Lung Involvement in Systemic Juvenile Idiopathic Arthritis: A Narrative Review.

Systemic juvenile idiopathic arthritis associated with lung disorders (sJIA-LD) is a subtype of sJIA characterized by the presence of chronic life-threatening pulmonary disorders, such as pulmonary hypertension, interstitial lung disease, pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia, which were exceptionally rare before 2013. Clinically, these children show a striking dissociation between the relatively mild clinical manifestations (tachypnoea, clubbing and chronic cough) and the severity of the pulmonary inflammatory process. Our review describes sJIA-LD as having a reported prevalence of approximately 6.8%, with a mortality rate of between 37% and 68%. It is often associated with an early onset (<2 years of age), macrophage activation syndrome and high interleukin (IL)-18 circulating levels. Other risk factors may be trisomy 21 and a predisposition to adverse reactions to biological drugs. The most popular hypothesis is that the increase in the number of sJIA-LD cases can be attributed to the increased use of IL-1 and IL-6 blockers. Two possible explanations have been proposed, named the "DRESS hypothesis" and the "cytokine plasticity hypothesis". Lung ultrasounds and the intercellular-adhesion-molecule-5 assay seem to be promising tools for the early diagnosis of sJIA-LD, although high resolution computed tomography remains the gold standard. In this review, we also summarize the treatment options for sJIA-LD, focusing on JAK inhibitors.

Etoricoxib as a treatment of choice for patients with SLCO2A1 mutation exhibiting autosomal recessive primary hypertrophic osteoarthropathy: A case report.

We reported a 22-year-old Emirati male with autosomal recessive primary hypertrophic osteoarthropathy caused by a possibly pathogenic homozygous non-synonymous variant in the SLCO2A1 gene (NM_005630.3: c.289C>T, p. Arg97Cys) presenting with joint swelling, forehead furrowing, and significant clubbing in all fingers and toes. Currently, no standard treatments are approved for this disease; medical care is palliative and includes non-steroidal anti-inflammatory drugs, corticosteroids, tamoxifen, retinoids, and risedronate. Colchicine may be helpful for the pain due to subperiosteal new bone formation. Our patient was treated with etoricoxib 60 mg once daily and showed a significant clinical improvement at the 6-month mark that was reversed upon the withdrawal of this medication. This case report highlights the importance of placing etoricoxib among first-line therapy recommendations for cases with confirmed primary hypertrophic osteoarthropathy diagnosis. To the best of our knowledge, this is the only case of primary hypertrophic osteoarthropathy from the Middle Eastern population of Arab ethnicity that has responded to non-steroidal anti-inflammatory drug therapy.

Primary hypertrophic osteoarthropathy - a rare cause of pain and arthritis in children. Description of 5 cases.

Primary hypertrophic osteoarthropathy (PHOA) is a very rare disease. The typical triad of symptoms, i.e. digital clubbing, periosteal bone formation with bone and joint deformities and skin hypertrophy, may be accompanied by other specific conditions. In the majority of patients, the picture of the disease is incomplete. The dominant clinical symptom may be osteoarticular complaints. Moreover, the final confirmation of the diagnosis of the primary form of hypertrophic osteoarthropathy requires the analysis of much more frequent secondary causes of the disease. Diagnosing primary osteoarthropathy in children is particularly difficult. Some children report joint pain before the onset of the other symptoms of osteoarthropathy, while the physical and imaging examinations show features of arthritis. This can lead to misdiagnoses including the diagnosis of juvenile idiopathic arthritis (JIA) and the unnecessary use of immunosuppressive treatment. The present description of five patients from the Paediatric Rheumatology Department indicates diagnostic difficulties in children with PHOA. All of them were examined due to pain and features of arthritis. We observed an incomplete clinical picture of the disease. One patient required a revision of the previous diagnosis of JIA and discontinuation of ineffective treatment with disease-modifying antirheumatic drugs (DMARDs). PHOA should always be considered in the differential diagnosis of arthritis in children, due to the slow and often atypical development of symptoms, including the presence of pain and arthritis as the predominant symptom of the disease.

Surfactant Protein C Deficiency in a Puerto Rican Adolescent With a Rare SFTPC Genetic Variant.

Surfactant protein C (SP-C) is a hydrophobic lipoprotein necessary for lowering alveolar surface tension and lung defense mechanisms. Defects in its function due to genetic mutations in the SFTPC gene have been increasingly identified in patients presenting with childhood interstitial lung disease. SFTPC mutations are inherited in an autosomal dominant pattern with reduced penetration and variable expressivity, although de novo mutations have also been documented. In this article, we present the case of an oxygen-dependent 13-year-old male with interstitial lung disease and severe pulmonary hypertension. Genetic analysis and lung biopsy confirmed the diagnosis of SP-C deficiency with the rare heterozygous mutation IVS4+2. To our knowledge, this is the first documented case of SP-C deficiency in the Puerto Rican population and the second worldwide with the IVS4+2 genetic mutation.

