Undifferentiated Connective Tissue Disease: Comprehensive Review.

PURPOSE OF REVIEW: Undifferentiated connective tissue disease (UCTD) is characterized by the presence of clinical symptoms of a systemic autoimmune disease in addition to laboratory evidence of autoimmunity with the patients not fulfilling any of the widely used classification criteria for classic autoimmune diseases. The presence of UCTD as a separate entity versus an early stage of such diseases as systemic lupus erythematosus (SLE) or scleroderma has long been debated. Given the uncertainty regarding this condition, we performed a systematic review on the topic. RECENT FINDINGS: UCTD can be subcategorized as evolving (eUCTD) or stable UCTD (sUCTD) based on its evolution towards a definable autoimmune syndrome. Analyzing the data from six UCTD cohorts published in the literature, we found that 28% of patients have an evolving course with the majority developing SLE or rheumatoid arthritis within 5-6 years of the UCTD diagnosis. From the remaining patients, 18% do achieve remission. Published treatment regimens were similar to other mild autoimmune diseases with low-dose prednisone, hydroxychloroquine, and NSAID. One-third of patients did need immune suppressive medications. Importantly, the reported outcomes were excellent with survival rates of more than 90% over 10 years. It has to be noted though that as data on patient related outcomes are not available to date, the exact impact of this condition on quality of life is unclear. UCTD is a mild autoimmune condition with generally good outcomes. There is still great uncertainty though regarding diagnosis and management. Going forward, consistent classification criteria are needed to advance UCTD research and eventually provide authoritative guidance on the management of the condition.

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.

Inhaled Glucocorticoid with or without Tiotropium Bromide for Asthma-Chronic Obstructive Pulmonary Disease Overlap Syndrome.

OBJECTIVE: To compare the efficacy of inhaled glucocorticoid with or without tiotropium bromide in the treatment of patients with asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS). STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: Department of Respiratory Medicine, Wuwei People's Hospital, Gansu Province, China, from October 2016 to October 2017. METHODOLOGY: A total of 86 ACOS patients were randomly divided into the control group and the observation group, with 43 cases in each group. Control group was given inhaled glucocorticoid. Observation group was treated with tiotropium bromide on the basis of the control group. The asthma control test (ACT) score, chronic obstructive pulmonary disease assessment test (CAT) score, serum high-sensitivity C-reactive protein (hs-CRP) and IL-6 levels were compared. RESULTS: Before treatment, there was no significant difference in ACT score, CAT score, serum hs-CRP and IL-6 levels between the two groups (p=0.808, 0.612, 0.872 and 0.921, respectively). After treatment, ACT score in observation group was higher than that in control group (p <0.001). CAT score, serum hs-CRP, and IL-6 levels in observation group were lower than those in control group (all p <0.001). The incidence of adverse reactions was lower in observation group than that in control group (p=0.033). CONCLUSION: Compared with inhaled glucocorticoid, inhaled glucocorticoid combined with tiotropium bromide treatment can more effectively reduce the serum levels of hs-CRP and IL-6 and is beneficial to control the development of ACOS.

Dystrophic calcinosis in a patient with overlap syndrome (scleroderma and rheumatoid arthritis) treated by leflunomide: A case report.

RATIONALE: Dystrophic calcinosis occurs in chronically damaged tissue in patients with complicated autoimmune diseases. The therapeutic options are limited, and the treatment response rate is variable. Here, we describe a rare case of dystrophic calcinosis treated with leflunomide in a patient with overlap syndrome. PATIENT CONCERNS: A 53-year-old woman who was diagnosed with overlaps syndrome (systemic sclerosis [SSc] with rheumatoid arthritis [RA]), presented to our hospital with pain and swelling in both wrists, and underwent radiography, bone scan, and biopsy examination. DIAGNOSES: This patient was diagnosed with dystrophic calcinosis in overlaps syndrome. INTERVENTIONS: The conventional disease-modifying drugs were not effective. Hence, leflunomide was administered. OUTCOMES: Simple radiography and bone scan showed resolved mass-like dystrophic calcinosis on both wrists of the patient after the use of leflunomide. LESSONS: The control of underlying disease is important in the treatment of dystrophic calcinosis. The use of leflunomide maybe an option in treatment of dystrophic calcinosis combined with RA.

