumatoid arthritis: Correlation between interferon lambda 1 (interleukin 29) and antimutated citrullinated vimentin antibody levels.

AIM: To assess serum type III or lambda (λ) interferons (IFN) levels and its clinical and laboratory associations in rheumatoid arthritis (RA). METHODS: A cross-sectional study including 43 patients with RA (86% females; age 45.3 ± 10.3 years) and 43 healthy individuals was performed. Clinical data including disease activity, acute-phase reactants, rheumatoid factor and anticyclic citrullinated peptide (anti-CCP) antibodies were collected. Serum IFNλ1, IFNλ2, IFNλ3, CXCL8 and anti-mutated citrullinated vimentin (anti-MCV) antibody levels were measured. RESULTS: Patients with RA had higher IFNλ1 (113.5 ± 118.6 pg/mL versus 55.9 ± 122.3 pg/mL; p < 0.0001) and IFNλ2 (245.4 ± 327.7 pg/mL versus 5.1 ± 11.0 pg/mL; p = 0.009) levels than controls, but not IFNλ3 levels. Notably, IFNλ1 levels were found to be higher in both patients with active disease (124.9 ± 135.9 pg/mL; p < 0.001) and quiescent disease (99.0 ± 93.7 pg/mL; p < 0.01), while IFNλ2 levels were higher only in patients with active disease (264.0 ± 356.1 pg/mL; p = 0.02). A noteworthy association between serum IFNλ1 levels and anti-MCV antibody titers (Spearman's rho coefficient 0.36, 95% CI 0.36 to 0.61; p = 0.02) was observed. CONCLUSION: Serum IFNλ1 and IFNλ2 levels are abnormally elevated in patients with RA and the former are linearly associated with circulating anti-MCV antibody levels. These results may place type-III IFN as an attractive new therapeutic target in RA.

Anti-Ro/SSA antibodies are associated with severe mitral valve regurgitation in patients with systemic lupus erythematosus.

OBJECTIVE: To assess whether anti-Ro/SSA antibodies are associated with cardiac valve disease in lupus. METHODS: A single-center, medical chart review was performed. Lupus patients were divided according to its anti-Ro/SSA status and subgroups were compared for valvular abnormalities and other characteristics. Dependence of anti-Ro/SSA reactivity to anti-Ro52/TRIM21 antibodies was also evaluated. RESULTS: Eighty-nine lupus patients were analyzed. The most common valvular abnormalities were tricuspid (60%), mitral (41%) and pulmonary (14%) regurgitation. Thirty-six patients were positive and 53 negative for anti-Ro/SSA antibodies. In patients positive to anti-Ro/SSA, a difference was noted for anti-dsDNA (67 versus 45%; p = 0.04) and anti-La/SSB (19 versus 2%; p = 0.004) antibodies. An association between anti-Ro/SSA antibodies and severe mitral regurgitation was observed; indeed, 4/15 patients with anti-Ro/SSA and mitral regurgitation had severe forms of valvulopathy as compared to only 1/22 patients with mitral regurgitation but negative to such antibody (27 versus 5%; p = 0.02). Anti-Ro/SSA antibodies significantly elevated the risk of severe mitral regurgitation (OR = 5). Anti-Ro52/TRIM21 levels (103 ± 29 versus 42 ± 43 U/mL; p = 0.03) and anti-Ro52/TRIM21: anti-Ro/SSA ratios (0.88 ± 0.02 versus 0.35 ± 0.37; p = 0.03) were higher in patients with mitral valve regurgitation than in those with no valvulopathy. CONCLUSION: Anti-Ro/SSA antibodies, mainly against Ro52/TRIM21 antigens, may be pathologically involved in lupus-associated mitral valve regurgitation.

Assessment of nailfold capillaries with a handheld dermatoscope may discriminate the extent of organ involvement in patients with systemic sclerosis.

