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BACKGROUND: Many of the familial Mediterranean fever (FMF) patients present with arthritis during attacks, which may vary in its characteristics. AIMS: In this study, we aimed to describe and characterise arthritis in FMF patients. METHODS: We used our hospital's record system to retrospectively identify FMF patients with arthritis who presented to our clinic between 2005 and 2020. The prevalence, laboratory results of attack, remission periods, genetic mutations, demographic data, characteristics of attacks, characteristics of arthritis, comorbidities, treatments and treatment responses were recorded. RESULTS: Nine hundred fifty-four patients from a cohort of 2350 FMF patients had arthritis (40%). The male/female ratio was 0.49 in patients with arthritis. The frequency of at least one exon 10 mutation was high. The age of onset of symptoms was earlier for patients with arthritis. Monoarticular pattern was more frequent compared to oligo- and polyarticular patterns. Colchicine resistance was higher; the required colchicine dose for disease control and the frequency of use of biological agents were higher compared to general FMF population. CONCLUSION: Since M694V mutation is common and the colchicine dose required for disease control is high, we can conclude that the disease activity is high in FMF patients with arthritis. The frequency of sacroiliitis and spondyloarthropathy is significantly increased, especially in individuals with M694V mutation, suggesting that there may be a common pathway in their pathogenesis. FMF should be included in the differential diagnosis in patients presenting with arthritis in FMF endemic regions.
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OBJECTIVE: The presence of FMF cases without MEFV (MEFV innate immunity regulator, pyrin) pathogenic variants led us to search for other genes' involvement in the disease development. Here, we describe the presence of genetic heterogeneity in a three-generation family with an FMF/mevalonate kinase deficiency (MKD)-overlapping phenotype without MEFV/MVK (mevalonate kinase) pathogenic variants. METHOD: Targeted sequencing revealed a rare, fully penetrant variant in PSTPIP1 (p.Arg228Cys, rs781341816). Computational stability analyses of PSTPIP1 protein were performed. PSTPIP1-pyrin protein interaction was examined by immunoprecipitation and immunoblotting in peripheral blood mononuclear cells (PBMCs) of patients and healthy controls. PBMCs were cultured, and inflammation was induced by LPS+ATP treatment, followed by protein level measurements of caspase-1, IL1ß, pyrin and PSTPIP1 in cell lysates and mature caspase-1 and mature IL1ß in supernatants. RESULTS: The conserved, rare (GnomAD, 0.000028) PSTPIP1 p.Arg228Cys variant, previously reported in ClinVar as a variant with uncertain significance, showed complete penetrance in the family presenting an autosomal dominant pattern. Computational analyses showed a potentially destabilizing effect of the variant on PSTPIP1 protein. Accordingly, PSTPIP1-pyrin interaction was increased in patients harboring the variant, which resulted in elevated levels of mature caspase-1 and IL1ß in the inflammation-induced patient samples. CONCLUSIONS: Unlike previously described cases with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA)-associated PSTPIP1 variants, our patients with the p.Arg228Cys variant presented with an FMF/MKD-overlapping phenotype. As additional data on the genetic heterogeneity in the variable clinical spectrum of autoinflammatory syndromes, we suggest that the p.Arg228Cys variant in PSTPIP1 is related to inflammation responses through strong PSTPIP1-pyrin interaction and pyrin inflammasome activation.