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)

Efficacy and Safety of Immunosuppressive Therapy for PBC-AIH Overlap Syndrome Accompanied by Decompensated Cirrhosis: A Real-World Study.

Aim: To explore the efficacy and safety of immunosuppressive therapy for the treatment of primary biliary cirrhosis-autoimmune hepatitis (PBC-AIH) overlap syndrome accompanied by decompensated cirrhosis. Methods: A cohort study was performed to evaluate the usefulness of immunosuppressive therapy in this unique group. This cohort study was performed between October 2013 and June 2017 and included 28 biopsy-proven patients diagnosed according to the Paris criteria. The therapies included ursodeoxycholic acid (UDCA) alone (N=14) or in combination with immunosuppression (IS) therapy (N=14). The primary endpoints were biochemical remission, liver-related adverse events, transplant-free survival, and drug side-effects. Results: The frequency of biochemical remission for the AIH features was significantly higher in the UDCA+IS group than in the UDCA-only group (60.0 versus 9.1%, P=0.024) after 12 months of therapy but not after 3 and 6 months (28.6 versus 0%, P=0.165; 35.7 versus 7.1%, P=0.098). The rates of liver-related adverse events were lower in the combined group (2/14 versus 9/14, P=0.018). The Kaplan-Meier estimate showed that the transplant-free survival was distinct between the two groups (P=0.019). In the UDCA+IS group, mild and transient leukopenia occurred in two patients receiving azathioprine (AZA), and an infection was observed in one patient receiving mycophenolate mofetil (MMF). Conclusions: PBC-AIH patients with decompensated cirrhosis receiving a combination of UDCA and immunosuppressors presented with higher biochemical remission rates and experienced fewer liver-related adverse events, implying that the combined treatment might be a better therapeutic option for strictly defined decompensated PBC-AIH overlap syndrome.

Systemic sclerosis-rheumatoid arthritis overlap syndrome complicated with Sweet's syndrome.

Herein, we report a case of a 34-year-old woman with systemic sclerosis (SSc)-rheumatoid arthritis (RA) overlap syndrome (OS) complicated with Sweet's syndrome. OS has been defined as entities satisfying classification criteria of at least two connective tissue diseases (CTD) occurring at the same or at different times in the same patient. The CTD include RA, SSc, systemic lupus erythematosus (SLE), polymyositis, and dermatomyositis. Sweet's syndrome also known as acute febrile neutrophilic dermatosis was first described by Robert Sweet in 1964. Sweet's syndrome is characterized by fever, neutrophilia, erythematous skin lesions, and a diffuse dermal infiltrate of mature neutrophils. There are sets of associations that we will discuss in this article between OS and Sweet's syndrome.

Primary cutaneous amyloidosis associated with autoimmune hepatitis-primary biliary cirrhosis overlap syndrome and Sjögren syndrome: A case report.

RATIONALE: Primary cutaneous amyloidosis (PCA) is a localized skin disorder characterized by the abnormal deposition of amyloid in the extracellular matrix of the dermis. The association between PCA and other diseases, although rare, has been documented for various autoimmune diseases. PCA associated with autoimmune hepatitis-primary biliary cirrhosis (AIH-PBC) overlap syndrome and Sjögren syndrome (SS) has not been previously reported in the literature. PATIENT CONCERNS: A 50-year-old woman presented with progressive abnormal liver enzyme levels and was referred to our department. DIAGNOSES: Due to the patient's symptoms, laboratory test results, radiographic findings, and pathologic results, she was diagnosed with PCA associated with AIH-PBC overlap syndrome and SS. INTERVENTIONS: She was subsequently treated with a combination of ursodeoxycholic acid (UDCA), prednisone, and azathioprine. OUTCOMES: While this treatment can achieve therapeutic success, it cannot prevent complications from cirrhosis. This patient remains alive but experienced an emergent gastrointestinal hemorrhage. LESSONS: While we acknowledge that this is a single case, these findings extend our knowledge of immunological diseases associated with PCA and suggest a common, immune-mediated pathogenic pathway between PCA, AIH-PBC overlap syndrome, and SS. After 12 years of follow up, clinical manifestations have developed, and these autoimmune diseases have progressed. The combination of UDCA, prednisone, and azathioprine can achieve therapeutic success but cannot prevent disease progression. Routine follow up for this patient is necessary to document disease progression.