Hypoxemia, high alveolar-arterial gradient, and bubbles in both sides of heart: A case of hepatopulmonary syndrome in the setting of COVID-19 pandemic.

In presence of tachypnea, digital clubbing and cyanosis in a patient with the hallmarks of chronic liver disease, hepatopulmonary syndrome should be suspected and investigated.

Clubbed Digits Presumably Caused by Lubiprostone.

Digital clubbing has been regarded as an important sign in medicine. A 33-year-old woman with no history of hepatic, pulmonary, or malignant disease was referred to our hospital. She had been taking lubiprostone every day for three years for constipation. Clubbing in her upper and lower limb digits began gradually about two years ago. The results of laboratory investigations were almost normal. We suspected the clubbed digits were a side effect of lubiprostone and confirmed that the levels of urinary prostaglandin E2 (PGE2), which can cause clubbed digits, were elevated. Thus, we instructed the woman to stop taking lubiprostone and monitored this lab value. However, the value continued to rise over 2 months to 41.9 µg/g Cr. During that time, she had been taking sennoside A B calcium instead of lubiprostone for constipation. Since sennoside A B calcium also has the effect of increasing PGE2, we ordered the discontinuation. Her urinary PGE2 to creatinine level normalized, and the clubbing improved after the discontinuation of these two medications.

Surgical lobectomy of pulmonary arteriovenous malformations in a patient with presentations regarded as sequela of tuberculosis: a case report.

BACKGROUND: Pulmonary arteriovenous malformations are uncommon conditions of abnormal communications between pulmonary arteries and veins, which are most commonly congenital in nature. Although such condition is not extremely rare, it is a challenge to the differential diagnosis of pulmonary problems such as hypoxemia and pulmonary lesions. CASE PRESENTATION: We report a meaningful case of a 23-year-old male presented with elevated hemoglobin (23.0 g/dl) on admission. Physical examination revealed cyanosis, digital clubbing and low oxygen saturation on room air. The patient was initially diagnosed as polycythemia vera while the subsequent result of bone marrow aspiration was negative. During further assessment, pulmonary arteriovenous malformations were detected by CT pulmonary angiography. Lobectomy was successfully performed with significant increase in oxygen saturation from 86 to 98%. The hemoglobin decreased to almost normal level of 14.9 g/dl 3 months after surgery and the patient had been followed up for nearly 5 years. CONCLUSIONS: Pulmonary arteriovenous malformations should be suspected in patients with central cyanosis, digital clubbing, polycythemia, pulmonary lesion and without cardiac malformations. Embolization or surgery is strongly recommended to reduce the risks caused by pulmonary arteriovenous malformations.

Hypertrophic osteoarthropathy.

Hypertrophic osteoarthropathy (HOA) is an orphan syndrome characterized by abnormal proliferation of the skin and osseous tissues at the distal parts of the extremities. The main clinical features are: a peculiar bulbous deformity of the tips of the digits conventionally described as "clubbing," periosteal proliferation of the tubular bones, and synovial effusions. In most instances, HOA develops a reaction to a severe internal illness, such as lung cancer, cyanotic heart disease, or liver cirrhosis. There is a subgroup of patients who do not have underlying pathology. Such cases are classified as having primary HOA. Digital clubbing is easy to recognize. Any patient with newly developed digital clubbing should undergo careful search for an underlying illness with special attention to intra-thoracic pathologies. Painful HOA is treated with non-steroidal anti-inflammatory medications. Vascular endothelial growth factor and prostaglandin E2 have been proposed as key bone proliferating mediators.

Pachydermoperiostosis: The value of molecular diagnosis.

BACKGROUND: Pachydermoperiostosis is a rare autosomal recessive genetic disorder characterized by the association of periostosis and pachydermia. To date, two genes involved in prostaglandin metabolism, HPGD and SLCO2A1, have been identified. PATIENTS AND METHODS: A 7-year-old girl presented digital clubbing of the hands and feet, curved nails, hyperhidrosis, and pachydermia, as well as eczema of the trunk and limbs. The diagnosis of pachydermoperiostosis was confirmed by the detection of a homozygous mutation in the HPGD gene. The second case concerned a 41-year-old male with acral and cephalic pachydermia (cutis verticis gyrata), and palmoplantar keratoderma. Bone X-rays showed changes in the distal ends of several bones. The diagnosis of pachydermoperiostosis was confirmed by the detection of a homozygous mutation in the SLCO2A1 gene. DISCUSSION: The genotype/phenotype correlation suggests that patients with SLCO2A1 mutations will develop the symptoms later in life, but that these will be more severe, with a greater likelihood of cutis verticis gyrata and joint involvement compared with patients presenting HPGD mutations. In addition, hereditary enteropathy has recently been described in patients with SLCO2A1 mutations, which could account for the gastrointestinal picture seen in the second patient. Finally, on account of cases involving myelofibrosis associated with mutations in the SLCO2A gene, these patients should have a hematologic follow-up. CONCLUSION: Given the genotype/phenotype correlations illustrated by these cases, it would appear useful to propose molecular diagnosis for patients presenting pachydermoperiostosis.

