Disease evolution and organ damage accrual in patients with stable UCTD: a long-term monocentric inception cohort.

OBJECTIVES: Undifferentiated connective tissue diseases (UCTDs) are systemic autoimmune conditions that cannot be diagnosed nor classified as defined CTD; the majority maintains an undifferentiated profile (stable UCTD, sUCTD) over time. Data on long-term outcomes of sUCTD are lacking. METHODS: Retrospective longitudinal analysis of an inception cohort of 141 patients with sUCTD.Disease evolution and damage accrual were evaluated at 1, 5 and 10 years. Partial least square (PLS) regression was used to identify the basal variables contributing to damage accrual at 1, 5 and 10 years of follow-up. Trend of damage over time was compared with a cohort of age-matched and sex-matched patients with systemic lupus erythematosus (SLE) by means of Nelson-Aalen analysis. RESULTS: 11.3% of patients evolved to a definite CTD after a median 11 years (IQR 6-25) from the first symptom. At last visit, 10% were on glucocorticoids and 6% on immunosuppressive therapy. In 27.3%, at least one item of organ damage was recorded according to the SLICC/DI score (mean score 1.19±0.46). At PLS analysis, age at diagnosis and age at first symptoms were related to damage at 1 year, not taking antimalarials and taking immunosuppressants were associated with damage at 5 years.The mean survival without damage was 9.3 years in sUCTD and 8.4 years in SLE. The 10-year probability without damage was 62% and 23% in SLE and sUCTD, respectively (p=0.015). CONCLUSIONS: Although less significantly impacted than in patients with SLE, in the long-term UCTDs can accumulate organ damage and evolve into defined connective tissue diseases.

Autoimmune hepatitis, primary sclerosing cholangitis, and inflammatory bowel disease. Sequential overlap syndrome: a twist to the mosaic of autoimmunity

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COVID-19 and rheumatic autoimmune systemic diseases: report of a large Italian patients series.

INTRODUCTION: Covid-19 infection poses a serious challenge for immune-compromised patients with inflammatory autoimmune systemic diseases. We investigated the clinical-epidemiological findings of 1641 autoimmune systemic disease Italian patients during the Covid-19 pandemic. METHOD: This observational multicenter study included 1641 unselected patients with autoimmune systemic diseases from three Italian geographical areas with different prevalence of Covid-19 [high in north (Emilia Romagna), medium in central (Tuscany), and low in south (Calabria)] by means of telephone 6-week survey. Covid-19 was classified as (1) definite diagnosis of Covid-19 disease: presence of symptomatic Covid-19 infection, confirmed by positive oral/nasopharyngeal swabs; (2) highly suspected Covid-19 disease: presence of highly suggestive symptoms, in absence of a swab test. RESULTS: A significantly higher prevalence of patients with definite diagnosis of Covid-19 disease, or with highly suspected Covid-19 disease, or both the conditions together, was observed in the whole autoimmune systemic disease series, compared to "Italian general population" (p = .030, p = .001, p = .000, respectively); and for definite + highly suspected diagnosis of Covid-19 disease, in patients with autoimmune systemic diseases of the three regions (p = .000, for all comparisons with the respective regional general population). Moreover, significantly higher prevalence of definite + highly suspected diagnosis of Covid-19 disease was found either in patients with various "connective tissue diseases" compared to "inflammatory arthritis group" (p < .000), or in patients without ongoing conventional synthetic disease-modifying anti-rheumatic drugs treatments (p = .011). CONCLUSIONS: The finding of a higher prevalence of Covid-19 in patients with autoimmune systemic diseases is particularly important, suggesting the need to develop valuable prevention/management strategies, and stimulates in-depth investigations to verify the possible interactions between Covid-19 infection and impaired immune-system of autoimmune systemic diseases. Key Points • Significantly higher prevalence of Covid-19 is observed in a large series of patients with autoimmune systemic diseases compared to the Italian general population, mainly due to patients' increased susceptibility to infections and favored by the high exposure to the virus at medical facilities before the restriction measures on individual movement. • The actual prevalence of Covid-19 in autoimmune systemic diseases may be underestimated, possibly due to the wide clinical overlapping between the two conditions, the generally mild Covid-19 disease manifestations, and the limited availability of virological testing. • Patients with "connective tissue diseases" show a significantly higher prevalence of Covid-19, possibly due to deeper immune-system impairment, with respect to "inflammatory arthritis group". • Covid-19 is more frequent in the subgroup of autoimmune systemic diseases patients without ongoing conventional synthetic disease-modifying anti-rheumatic drugs, mainly hydroxyl-chloroquine and methotrexate, which might play some protective role against the most harmful manifestations of Covid-19.