Severe Stevens-Johnson syndrome/toxic epidermal necrolysis overlap syndrome-beyond skin involvement.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but serious dermatologic diseases with many potential multisystem complications. We describe the case of an 8-year-old girl who developed severe SJS/TEN overlap syndrome (25% of her body surface area was affected) complicated by pancreatitis and bronchiolitis obliterans. These rare complications emphasize the need for careful, intensive monitoring of possible complications and an interdisciplinary team approach to provide optimal treatment and follow-up.

Pulmonary Aspergillus Overlap Syndromes.

BACKGROUND: Broadly, there are three main categories in pulmonary aspergillosis: chronic forms of aspergillosis; allergic bronchopulmonary aspergillosis; and invasive aspergillosis (IPA). IPA has been further subdivided into angioinvasive and airway-invasive aspergillosis. Aspergillus overlap syndromes is defined as the occurrence of more than one form aspergillus disease in a single individual. OBJECTIVES: To help clinicians correctly deal with AOS. METHODS: Retrospectively study the clinical findings of nine patients presenting with AOS. RESULTS: Four cases were diagnosed as angioinvasive aspergillosis complicated with ABPA, three cases as IPA overlap aspergilloma, and two cases as ABPA with AWIA. All the patients presented with cough and expectoration. In three patients with IPA overlap aspergilloma, two had hemoptysis, two had wheezing and fever. All of patients with IPA overlap ABPA had wheezing, dyspnea, and fever, three had sputum plugs, two had hemoptysis, and five patients had mucopurulent discharge and rhonchi in auscultation. Their total IgE ranged from 129 to 2124 IU/ml (676.5 ± 557.33 IU/ml). Fungal culture in sputum showed A. Fumigatus in three patients. All the six patients with IPA overlap ABPA applied steroid therapy and antifungal therapy. Three of them received two or more antifungal drugs successively, and three received combinational therapy. All the patients improved except one diagnosed ABPA overlap IPA. CONCLUSIONS: Clinical manifestation of AOS is not typical. Poor first-line therapeutic effects and complicated diagnosis criteria require clinicians to be aware of AOS when facing patients with aspergillosis.

Anterior ST-elevation myocardial infarction induced by rituximab infusion: A case report and review of the literature.

WHAT IS KNOWN AND OBJECTIVES: Rituximab is a chimeric monoclonal anti-CD20 antibody approved for the treatment of some lymphoid malignancies as well as for autoimmune diseases including rheumatoid arthritis (RA), idiopathic thrombocytopenic purpura (ITP) and vasculitis. Generally, rituximab is well tolerated; nevertheless, some patients develop adverse effects including infusion reactions. Albeit rare, these reactions may in some cases be life-threatening conditions. Rituximab cardiovascular side effects include more common effects such as hypertension, oedema and rare cases of arrhythmias and myocardial infarction. CASE SUMMARY: In this article, we report a case of a 58-year-old man with a history of overlap syndrome including RA and limited scleroderma who was treated with rituximab and developed a dramatic ST-elevation myocardial infarction (STEMI) during the drug administration. WHAT IS NEW AND CONCLUSION: This report underlines previous published reports emphasizing the awareness of such an association. This communication also warrants the importance of screening for ischaemic heart disease in selected cases of patients treated with rituximab.