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Abstract Although the terms “rare diseases” (RD) and “orphan diseases” (OD) are often used interchangeably, specific nuances in definitions should be noted to avoid misconception. RD are characterized by a low prevalence within the population, whereas OD are those inadequately recognized or even neglected by the medical community and drug companies. Despite their rarity, as our ability on discovering novel clinical phenotypes and improving diagnostic tools expand, RD will continue posing a real challenge for rheumatologists. Over the last decade, there has been a growing interest on elucidating mechanisms of rare autoimmune and autoinflammatory rheumatic diseases, allowing a better understanding of the role played by immune dysregulation on granulomatous, histiocytic, and hypereosinophilic disorders, just to name a few. This initiative enabled the rise of innovative targeted therapies for rheumatic RD. In this review, we explore the state-of-the art of rare RD and the critical role played by rheumatologists in healthcare. We also describe the challenges rheumatologists may face in the coming decades.

Abstract Introduction The deficiency of ADA2 (DADA2) is a rare autoinflammatory disease provoked by mutations in the ADA2 gene inherited in a recessive fashion. Up to this moment there is no consensus for the treatment of DADA2 and anti-TNF is the therapy of choice for chronic management whereas bone marrow transplantation is considered for refractory or severe phenotypes. Data from Brazil is scarce and this multicentric study reports 18 patients with DADA2 from Brazil. Patients and methods This is a multicentric study proposed by the Center for Rare and Immunological Disorders of the Hospital 9 de Julho - DASA, São Paulo - Brazil. Patients of any age with a confirmed diagnosis of DADA2 were eligible for this project and data on clinical, laboratory, genetics and treatment were collected. Results Eighteen patients from 10 different centers are reported here. All patients had disease onset at the pediatric age (median of 5 years) and most of them from the state of São Paulo. Vasculopathy with recurrent stroke was the most common phenotype but atypical phenotypes compatible with ALPS-like and Common Variable Immunodeficiency (CVID) was also found. All patients carried pathogenic mutations in the ADA2 gene. Acute management of vasculitis was not satisfactory with steroids in many patients and all those who used anti-TNF had favorable responses. Conclusion The low number of patients diagnosed with DADA2 in Brazil reinforces the need for disease awareness for this condition. Moreover, the absence of guidelines for diagnosis and management is also necessary (t).

Abstract Background Fabry disease (FD) is an X-linked lysosomal disorder due to mutations in the GLA gene resulting in defective enzyme alpha-galactosidase A. FD patients are frequently misdiagnosed, commonly for rheumatic diseases. Determining pathogenicity of a mutation depends of in silico predictions but mostly on available clinical information and interpretation may change in light of evolving knowledge. Similar signs and symptoms in carriers of GLA gene genetic variants of unknown significance or of benign variants may hamper diagnosis. This study reviews rheumatic and immune-mediated manifestations in a cohort of Brazilian FD patients with classic mutations and also in subjects with GLA gene A143T and R118C mutations. Misdiagnoses, time to correct diagnosis or determination of GLA gene status, time to treatment initiation and reasons for treatment prescription in A143T and R118C subjects are reviewed. Methods Genotype confirmed classic FD patients (n = 37) and subjects with GLA gene mutations A143T and R118C (n = 19) were referred for assessment. Subjects with R118C and A143T mutations had been previously identified during screening procedures at hemodialysis units. All patients were interviewed and examined by a rheumatologist with previous knowledge of disease and/or mutation status. A structured tool developed by the authors was used to cover all aspects of FD and of common rheumatic conditions. All available laboratory and imaging data were reviewed. Results Thirty-seven consecutive FD patients were interviewed – 16 male / 21 female (mean age: 43.1 years) and 19 consecutive subjects with GLA gene mutations R118C and A143T were evaluated – 8 male / 11 female (mean age: 39.6 years); 15 [R118C] / 4 [A143T]. Misdiagnosis in FD patients occurred in 11 males (68.8%) and 13 females (61.9%) of which 10 males and 9 females were previously diagnosed with one or more rheumatic conditions, most frequently rheumatic fever or “rheumatism” (unspecified rheumatic disorder). Median time for diagnosis after symptom onset was 16 years (range, 0–52 years). Twenty-two patients were treated with enzyme replacement therapy (ERT) – 13 male and 9 female. Median time to ERT initiation after FD diagnosis was 0.5 years (range, 0–15 years). Rheumatic manifestations occurred in 68.4% of R118C and A143T subjects. Two subjects had been prescribed ERT because of renal disease [R118C] and neuropsychiatric symptoms [A143T]. Conclusion Misdiagnoses occurred in 64.8% of FD patients, most frequently for rheumatic conditions. Median time for correct diagnosis was 16 years. Rheumatic manifestations are also frequent in subjects with GLA gene R118C and A143T mutations. These results reinforce the need to raise awareness and increase knowledge about Fabry disease among physicians, notably rheumatologists, who definitely have a role in identifying patients and determining disease burden. Decision to start treatment should consider expert opinion and follow local guidelines.