Nailfold capillaroscopy and autoimmune connective tissue diseases in patients from a Portuguese nailfold capillaroscopy clinic.

Raynaud's phenomenon (RP) is frequent in autoimmune connective tissue diseases (AICTD) and its approach includes nailfold capillaroscopy (NFC), as it is a non-invasive technique that permits direct visualization of the microcirculation. The aim of this study is to analyze and establish clinical correlations between NFC findings and particular aspects of autoimmune disorders. This is a retrospective study. Clinical data from patients attending our NFC clinic were reviewed. Inclusion criteria included AICTD previous diagnosis, which included systemic sclerosis (SSc), mixed connective tissue disease (MCTD), systemic lupus erythematosus (SLE), Sjögren syndrome, inflammatory idiopathic myopathies (IIM), rheumatoid arthritis, undifferentiated connective tissue disease and antiphospholipid syndrome (APS). Videocap® version 3.0 biomicroscope was used. NFC score was determined. For statistics, SPSS software was utilized. 384 patients were included; most of them were women, with mean age of 47 years. RP was present in 91% of the patients, with greater prevalence in SSc and MCTD. Scleroderma pattern was the most prevalent NFC pattern, mainly in SSc, MCTD and IIM. Mean capillary density was reduced in IIM, SSc and MCTD. NFC score was worse in SSc, IIM and MCTD. In patients with AICTD, RP is related to microvascular damage and worse NFC score. NFC scleroderma pattern correlates with SSc classification criteria score. In MCTD, scleroderma pattern relates to myositis. SLE and APS reveal significant hemorrhages, but not related to APS antibodies. This study highlights the possible role of NFC as biomarker of AICTD, particularly in SSc and IIM.

Systemic lupus erythematosus and thyroid disease - Experience in a single medical center in Taiwan.

BACKGROUND: To investigate the association of systemic lupus erythematosus (SLE) with thyroid diseases in a medical center in central Taiwan. METHODS: This is a retrospective cohort of 2796 SLE patients in a tertiary referral medical center from 2000 to 2013. We screened SLE by catastrophic illness registration from national insurance bureau; and thyroid diseases by ICD 9 codes, then confirmed by thyroid function test, auto-antibody, medical and/or surgical intervention. We compared the rate of hyperthyroidism, hypothyroidism and autoimmune thyroid disease (AITD) in SLE patients and the 11,184 match controls. We calculated the rate of these thyroid diseases and positive antibodies to thyroglobulin (ATGAb), thyroid peroxidase (TPOAb) in SLE patients grouped by the presence of overlap syndrome and anti-dsDNA antibody. We also compared the association of thyroid diseases to severe SLE conditions, including renal, central nervous system (CNS) involvement, and thrombocytopenia. RESULTS: Compared to the matched controls, the cumulative incidence of thyroid disease, including hyperthyroidism, hypothyroidism and AITD, were all higher in SLE patients (p < 0.0001). The average age of SLE patients with thyroid diseases patients were older than those without thyroid diseases (p = 0.002). Those had euthyroid AITD were younger than other patients with thyroid diseases (p = 0.02). Up to 30.3% SLE patients had overlap syndrome and had higher relative risk of thyroid diseases than those without overlap syndrome, in terms of hypothyroidism and AITD, but not hyperthyroidism. SLE patients with thyroid diseases also carry higher risk for severe complications such as renal involvement (p = 0.024) central nervous system involvement (p < 0.0001). CONCLUSION: SLE patients had significantly higher rate of hyperthyroidism, hypothyroidism, and AITD than the matched control. Among lupus patients, the risks of thyroid diseases are even higher in the presence of overlap syndrome. SLE patients with thyroid diseases had higher risk of renal and CNS involvement.