To investigate whether nailfold capillaroscopy (NFC) patterns assessed through an in-office handheld dermatoscope may reflect the extent of disease severity in systemic sclerosis (SSc). NFC patterns were evaluated with a non-contact, polarized light dermatoscope in 40 consecutive patients with SSc and graded in sequence as 0 = normal, 1 = early, 2 = active, or 3 = late patterns. Disease severity was measured according to a modified Medsger severity scale (MSS). For comparisons, patients were grouped in tertiles according to disease severity, and a numerical correlation between the NFC patterns and the composite MSS score was assessed. Twenty patients had normal or early NFC patterns, most of them (17 individuals, 85 %) having low to moderate disease severity. In contrast, 18 out of 20 (90 %) patients with active or late NFC patterns had moderate to high disease severity. Accordingly, patients with normal/early NFC patterns had a median MSS score of 4 (interquartile range (IQR), 3-5) as compared with 7 (4-8; P = 0.02) in those with active/late patterns. A Spearman's rho coefficient of 0.45 (95 % CI, 0.15-0.67; P = 0.003) was found between the graded scale of NFC patterns and the composite MSS score. A handheld dermatoscope is useful to visualize the NFC patterns in SSc patients, and it is efficient enough to reflect the extent of disease severity.

Pulmonary hypertension in systemic lupus erythematosus: echocardiography-based definitions predict 6-year survival.

OBJECTIVE: The aim of this study was to investigate whether a core of echocardiography-based definitions of pulmonary hypertension (PH), as proposed by the European Society of Cardiology, European Respiratory Society and International Society of Heart and Lung Transplantation (ESC/ERS/ISHLT), may predict long-term survival in patients with SLE. METHODS: A post hoc analysis from a cohort of SLE patients followed over 6 years was performed. Clinical associations, serum biomarkers, autoantibody profile, length of survival and all-cause mortality were assessed. RESULTS: Out of 115 patients from the original cohort, 55 satisfied our inclusion criteria and were grouped according to echocardiography as unlikely (n = 26), possible (n = 16) or likely (n = 13) to have PH. Likely PH was associated with a history of pulmonary thromboembolism, higher cumulated organ damage and active arthritis. The 6-year survival rate was 88% in the unlikely PH group, 87% in the possible PH group and 68% in the likely PH group (P < 0.05). Serum levels of endothelin-1, monocyte chemotactic protein-1, IL-17, and IFN-γ as well as a number of autoantibodies were no different between groups. CONCLUSION: The ESC/ERS/ISHLT echocardiography-based definitions of PH are useful to predict 6-year mortality in SLE patients. A history of pulmonary thromboembolism and lung vasculitis/haemorrhage, cumulated organ damage and long-lasting disease are associated with PH in SLE.

Joint involvement in primary Sjögren's syndrome: an ultrasound "target area approach to arthritis".

OBJECTIVE: To characterize the ultrasound (US) pattern of joint involvement in primary Sjögren's syndrome (pSS). METHODS: Seventeen patients with pSS, 18 with secondary Sjögren's syndrome (sSS), and 17 healthy controls underwent US examinations of various articular regions. Synovitis (synovial hypertrophy/joint effusion), power Doppler (PD) signals, and erosions were assessed. RESULTS: In patients with pSS, synovitis was found in the metacarpophalangeal joints (MCP, 76%), wrists (76%), and knees (76%), while the proximal interphalangeal joints, elbows, and ankles were mostly unscathed. Intra-articular PD signals were occasionally detected in wrists (12%), elbows (6%), and knees (6%). Erosions were evident in the wrists of three (18%) patients with pSS, one of these also having anti-cyclic citrullinated peptide (anti-CCP) antibodies. While US synovitis does not discriminate between sSS and pSS, demonstration of bone erosions in the 2nd MCP joints showed 28.8% sensitivity and 100% specificity for diagnosing sSS; in comparison, these figures were 72.2 and 94.1% for circulating anti-CCP antibodies. CONCLUSIONS: In pSS, the pattern of joint involvement by US is polyarticular, bilateral, and symmetrical. Synovitis is the US sign most commonly found in patients with pSS, especially in MCP joints, wrists, and knees, and bone erosions also may occur.