OBJECTIVES: Fabry disease (FD) is an X-linked lysosomal disease caused by variants of the GLA gene; the formation of defective alpha-galactosidase A contributes to the accumulation of substrates in several organs. Chronic inflammation is thought to contribute to organ damage in FD patients. METHODS: In total, 36 classic FD patients (15 men/21 women) and 25 healthy controls (20 men/8 women) were assessed. The Mainz Severity Score Index (MSSI) was established after conducting interviews with the patients and chart review. Serum IL-6, IL-1β, and TNF-α levels were evaluated in both groups. RESULTS: The mean age (years) for FD patients was 43.1±15.4 and that for the controls was 47.4±12.2 (p>0.05). Twenty-two patients (59.5%) were treated with enzyme replacement therapy (ERT). Serum IL-6 and TNF-α levels were significantly higher in FD patients than in the controls. Patients treated with ERT had higher serum IL-6 and TNF-α levels than those not treated with ERT. There was no difference in the serum IL-1β levels between patients treated with ERT and those who were not. The MSSI scores in the patients were correlated with serum levels of IL-6 (r=0.60, p

Abstract Background Fabry disease (FD) is caused by pathogenic variants in the GLA gene. A143T and R118C variants are considered not disease causing. Patient-reported outcomes provide information concerning the effects of their disease but should be carefully analyzed in rare diseases. Objectives To evaluate pain, depression, sleep disturbances, disability and quality of life in A143T or R118C Brazilian subjects and compare to data published for classic FD patients. Methods Nineteen subjects - 8:11 male:female - were evaluated and answered the questionnaires: Brief Pain Inventory (BPI), Hamilton Depression Rating Scale, Pittsburgh Sleep Quality Index, Health Assessment Questionnaire Disability Index (HAQ-DI), Short-Form Health Survey 36 (SF-36). Lyso-Gb3 and residual enzyme activity were obtained. Results Alpha-galactosidase A activity was low in males. Lyso-Gb3 levels were normal in all subjects. Comparing A143T/R118C subjects and FD patients, BPI severity, BPI interference, HAQ-DI values were not different (p>0.05) whereas raw scores for physical functioning (p=0.01) and general health perception (p

Background: Fabry disease (FD) is a lysosomal disease in which mutations affect the GLA gene located on the X chromosome. The defective product, the enzyme alpha-galactosidase A, causes accumulation of substrate and contributes to the disruption of cell function in several organs, with variable severity and consequent damage of tissue or organ function. Patient reported outcomes (PROs) enable patients to provide information regarding the consequences of their disease and its treatment and are often recognized as the most important outcomes for them.Objectives: To evaluate pain, depression, sleep disturbances, disability and disease impact on quality of life in a cohort of Brazilian FD patients and compare between groups stratified by the Mainz Symptom Severity Index (MSSI) Methods: Thirty-seven genotype confirmed classic FD patients – 16 male and 21 female – (mutations: C142R, A156D, L180F, R227X, W262X, G271A, P293S, Y264SX) were evaluated and answered the following questionnaires: Brief Pain Inventory (BPI), Hamilton Depression Rating Scale (HAM-D), Pittsburgh Sleep Quality Index (PSQI), Health Assessment Questionnaire Disability Index (HAQ-DI), Short-Form Health Survey 36 (SF-36).Results: In FD patients, mean ± SD BPI severity result was 2.78 ± 2.66 for severe; 2.80 ± 2.55 for moderate and 1.55 ± 2.38 for mild severity patients. Mean ± SD BPI interference result was 2.55 ± 2.44 for severe; 2.80 ± 3.18 for moderate and 1.36 ± 2.83 for mild patients. BPI severity and interference values correlated with MSSI scores (r = 0.24; p