Prevalence of overlap of antineutrophil cytoplasmic antibody associated vasculitis with systemic autoimmune diseases: an unrecognized example of poliautoimmunity.

We aimed to estimate the frequency of overlap of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with systemic autoimmune diseases. Retrospective single-center study to identify patients with AAV diagnosis and concomitant autoimmune systemic diseases, simultaneously, before or after the diagnosis of AAV. Sociodemographic characteristics, such as comorbidities; follow-up time; type of AAV; disease duration; relapses; treatment and response; clinical, serological, and histological characteristics; disease activity and damage; prognosis; dialysis requirements, and death were assessed. Twenty-eight of two hundred and forty-seven patients (11.3%) with AAV had a concomitant diagnosis of autoimmune disease. The predominant AAV type was renal-limited vasculitis (39%), followed by granulomatosis with polyangiitis (29%), mycroscopic polyangiitis (25%), and eosinophilic granulomatosis with polyangiitis (7%). Mean age at AAV diagnosis was 50 ± 17 years and 24/28 were ANCA positive. The main clinical manifestations were renal (79%), otorhinolaryngologic (43%), and pulmonary and peripheral neuropathy (32%). Sixteen patients (57%) experienced partial or total remission at a median follow-up of 34 months, and four patients (14%) died. The most frequent autoimmune disease overlapped was rheumatoid arthritis (39%), followed by Sjögren's syndrome and systemic sclerosis (14%), mixed connective tissue disease (11%), systemic lupus erythematosus and juvenile idiopathic arthritis (7%), and ankylosing spondylitis and IgG4-related disease (4%). In nine patients (32%), both diagnoses were simultaneous; in the rest, median time elapsed between the autoimmune disease and AAV diagnosis was 173 months. The prevalence of overlap AAV with other autoimmune diseases was low. The most common AAV phenotype was renal-limited vasculitis, and the most frequent overlap disease was rheumatoid arthritis.

Las enfermedades del tejido conectivo: nuevas opciones y retos / Connective tissue diseases: new options and challenges