Self-reactivity against stress-induced cell molecules: the missing link between Takayasu's arteritis and tuberculosis?

Takayasu's arteritis (TA) is a chronic, occlusive, inflammatory disease of the aorta, its major branches and the pulmonary arteries. Its etiology remains unclear, although it has been suggested that a variety of antigens from Mycobacterium tuberculosis and probably other mycobacteria may trigger inflammatory pathology either directly in the arterial wall or remote from the actual location of mycobacterial infection, possibly through molecular mimicry mechanisms. However, recent evidence showing absence of both mycobacteria directly into arterial tissue as well as latent M. tuberculosis infection is challenging this notion. The hypothesis offered in this manuscript postulates that the lost of tolerance against self stress proteins is a primal pathogenic event in TA with the innate immune system as key culprit in the initiation and amplification of inflammatory response, while the extensive sequence homology between mycobacterial and human stress proteins leads to epiphenomenal cross-reactions mediated by adaptive immune system. If it is so, this postulate reconciles epidemiological, immunological and genetic linkage between TA and mycobacteria, while supporting the widespread Bacille Calmette-Guérin (BCG) vaccination worldwide and giving rationale to a safety use of anti-tumor necrosis factor (TNF) therapy in patients with TA.

C-reactive protein and complement components but not other acute-phase reactants discriminate between clinical subsets and organ damage in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by tissue injury mediated by inflammatory mechanisms. Nonetheless, several acute-phase proteins may remain normal or are decreased. We explore the association of diverse biomarkers with selected clinical features, disease activity, and organ damage in SLE. METHODS: One hundred and fifteen SLE patients were analyzed for clinical manifestations, disease activity, and organ damage. Serum C-reactive protein (CRP), complement C3, C4 and CH50%, alpha-1-antitrypsin (AAT), transferrin (Tf), procalcitonin, erythrosedimentation rate (ESR), and interleukin-6 were measured in patients and twenty-six healthy blood donors. Statistics include chi-square, Kruskal-Wallis (post hoc by Mann-Whitney) or one-way ANOVA tests (post hoc by t tests) as appropriate. Associations were evaluated by the Spearman's correlation coefficient (p). RESULTS: SLE patients have lower C3 (85 vs. 110 mg/dL; p < 0.0001) and C4 (14.2 vs. 24.2 mg/dL; p < 0.0001) than controls, while CRP (4.1 vs. 1.4 mg/L; p = 0.005) and AAT (147 vs. 138 mg/dL; p = 0.03) were higher, other biomarkers were irrelevant. Disease activity score positively correlated with ESR (p = 0.23, 95 % CI 0.04 to 0.4; p = 0.01) and CRP (p = 0.19, 0.0007 to 0.36; p = 0.04), while inverse correlations with C3 (p = -0.26, -0.43 to -0.08; p = 0.004), C4 (p = -0.18, -0.36 to 0.005; p = 0.04), CH50 % (p = -0.20, -0.38 to -0.01; p = 0.02), and Tf (p = -0.35, -0.53 to -0.12; p = 0.002) were found. According to clinical manifestations, patients with arthritis showed higher levels of ESR (34 vs. 20 mm/h), CRP (10 vs. 2.8 mg/L), and AAT (179 vs. 145 mg/dL), but lower Tf (192 vs. 226 mg/dL) than those without arthritis; whereas active nephritis was characterized by lower serum concentrations of complement C3 (73 vs. 92 mg/dL), C4 (10 vs. 15 mg/dL), CH50% (80 vs. 160 U/mL) and Tf (196 vs. 232 mg/dL) than those patients without this manifestation. No other significant differences were found. CONCLUSIONS: In patients with SLE, acute-phase proteins behave differently depending on the kind of organ damage evaluated. Serum complement proteins remained as the most reliable laboratory markers for nephritis, while CRP was determined the best in patients with arthritis. The muted CRP response seen in SLE patients with active nephritis could have important pathogenic implications.