A borreliose humana brasileira, também conhecida como Síndrome de Baggio-Yoshinari (SBY), é uma enfermidade infecciosa própria do território brasileiro, transmitida por carrapatos não pertencentes ao complexo Ixodes ricinus, causada por espiroqueta do gênero Borrelia e que apresenta semelhanças clínicas e laboratoriais com a Doença de Lyme (DL). A SBY distingue-se da DL por apresentar evolução clínica prolongada, com episódios de recorrência e importante disfunção autoimune. Descreveremos o caso de uma paciente jovem, que desenvolveu progressivamente durante cerca de um ano oligoartrite de grandes articulações, seguida de distúrbio do cognitivo, meningoencefalite e eritema nodoso. O diagnóstico foi firmado devido à concomitância de queixas articulares e neurológicas com sorologia positiva para Borrelia burgdorferi sensu stricto. A paciente foi medicada com ceftriaxone 2 g/EV/dia por 30 dias, seguido de dois meses de doxiciclina 100 mg duas vezes ao dia. Houve remissão dos sintomas e normalização dos exames sorológicos para a borreliose. A SBY é uma zoonose emergente descrita apenas no Brasil, cuja frequência tem crescido bastante, e que, em razão das importantes diferenças nos aspectos epidemiológicos, clínicos e laboratoriais em relação à DL, merece especial atenção da classe médica do país. Trata-se de zoonose camuflada e de difícil diagnóstico, mas este deve ser perseguido com tenacidade, pois a enfermidade responde aos antibióticos no estágio inicial, podendo evoluir com sequelas neurológicas e articulares nos casos reconhecidos tardiamente ou recorrentes.

A dermatomiosite juvenil (DMJ) é uma doença autoimune caracterizada por vasculopatia sistêmica. Manifestações principais da DMJ incluem fraqueza muscular proximal simétrica, elevação de enzimas musculares séricas e lesões cutâneas, dentre as quais o heliotropo e as pápulas de Gottron são patognomônicas. Reconhecimento precoce e instituição rápida de terapia adequada permitem melhorar o prognóstico da doença e evitar o aparecimento de calcinose. Embora a base do tratamento seja o glicocorticoide, os imunossupressores mais frequentemente associados são metotrexato, ciclosporina, azatioprina e ciclofosfamida, dependendo da gravidade da DMJ. Atualmente investiga-se a utilidade dos imunobiológicos nos casos refratários, mas os resultados são controversos ou pouco expressivos. Pretende-se neste artigo fazer uma revisão sobre DMJ, com ênfase em recentes atualizações na sua patogênese e tratamento.Juvenile dermatomyositis (JDM) is an autoimmune disease characterized by systemic vasculopathy. Its main manifestations include symmetrical proximal muscle weakness, elevated serum muscle enzymes and cutaneous lesions, among which the heliotrope and Gottron's papules are pathognomonic. Early recognition and prompt therapy allow better prognosis and prevent the development of calcinosis. Although the treatment is based on glucocorticoids, the more commonly associated immunosuppressors include methotrexate, azathioprine, cyclosporine, and cyclophosphamide, depending on the severity of disease. The use of immunobiologicals for refractory cases remains under investigation, but the results are controversial or inexpressive. In this review, we highlight recent updates on the pathogenesis and treatment of JDM.

A linfadenopatia no lúpus eritematoso sistêmico (LES) é um achado benigno encontrado comumente em jovens, com atividade cutânea e sintomas constitucionais, apresentando boa resposta à corticoterapia. O achado mais frequente à biópsia é a hiperplasia folicular reacional. Relatamos o caso de um paciente que, desde os 13 anos de idade, apresentava surtos recorrentes de linfadenopatia, acompanhados de hepatoesplenomegalia, febre e emagrecimento. Na evolução, apareceram artrite, hipertensão arterial, proteinúria, miocardiopatia e neuropatia periférica. Foi amplamente investigado sem esclarecimento diagnóstico e submetido a tratamento empírico de tuberculose. Somente após cinco anos de evolução firmou-se o diagnóstico de LES e recebeu tratamento específico. O diagnóstico precoce nestes casos é difícil, pois a investigação laboratorial pode ainda não demonstrar presença de autoanticorpos ou hipocomplementemia.Lymphadenopathy is a benign finding in systemic lupus erythematosus (SLE), commonly seen in young patients with cutaneous involvement and constitutional symptoms, with good response to corticosteroids. Reactive follicular hyperplasia is the most frequent finding in biopsies. We report the case of a patient with recurrent episodes of lymphadenopathy associated with hepatosplenomegaly, fever, and weight loss since the age of 13 years. The patient also developed arthritis, hypertension, proteinuria, cardiomyopathy, and peripheral neuropathy. His condition was investigated extensively without diagnostic clarification; he was treated, empirically, for tuberculosis. The patient received a diagnosis of SLE only five years after the original presentation and received the specific treatment. Early diagnosis in those cases is difficult because laboratorial exams may not show the presence of auto-antibodies and low complement levels.