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Fiebre Mediterránea Familiar , Deficiencia de Mevalonato Quinasa , Humanos , Pirina/genética , Leucocitos Mononucleares , Fenotipo , Inflamación , Caspasa 1/genética , Fiebre Mediterránea Familiar/genética , Mutación , Proteínas del Citoesqueleto/genética , Proteínas Adaptadoras Transductoras de Señales/genéticaRESUMEN
This study aimed to investigate whether patients regularly using colchicine or hydroxychloroquine (HCQ) have an advantage of protection from coronavirus disease 2019 (COVID-19) or developing less severe disease. Patients who were taking colchicine or HCQ regularly for a rheumatic disease including Familial Mediterranean Fever, Behçet's syndrome, Systemic Lupus Erythematosus, Rheumatoid Arthritis, and Sjogren's syndrome, as well as their healthy household contacts as the control group, were included in the study. The clinical data regarding COVID-19 were collected using a standard form, and serum samples were analyzed for anti-severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) nucleocapsid immunoglobulin G (IgG). A total of 635 regular colchicine users with their 643 household contacts and 317 regular HCQ users with their 333 household contacts were analyzed. Anti-SARS-COV-2 IgG was positive in 43 (6.8%) regular colchicine users and 35 (5.4%) household contacts (odds ratio [OR] = 1.3; 95% confidence interval [CI]:0.8-2; p = 0.3). COVID-19-related symptoms were described by 29 (67.4%) of the patients and 17 (48.6%) household contacts (OR = 2.2; 95% CI :0.9-5.5; p = 0.09), and hospital admission was observed in five (11.6%) and one (2.9%) of these subjects (OR = 4.5; 95% CI: 0.5-40.2; p = 0.1), respectively. Seropositive subjects were observed in 22 (6.9%) regular HCQ users and 24 (7.2%) household contacts (OR = 1.1; 95% CI: 0.6-1.9; p = 0.8). COVID-19-related symptoms occurred in 16 (72.7%) of the 22 patients and 12 (50%) of 24 household contacts (OR = 2.7; 95% CI: 0.8-9.1; p = 0.1). Three patients (13.6%) were admitted to hospital, while one household contact (4.2%) was hospitalized (OR = 3.6; 95% CI: 0.3-37.8; p = 0.2). Being on a regular treatment of colchicine or HCQ did not result in the prevention of COVID-19 or amelioration of its manifestations.
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Tratamiento Farmacológico de COVID-19 , Enfermedades Reumáticas , Colchicina/uso terapéutico , Humanos , Hidroxicloroquina/uso terapéutico , Inmunoglobulina G , Enfermedades Reumáticas/tratamiento farmacológico , SARS-CoV-2RESUMEN
OBJECTIVE: A decline in the frequency of AA amyloidosis secondary to RA and infectious diseases has been reported. We aimed to determine the change in the frequency of AA amyloidosis in our Behçet's syndrome (BS) patients and to summarize the clinical characteristics of and outcomes for our patients, and also those identified by a systematic review. METHODS: We identified patients with amyloidosis in our BS cohort (as well as their clinical and laboratory features, treatment, and outcome) through a chart review. The primary end points were end-stage renal disease and death. The prevalence of AA amyloidosis was estimated separately for patients registered during 1976-2000 and those registered during 2001-2017, in order to determine whether there was any change in the frequency. We searched PubMed and EMBASE for reports on BS patients with AA amyloidosis. Risk of bias was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool. RESULTS: The prevalence of AA amyloidosis was 0.62% (24/3820) in the earlier cohort and declined to 0.054% (3/5590) in the recent cohort. The systematic review revealed 82 cases in 42 publications. The main features of patients were male predominance and a high frequency of vascular involvement. One-third of patients died within 6 months after diagnosis of amyloidosis. CONCLUSION: The frequency of AA amyloidosis has decreased in patients with BS, which is similar to the decrease observed for AA amyloidosis due to other inflammatory and infectious causes. However, AA amyloidosis is a rare, but potentially fatal complication of BS.