[Genetic analysis of a pedigree with primary hypertrophic osteoarthropathy].

Objective: To analyze the clinical and genetic features of primary hypertrophic osteoarthropathy (PHO). Methods: The clinical data of one Chinese pedigree of PHO, namely pachydermoperiostosis (PDP) were collected.Blood samples were drawn from the propositus and other family members.DNA was extracted and genetic analysis was performed by Sanger method after PCR.The sequencing data of HPGD gene exons were analyzed by alignment with sequences from National Center for Biotechnology Information (NCBI). Results: (1)The propositus represented symptoms in childhood including clubbing fingers, sweating, seborrhea, joint swelling and so on.Periosteal thickening and bone hyperplasia were found by X-ray. (2)The homozygous mutation named c. 310_311delCT in propositus, which located in the third exon of HPGD, was identified.His parents carried the same heterozygous mutation, while his sister did not inherit any mutation of this gene. (3)The prediction of spatial structure of proteins revealed that the mutant proteins had about 60% discrepancy compared with wild-type protein, losing a lot of motifs responsible for combining with coenzyms and prostaglandin E(2), as well as active sites of enzymes. Conclusions: The clinical manifestations and imaging findings are helpful to diagnose PDP. Moreover gene mutation analysis ensures the diagnosis.The structure and function of HPGD gene mutation induce 15-hydroxy prostaglandin dehydrogenase mutation, contributing to the occurrence of PDP.

Clubbing and hypertrophic osteoarthropathy: insights in diagnosis, pathophysiology, and clinical significance.

BACKGROUND: Digital clubbing and hypertrophic osteoarthropathy (HOA) form a diagnostic challenge. Subtle presentations of clubbing are often missed. The underlying pathophysiology remains unclear. Establishing a differential diagnosis based on nonspecific signs can be cumbersome. Finally, the prognostic value of clubbing and HOA remains unclear. OBJECTIVE: This article reviews clinical criteria and pathophysiology of clubbing and HOA. A diagnostic algorithm is proposed, based on etiology and current insights. The prognostic impact on associated diseases is discussed. METHODS: The Internet databases Medline and Embase were searched. Articles were selected based on relevance of abstract, article type and impact of the journal. RESULTS: Diagnostic criteria include Lovibond's profile sign, distal/interphalangeal depth ratio and Schamroth's sign. Three pathophysiological causes of clubbing can be distinguished: hypoxia, chronic inflammation and aberrant vascularization. A prominent role for vascular endothelial growth factor is suggested. Associated symptoms and clinical signs should guide the initial diagnostic evaluation. Finally, clubbing is a negative prognostic factor in certain pulmonary disorders, including cystic fibrosis.

Digital clubbing.

Digital clubbing is an ancient and important clinical signs in medicine. Although clubbed fingers are mostly asymptomatic, it often predicts the presence of some dreaded underlying diseases. Its exact pathogenesis is not known, but platelet-derived growth factor and vascular endothelial growth factor are recently incriminated in its causation. The association of digital clubbing with various disease processes and its clinical implications are discussed in this review.

Hipocratismo digital em pacientes com fístula arteriovenosa e insuficiência renal crônica