Vasculites de órgão único, ou isoladas, já foram descritas em diversos órgãos e seu achado pode ser acidental. Relatamos um caso de vasculite granulomatosa necrosante isolada de colo uterino em uma paciente de meia-idade, previamente hígida, sexualmente ativa, e cuja pesquisa de DNA de papilomavírus humano (Human Papiloma Virus - HPV) por captura híbrida foi positiva. Não foi identificado comprometimento sistêmico e, como houve excisão completa da lesão, optou-se pelo acompanhamento clínico. Há poucos relatos, na literatura, de acometimento do trato genital feminino de forma isolada, alguns com presença simultânea de lesões que podem ser causadas pelo HPV, postulando-se uma associação patogênica.Single organ vasculitis (SOV), or isolated vasculitis, has been described in several organs and it can be an accidental finding. We report a case of isolated necrotizing granulomatous vasculitis of the uterine cervix in a middle-aged woman, previously healthy, and sexually active, and whose human papillomavirus (HPV) DNA hybrid capture assay was positive. Systemic involvement was not detected and, since the lesion was completely removed, we opted for a clinical follow-up. The literature has very few reports on the isolated involvement of the female genital tract, and some had concomitant lesions that could be caused by the HPV, indicati.

A inflamação, localizada ou sistêmica, é uma das características de doenças reumatológicas. A resposta a uma lesão tecidual desencadeia uma série de modificações que promovem eliminação de patógenos, limitação do dano tecidual e restauração da estrutura lesada. Essas modificações dependem do aumento ou da diminuição da concentração sérica de proteínas, conhecidas como biomarcadores inflamatórios, que atuam na resposta inflamatória. A análise laboratorial desses marcadores permite, juntamente com os dados clínicos e outros exames complementares, acessar a atividade de algumas doenças e monitorar a resposta à terapêutica, assim como pode sugerir presença de infecção. Atualmente, o reumatologista tem à sua disposição algumas opções de exames que avaliam a resposta inflamatória, como a proteína C-reativa, a velocidade de hemossedimentação e a eletroforese de proteínas, entre outros. Este artigo revisa as características de alguns desses biomarcadores e o emprego das provas de atividade inflamatória em doenças reumatológicas.Inflammation is the hallmark of rheumatic diseases. Tissue injury response promotes several modifications, which result in elimination of the offending agent, limitation of tissue damage, and restoration of affected structures. Such modifications depend on the increase or decrease of the serum concentration of certain proteins known as inflammatory biomarkers. Laboratory analysis of these markers assists in monitoring disease activity and treatment response. Rheumatologists have available methods that evaluate inflammatory reaction such as C-reactive protein, erythrocyte sedimentation rate, and protein electrophoresis, among others. In this paper, we review some of those biomarkers and their use in rheumatic diseases.

Fabry disease (FD) is an inborn error of metabolism characterized by deficient/absent activity of lysosomal enzyme alpha-galactosidase A, which results in systemic accumulation of glycosphingolipids and progression to renal failure, heart and cerebrovascular disease, and small-fiber peripheral neuropathy. This article describes a Brazilian family affected by FD caused by a novel mutation in exon 6 of the alpha-galactosidase A ( GLA ) gene (c.812G>C). Signs and symptoms identified were pain crisis, acroparesthesia, hypohidrosis, abdominal cramps and diarrhea, chronic kidney disease, cornea verticillata, left ventricular hypertrophy, and complete heart block. Headache was a common complaint and 1 of the patients presented with aseptic meningitis. The novel missense mutation in the GLA gene identified in this Brazilian family is consistent with the classic FD phenotype.

Abstract Amyloidosis is a localized or systemic disease caused by deposition of proteins in the extracellular space of various organs and tissues. As part of the disease, proteins that were originally soluble misfold and acquire a fibrillar conformation that renders them insoluble and resistant to proteolysis. Systemic amyloidosis is a rare, often underdiagnosed condition. In recent years, the incidence of newly diagnosed cases of amyloidosis has been increasing in association with the aging of the population and greater access to diagnostic tests. From a clinical perspective, systemic amyloidosis is frequently associated with involvement of the kidneys (causing nephrotic syndrome), heart (cardiac failure and arrhythmia), and peripheral nervous system (sensorimotor polyneuropathy and autonomic dysfunction). This condition is important to the rheumatologist for several reasons, such as its systemic involvement that mimics autoimmune rheumatic diseases, its musculoskeletal manifestations, which when recognized can allow the diagnosis of amyloidosis, and also because reactive or secondary AA amyloidosis is a complication of rheumatic inflammatory diseases. The treatment of amyloidosis depends on the type of amyloid protein involved. Early recognition of this rare disease is fundamental for improved clinical outcomes.