Las enfermedades del tejido conectivo (ETC) son entidades de baja prevalencia en la población general. Comprenden alrededor de 200 entidades. Solo 20 por ciento de la población las padece y un tercio de las personas van a padecer alguna de ellas en el transcurso de la vida. Son de naturaleza inflamatoria y autoinmune, tienden a la cronicidad y al compromiso de muchos parénquimas, órganos y tejidos, lo que deja daños estructural y funcional. Representan 30 por ciento de invalidez temprana, incrementan el riesgo a adquirir otras enfermedades como cáncer, enfermedades cardiovasculares, gastrointestinales, diabetes mellitus y trastornos mentales. El diagnóstico y tratamiento precoz de estas entidades permite cambiar su curso y muchas veces lograr remisión. Por tanto es de suma importancia tenerlas presente y sospecharlas como enfermedades e iniciar un tratamiento oportuno. Las ETC más reconocidas son: artritis reumatoidea (AR), lupus eritematoso sistémico (LES), síndrome de Sjögren (SS), esclerosis sistémica (ES), polimiositis (PM) y dermatomiositis (DM), enfermedad mixta del tejido conectivo (EMTC) y el síndrome Antifosfolípidos (SAFL), este último es reconocido como afección autoinmune pero no de carácter inflamatorio asociado a las ETC, especialmente al LES. Hasta hace algunas décadas se pensaba que el tejido conjuntivo tenía un papel pasivo en el organismo, cuya única función era ser soporte o armazón de otros tejidos y órganos. Sin embargo hoy ya se sabe que tiene gran capacidad biosintética, regenerativa y de proliferación celular y que desempeña una función importante en la regulación del comportamiento celular. Existen varios tipos de tejidos conectivos localizados en diversas partes del organismo los cuales se adaptan a funciones específicas tales como: · Mantener unidos entre sí los otros tejidos del individuo, formando el estroma de diversos órganos. · Contener las células que participan en los procesos de defensa ante agentes extraños en sitios donde se inicia la reacción inflamatoria. · Constituir un medio tisular adecuado para alojar células en proceso de proliferación y diferenciación para formar los elementos figurados de la sangre. · Almacenar grasa para su uso posterior como fuente de energía. · Formar láminas con resistencia a la tracción (piel y ligamentos). · Formar láminas o placas relativamente solidas (cartílago). · Formar el principal tejido de soporte del organismo, caracterizado por su resistencia tanto a la tracción como a la compresión (hueso). En la clasificación de las enfermedades reumáticas, las enfermedades de tejido conectivo ocupan un capítulo independiente y constituyen un grupo de entidades autoinmunes, de etiología desconocida. Este capítulo está integrado por enfermedades complejas, sistémicas, que obligan a un conocimiento amplio de la medicina interna para poder tratar a estos enfermos. El primer lugar dentro de estas entidades lo ocupa la AR por su frecuencia, prevalencia incapacidad funcional y pérdida de la calidad de vida. El LES en segundo lugar, más frecuente en las mujeres en edad fértil, de manejo complejo por lo multisistémica que puede comportarse y con la afectación de órganos importantes como el riñón y el sistema nervioso central. La esclerosis sistémica es menos frecuente pero compleja por el daño que produce con deterioro de las funciones y pérdida de la calidad de vida tanto por los cambios en la piel como el sistema digestivo. Las miopatías inflamatorias también se encuentran dentro de este grupo de entidades con menos prevalencia que las anteriores pero también con afectación de varios órganos y sistemas que pueden tener un curso complejo y grave. Las vasculitis es un grupo variado de enfermedades que comprometen vasos de pequeño mediano y gran calibre y que pueden tener afectación fundamentalmente cutánea, respiratoria y renal y en dependencia de ello será su comportamiento y conducta. Además de mencionar las enfermedades más frecuente y conocidas de este grupo existen tambien las hereditarias: osteogénesis imperfecta, síndrome de Marfán, síndrome de Ehlers-Danlos entre otros. El tratamiento de las enfermedades del tejido conectivo ha cambiado con el advenimiento de las terapias biológicas modificadoras de la enfermedad en Reumatología. Las primeras fueron los antifactores de necrosis tumoral (TNF), en los que se incluyen el infliximab, adalimumab y etanercept. No solo cambiaron la eficacia, sino los objetivos de tratamiento. Se logró la remisión o la actividad más baja posible de la enfermedad y se evitó el deterioro articular, la disminución de la capacidad funcional y de la calidad de vida. Estas terapias además han permitido mejorar el manejo de los medicamentos tradicionales modificadores de la enfermedad como el metotrexate y la sulfasalacina, entre otros. La obtención de dichos medicamentos fue precedida por un mayor conocimiento de la patogenia de las ETC sobre todo en el campo de la genética, epigenética, y por la identificación de múltiples citocinas, moléculas de adhesión que participan en los procesos inflamatorios. No solo aparecieron los anticuerpos monoclonales anti TNF, existen otros con un amplio uso en estas enfermedades como los inhibidores de la interleucina 1 (Anakinra), Interleucina 6 (Tocilizumab), anti CD20 (Rituximab) entre otros. También han aparecido diferentes moléculas que pueden ser administrados por vía oral, los inhibidores de las kinasas los cuales bloquean procesos de señalización de la patogenia de la AR, son la familia de los inhibidores del JAK, el más identificado es el Tofanitinib. Tener más opciones de tratamiento facilita disponer de biomarcadores para diagnóstico temprano, establecer pronóstico e identificar el más eficaz. Estos biomarcadores dan las herramientas para el tratamiento personalizado. Actualmente algunos son utilizados como parte de la clasificación de los pacientes con artritis, por ejemplo el factor reumatoideo IgM anticuerpos contra proteína citrulinada, proteína C reactiva y el antígeno leucocitario humano B27 aun muy pocos en la práctica diaria. Los próximos años brindarán un mayor conocimiento y surgirán nuevos medicamentos, por lo que será necesario la aplicación de la medicina personalizada en la toma de decisiones más acertadas(AU)