Introdução: A associação entre hipocratismo digital (HD) e doença subjacente é reconhecida desde a época de Hipócrates. A fistula arteriovenosa desperta significativo interesse, principalmente pelo fato de nesses casos a incidência de hipocratismo ser unilateral. Objetivos:Descrever a prevalência de hipocratismo digital em pacientes com insuficiência renal crônica e fístula arteriovenosa (FAV). Descrever as relações entre as variáveis sociodemográficas, clínicas e laboratoriais e a presença de HD. Métodos: Foi realizado um estudo transversal em90 indivíduos nefropatas crônicos, maiores de 18 anos, em hemodiálise por FAV na Clínica de Doenças Renais de Tubarão ? SC ? Ltda. Foram excluídos aqueles em uso de catéter venoso central, portadores de cardiopatia congênita, e os que se recusaram a participar do estudo.Com a utilização de um paquímetro, foi mensurada a espessura da falange distal e da articulação interfalangeana distal do dedo indicador, e a razão entre elas foi chamada de índice digital. Valores maiores ou iguais a 1foram considerados como presença de HD. Foram avaliadas as variáveis idade, gênero, grupo étnico, hábito tabágico, etiologia da insuficiência renal crônica, tempo de diálise, tempo de fístula, tempo de maturação da fístula, localização da fístula, velocidade do fluxo, freqüência semanal de diálise, cálcio, fósforo, potássio, hematócrito, hemoglobina, clereance fracional de uréia (Kt/V) e paratormônio. Resultados: A maioria das participantes eram homens (46,7%), caucasianos (87,8%), não tabagistas (60,7%), em hemodiálise há mais de um ano (80,5%), com FAVlocalizada no membro superior esquerdo (80%). A prevalência de HD foi de 30,3%. O gênero feminino apresentou uma prevalência de HD quase duas vezes maior comparada ao gênero masculino (RP= 1,97; IC 95%:1,02- 3,78; p 0,036). O Kt/V baixo/normal (<1,2) apresentousecomo um fator de proteção para HD, sendo cerca de 80% menor quando comparado aos pacientes com Kt/V ideal/elevado (>1,2) (RP = 0,23; IC 95%:0,06-0,89; p = 0,008). Conclusões: A prevalência de HD foi de 30,3%.A prevalência de HD unilateral na mão da FAV foi de 23,5%.

Introduction: The association between digital clubbing (DC) and subjacent diseases is recognized since the time of Hippocrates. One of the entities associated with DC that generates significant interest is arteriovenousfistula (AVF), especially because in these cases it is found to be unilateral.Objectives: To describe the prevalence of DC in patients with chronic renal failure and AVF. Describe the relationship between the socio-demographic, clinical, and laboratorial variables and HD. Methods: A cross sectional study was conducted with 90 patients, aged over 18 years, undergoing hemodialysis via AVF in the Kidney Disease Clinic of Tubarão, Santa Catarina. Patients with congenital heart disease, those in use of central venous catheter, and those who refused to participate in the study,were excluded. With the use of a caliper, the thickness of the distal phalange and the interphalange articulation of the index finger were measured; the ratio between them was established as the digital index. Values greater than or equal to 1 were considered as presence of HD.Variables including age, gender, ethnic group, smoking habit, etiology of the chronic renal failure, time of dialysis, time of fistula, time of fistula maturation, location of the fistula, flux velocity, weekly frequency of dialysis, Ca++, phosphorus, haematocrit, hemoglobin, Kt/V, PTH, and K+ were evaluated. Results: Most participants were men (46.7%), Caucasian (87.8%), non-smokers (60.7%), on hemodialysis for more than a year (80.5%), with arteriovenous fistula located on the left arm (80%). The prevalence of DC was 30.3%. Females showed a prevalence of HD almosttwo times higher compared to males (RP=1.97; CI 95%: 1.02-3.78; p = 0.036). The Kt/V low/normal (<1.2) revealed as a protective factor for HD, with about 80% lower when compared to patients with Kt/V ideal/high(>1.2) (RP = 0.23; CI 95%: 0.06?0.89; p = 0.008). Conclusion: Prevalence of DC was 30.3%. Prevalence of unilateral DC on the AVF hand was 23.5%.

The hepato-pulmonary-cutaneous syndrome: description of a case and suggestion of a unifying hypothesis.

We report a 54-year-old patient with the association of hepatic dysfunction with cyanosis, severe hypoxemia, platypnea-orthodeoxia, diffuse cutaneous spider nevi, telangiectasia, palmar erythema, digital clubbing and findings of marked intrapulmonary vascular dilation and arterovenous shunt. The diagnosis of hepato-pulmonary-cutaneous syndrome, a term we think more appropriate and inclusive than that of hepato-pulmonary syndrome for this clinicopathological picture, is proposed. The putative underlying mechanism for these connected pulmonary and extrapulmonary syndromic features is discussed.

Dor articular na osteoartropatia hipertrófica primária: descrição de caso e revisão de tratamento / Arthralgia in primary hipertrophic osteoarthropathy: case report and review of the treatment

Apresentamos o caso de um paciente com baqueteamento digital e artrite que foi diagnosticado como tendo osteoartropatia hipertrófica primária. Essa é uma doença rara e benigna. Entretanto, artralgia e alterações cutâneas podem reduzir significativamente a qualidade de vida do paciente. Além de um breve resumo da doença, apresentamos o caso e a revisão da literatura, enfatizando o tratamento dessa condição para os clínicos em geral.

We report the case of a patient with clubbing of the digits and arthritis who was diagnosed as having primary hipertrophic osteoarthropathy. This is a rare, benign disease. However, the arthralgia and skin changes can significantly impair the quality of life of the patient. In addition to a brief description of the disease, we present the case and a review of the literature regarding the treatment of this condition to the general practitioner.