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Amiloidosis , Síndrome de Behçet , Humanos , Masculino , Femenino , Síndrome de Behçet/complicaciones , Síndrome de Behçet/epidemiología , Estudios Retrospectivos , Estudios de Seguimiento , Amiloidosis/etiología , Amiloidosis/complicacionesRESUMEN
It is assumed that in candidates for TNF-alpha inhibitor (TNFi) treatment, tuberculin skin test (TST) may be unreliable, since BCG vaccination causes false positive and drugs cause false negative results, favoring the use of Quantiferon or T-spot assays. However, these tests may not be readily available in all parts of the world. We aimed to determine the reliability of TST with respect to BCG vaccination and drugs in candidates for TNFi treatment, and how isoniazid is tolerated, assuming that the use of TST would result in increased isoniazid use. We included 1031 adult patients who were prescribed a TNFi for the first time. We analysed the association of BCG and drugs with TST and Quantiferon results, the determinants of a positive TST, and evaluated the tolerability of isoniazid. BCG vaccination and male sex were associated with positive TST (OR 3.56, 95% CI 1.98-6.41 and OR 2.54, 95% CI 1.75-3.68, respectively), while prednisolone and azathioprine were associated with negative TST (OR 0.63, 95% CI 0.43-0.91 and OR 0.40, 95% CI 0.11-0.76). Isoniazid was prescribed to 684 (66.3%) patients and had to be discontinued in 12.2% of these before 9 months, most commonly due to hepatotoxicity (44%). One patient developed tuberculosis despite isoniazid use. BCG vaccination may be associated with false positive TST, despite a long time since vaccination in candidates for TNFi treatment. Prednisolone and azathioprine use were associated with negative TST. Despite the high frequency of isoniazid use associated with using TST instead of QTF, isoniazid was generally well tolerated.
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Vacuna BCG , Isoniazida , Tuberculosis Latente , Inhibidores del Factor de Necrosis Tumoral , Adulto , Azatioprina , Vacuna BCG/administración & dosificación , Humanos , Isoniazida/uso terapéutico , Tuberculosis Latente/diagnóstico , Masculino , Prednisolona , Reproducibilidad de los Resultados , Prueba de Tuberculina/métodos , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , VacunaciónRESUMEN
OBJECTIVES: Anakinra is proven to be effective in controlled trials in terms of attack frequency and subclinical inflammation in colchicine-resistant patients. The objective of this study was to review the patients followed in our single centre with FMF who received anakinra because of insufficient colchicine response. METHODS: The study was conducted at a tertiary rheumatology centre experienced in autoinflammatory diseases. The patients were treated for at least 1 month with anakinra. Patients with amyloidosis and pregnancy were not included. Attack frequency, patient global assessment scales of disease severity and acute phase reactants were recorded before and throughout anakinra treatment. Criteria of treatment termination were side effects, disease remission, inadequate response, pregnancy plan and non-compliance. RESULTS: One hundred and six patients diagnosed with FMF were treated with anakinra; 45.92% of the patients had a homozygous M694V mutation; 83 of the 98 patients tested for MEFV carried at least one copy of M694V. Attack frequency decreased while on anakinra treatment; in fact, no attacks were observed in 75 patients. Visual analogue scale score decreased from 7.49 (2.03) to 3.08 (2.82) (P = 0.001). Currently, 71 patients are still on anakinra treatment. Treatment of 34 patients was discontinued (32%). Insufficient response and side effects were the most common reasons for treatment discontinuation. All of the side effects observed were reversible and the patients alleviated after treatment cessation. In four patients, leukopenia was observed. CONCLUSION: In patients who were refractory to colchicine, anti-IL-1 agent anakinra was shown to be effective and safe. The effectiveness of anakinra stems from preventing attacks and increasing the quality of life.
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Antirreumáticos/uso terapéutico , Fiebre Mediterránea Familiar/tratamiento farmacológico , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Adulto , Colchicina/uso terapéutico , Fiebre Mediterránea Familiar/diagnóstico , Fiebre Mediterránea Familiar/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Pirina/genética , Calidad de Vida , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
Objectives: Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) is a monocyte and neutrophil receptor functioning in innate immunity. TREM-1 activity has been studied in various autoimmune diseases such as RA and SLE but there is no data in autoinflammatory pathologies. We studied soluble TREM-1 (sTREM-1) activity in Familial Mediterranean Fever (FMF) cases to evaluate the clinical role of TREM-1 in amyloidosis. Methods: The study includes 62 patients with FMF (42 with amyloidosis) who are regular attendees of a tertiary center for autoinflammatory diseases. For control purposes, 5 patients with AA amyloidosis secondary to other inflammatory diseases, and 20 healthy individuals were also included. Soluble TREM-1 levels were measured using enzyme-linked immunosorbent assay (ELISA). All FMF patients were in an attack-free period during the collection of the blood samples.Results: Soluble TREM-1 levels were found to be significantly higher in the FMF amyloidosis group compared to FMF without amyloidosis group and healthy controls (p = .001 and 0.002). Nevertheless, this difference between sTREM-1 levels was not found among FMF amyloidosis and other AA amyloidosis groups (p = .447) as well as between only FMF patients and healthy controls (p = .532). Soluble TREM-1 levels were found in correlation with creatinine and CRP in the FMF patient group regardless of their amyloidosis diagnosis (r = 0.314, p = .013; r = 0.846, p < .001).Conclusion: TREM-1 seems to be related to renal function rather than disease activity in FMF. Its role as an early diagnostic marker of amyloidosis in FMF complicated with AA amyloidosis should be tested in larger patient groups.