Epidemiology and Survival of Systemic Sclerosis-Systemic Lupus Erythematosus Overlap Syndrome.

OBJECTIVE: Systemic sclerosis (SSc) may overlap with systemic lupus erythematous (SLE). Little is known about the epidemiology, clinical characteristics, and survival of SSc-SLE overlap. We evaluated the prevalence of SSc-SLE overlap and differences in SSc characteristics, and compared survival with SSc without SLE. METHODS: A cohort study was conducted including subjects who fulfilled the American College of Rheumatology (ACR)/European League Against Rheumatism classification criteria for SSc and/or the ACR criteria for SLE. The primary outcome was time from diagnosis to all-cause mortality. Survival was evaluated using Kaplan-Meier and Cox proportional hazard models. RESULTS: We identified 1252 subjects (SSc: n = 1166, SSc-SLE: n = 86) with an SSc-SLE prevalence of 6.8%. Those with SSc-SLE were younger at diagnosis (37.9 yrs vs 47.9 yrs, p < 0.001), more frequently East Asian (5.5% vs 20%) or South Asian (5.1% vs 12%), had lupus anticoagulant (6% vs 0.3%, p < 0.001), anticardiolipin antibody (6% vs 0.9%, p < 0.001), and pulmonary arterial hypertension (PAH; 52% vs 31%, p < 0.001). Those with SSc-SLE less frequently had calcinosis (13% vs 27%, p = 0.007), telangiectasia (49% vs 75%, p < 0.001), and diffuse subtype (12% vs 35%, p < 0.001). There were no significant differences in the occurrence of renal crisis (7% vs 7%), interstitial lung disease (ILD; 41% vs 34%), and digital ulcers (38% vs 32%). Those with SSc-SLE had better median survival time (26.1 vs 22.4 yrs), but this was not statistically significant (log-rank p = 0.06). Female sex and diffuse subtype attenuated survival differences between groups (HR 1.07, 95% CI 0.67-1.67). CONCLUSION: Patients with SSc-SLE are younger at diagnosis, more frequently have PAH, and less frequently have cutaneous manifestations of SSc. They should be monitored for ILD, renal crisis, and digital ulcers.

Prevalence of overlap syndrome in chronic obstructive pulmonary disease patients without sleep apnea symptoms.