Abstract Advances in DNA sequencing technologies, especially next-generation sequencing (NGS), which is the basis for whole-exome sequencing (WES) and whole-genome sequencing (WGS), have profoundly transformed immune-mediated rheumatic disease diagnosis. Recently, substantial cost reductions have facilitated access to these diagnostic tools, expanded the capacity of molecular diagnostics and enabled the pursuit of precision medicine in rheumatology. Understanding the fundamental principles of genetics and diversity in genetic variant classification is a crucial milestone in rheumatology. However, despite the growing availability of DNA sequencing platforms, a significant number of autoinflammatory diseases (AIDs), neuromuscular disorders, hereditary collagen diseases, and monogenic bone diseases remain unsolved, and variants of uncertain significance (VUS) pose a formidable challenge to addressing these unmet needs in the coming decades. This article aims to provide an overview of the clinical indications and interpretation of comprehensive genetic testing in the medical field, addressing the related complexities and implications.

Abstract Sarcoidosis is a systemic inflammatory disease of unknown origin, which consists of the formation of multiple sterile noncaseating granulomas. Inhaled antigens are believed to initiate disease in prone individuals, considering that almost all patients present pulmonary or mediastinal lymph node disease. Extrapulmonary manifestations are common and diverse: practically any organ system can be affected, and treatment can range from simple watchful waiting to intense immunosuppression. In this article, we review current concepts about sarcoidosis in an overview, focusing on recognition and treatment of its major clinical phenotypes.

Abstract Hereditary connective tissue disorders include more than 200 conditions affecting different organs and tissues, compromising the biological role of the extracellular matrix through interference in the synthesis, development, or secretion of collagen and/or its associated proteins. The clinical phenotype includes multiple signs and symptoms, usually nonspecific but of interest to rheumatologists because of musculoskeletal involvement. The patient´s journey to diagnosis is long, and physicians should include these disorders in their differential diagnoses of diseases with systemic involvement. In this review, insights for the diagnosis and treatment of osteogenesis imperfecta, hypermobility spectrum disorder/Ehlers–Danlos syndrome, Marfan, Loeys–Dietz, and Stickler syndromes are presented.

Abstract Gaucher and Fabry diseases are lysosomal storage disorders in which deficient enzyme activity leads to pathological accumulation of sphingolipids. These diseases have a broad phenotypic presentation. Musculoskeletal symptoms and pain complaints are frequently reported by patients. Thus, rheumatologists can be contacted by these patients, contributing to the correct diagnosis, earlier indication of appropriate treatment and improvement of their prognosis. This review describes important concepts about Gaucher and Fabry diseases that rheumatologists should understand to improve patients’ quality of life and change the natural history of these diseases.

Tumor-induced osteomalacia is caused by excessive fibroblast growth factor 23 production mainly from phosphaturic mesenchymal tumors. Surgical excision or tumor ablation are the preferred treatment. Information on bone microarchitecture parameters assessed by high-resolution peripheral quantitative computed tomography is limited. We report a woman with hypophosphatemic osteomalacia with generalized pain, weakness and recurrent fractures, and a large thoracic vertebral mass extending to the posterior mediastinum. Detailed radiologic and histopathologic evaluation revealed a phosphaturic mesenchymal tumor. Two surgeries were necessary for complete removal of the mass. Clinical symptoms improved after attaining normophosphatemia. Four-year post-surgical HR-pQCT parameters, compared to baseline, showed in the left distal radius, stable trabecular and cortical volumetric bone mineral density although below reference range. There was stability of trabecular number and thickness. Both stiffness and failure load decreased. A shift in cortical parameters was noted in year 2. In the left distal tibia, trabecular volumetric bone mineral density decreased whereas cortical volumetric bone mineral density markedly increased, as did cortical area. There was stability in the trabecular number and thickness. Both stiffness and failure load improved. Findings from HR-pQCT measurements in this patient disclosed that the healing of osteomalacia is not similar across the peripheral skeletal sites in the first years following tumor removal. Results contrasted low but stable volumetric bone mineral density in the distal radius with increase in the distal tibia at the expense of cortical bone. Our report helps further delineate the pattern of bone healing after treatment of this rare bone disorder.