BACKGROUND: The co-existence of chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) is a common phenomenon referred to as overlap syndrome (OS). In this study, we evaluated the prevalence of OS in mild hypoxemic COPD patients without OSA symptoms and compared characteristics of OS and COPD patients. METHODS: Forty-five COPD patients (mean FEV1 1671.3 ± 532.0 mL) with mild hypoxemia presenting no sleep apnea symptoms (96% men, mean age 67.7 ± 8.5 years) were involved in this study. Clinical characteristics were recorded, biochemical analysis and polygraphy were performed. RESULTS: Twenty-six patients with a RDI of ≥15 events/h were defined as OS (58%). When OS (n = 26) and COPD without OSA (n = 19) groups were compared, BMI (29.6 ± 6.6 vs 25.6 ± 4.9 kg/m2 ; P = 0.03), TNF-α level (24.8 ± 8.1 vs 3.6 ± 0.8 ng/mL; P = 0.03) and sleep time with SpO2 < 90% (23.9 ± 29.4 vs 9.7 ± 21.9%; P = 0.02) were significantly increased in OS. Univariate analysis showed a correlation between RDI and BMI (P < 0.01), Epworth score (P = 0.050), COPD exacerbation frequency (P = 0.046) and TNF-α (P = 0.048). However, multivariate linear regression analysis revealed a significant correlation only between RDI and BMI (P < 0.01). BMI as a predictor of OSA was examined through ROC curve analysis and the area under curve was 0.691 (P = 0.03). To identify OS patients, BMI > 27.2 kg/m2 had a sensitivity of 73% and specificity of 68%. CONCLUSIONS: This findings support that high prevalence (58%) of OS in COPD patients without OSA symptoms is related to BMI. Therefore, sleep study should be considered in especially overweight or obese COPD patients, even in those without sleep apnea symptoms.

Undifferentiated connective tissue diseases and adverse pregnancy outcomes. An undervalued association?

Undifferentiated connective tissue diseases (UCTDs) are a heterogeneous group of disorders characterized by symptoms and signs suggestive of systemic autoimmune rheumatic disease (ARD), but which do not fulfill all the established criteria for definite diagnosis of a condition. Although a third of UCTDs can progress to a definite ARD within months or years, most UCTDs can remain stable for years with minimal disease activity. The annual incidence of UCTD in the general population ranges from 14 to 140 per 100 000 people. UCTDs are associated with the persistence of several circulating autoantibodies including antinuclear, antiphospholipid or antithyroid antibodies. Immunological evaluation of subjects with UCTDs suggests a proinflammatory state and dysregulation of the Th1/Th2 balance. Autoantibodies have well-known deleterious effects on placentation and have been associated with an increased risk of prematurity, fetal growth restriction (FGR), preeclampsia, and congenital atrioventricular heart block. Although epidemiological and biological data suggest a potential negative impact on reproductive outcomes, the relationship between UCTD and pregnancy outcomes has not been adequately studied. While awaiting definitive data from large studies, obstetricians should be aware that rheumatic disorders in their early, incomplete, or undifferentiated phases can adversely affect pregnancy outcomes, increasing the likelihood of pregnancy loss, FGR, preeclampsia, and prematurity.

Undifferentiated connective tissue disease, fibromyalgia and the environmental factors.

PURPOSE OF REVIEW: The aim of this study was to discuss the role of environmental factors in the induction and perpetuation of autoimmunity, with particular focus on undifferentiated connective tissue disease (UCTD) and fibromyalgia. These two entities may share undefined clinical and laboratory features and recognize environmental exposures as triggering factors. From this particular point of view, both UCTD and fibromyalgia may resemble the picture of the 'Autoimmune/Inflammatory Syndrome Induced by Adjuvants' (ASIA). RECENT FINDINGS: A case-control study on environmental exposures showed that patients with UCTD were significantly more exposed to several adjuvants (vaccines, metal implants, proximity to metal factories and foundries) than age and sex-matched healthy controls. UCTD exposed to major ASIA triggers (vaccines, silicone) displayed typical features of ASIA (general weakness, chronic fatigue, irritable bowel syndrome) in the context of a predisposing genetic background (familiarity for autoimmunity). SUMMARY: The induction and perpetuation of autoimmunity is a complex process that requires the interaction between the individual genetic background and the environment. Environmental factors are gaining increasing attention since the description of ASIA, a syndrome that includes symptoms typically seen in patients with fibromyalgia and UCTD. A recent case-control study focusing on environmental exposures suggested that nearly half of patients with UCTD may fall within the ASIA spectrum.