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Amiloidosis Familiar/metabolismo , Biomarcadores/sangre , Fiebre Mediterránea Familiar/metabolismo , Riñón/metabolismo , Receptor Activador Expresado en Células Mieloides 1/sangre , Adulto , Amiloidosis Familiar/complicaciones , Creatinina/sangre , Fiebre Mediterránea Familiar/complicaciones , Femenino , Humanos , Inmunidad Innata , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: To evaluate the long-term efficacy and safety of canakinumab to treat patients with colchicine-resistant familial Mediterranean fever (crFMF) during Epoch 4 (weeks 41 to 113) of the CLUSTER study. METHODS: Patients received open-label canakinumab 150 or 300 mg, every 4 or 8 weeks during a 72-week period. We evaluated disease activity every 8 weeks using the physician global assessment (PGA) of disease activity, counting the number of flares, and measuring concentrations of C reactive protein (CRP) and serum amyloid A (SAA). Safety was studied by determination and classification of observed adverse events (AEs). We analysed safety and efficacy separately in two subgroups of patients receiving a cumulative dose of less than 2700 mg, or equal or more than 2700 mg. RESULTS: Of the 61 patients that started the CLUSTER study, 60 entered Epoch 4 and 57 completed it. During the 72-week period, 35/60 (58.3%) patients experienced no flares, and 23/60 (38.3%) had one flare, as compared with a median of 17.5 flares per year reported at baseline. PGA scores indicated no disease activity for the majority of patients throughout the study. Median CRP concentrations were always lower than 10 mg/L, while median SAA concentrations remained over the limit of normal (10 mg/L) but under the 30 mg/L threshold. No new or unexpected AEs were reported. CONCLUSION: crFMF patients treated with canakinumab during 72 weeks experienced a minimal incidence of flares and good control of clinical disease activity, with no new safety concerns reported.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Fiebre Mediterránea Familiar/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Adolescente , Adulto , Femenino , Humanos , Masculino , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: The main devastating complication of FMF is AA amyloidosis. Approximately 10-15% of the patients are either intolerant or have an insufficient response to colchicine treatment. The most promising alternative treatment approach is anti-IL-1 agents. The aim of this study was to evaluate the efficacy and safety of anti-IL-1 therapy in FMF amyloidosis. METHODS: Forty-four patients with amyloidosis who had been treated with anti-IL-1 agents, anakinra and/or canakinumab, were assessed retrospectively for efficacy and safety. Five patients were on haemodialysis and four had received a renal transplant. RESULTS: The mean duration of anti-IL-1 treatment was 21.4 (18) months. Among 35 patients who were not on dialysis, renal function was maintained or improved in 79.4% but deteriorated in 20.6%. Patients with creatinine levels below 1.5 mg/dl at onset benefitted more from IL-1 inhibition with regard to their kidney functions and acute phase reactants. No additional side effects were observed in patients with renal replacement treatments. The major side effect of anakinra was injection-site reaction observed in four patients. CONCLUSION: Anti-IL-1 agents are well tolerated and effective in the treatment of amyloidosis secondary to FMF, including patients on dialysis and renal transplant recipients. This approach may improve the lifespan of transplanted kidneys in FMF patients.
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Amiloidosis/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antirreumáticos/uso terapéutico , Fiebre Mediterránea Familiar/complicaciones , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Interleucina-1/antagonistas & inhibidores , Adulto , Amiloidosis/etiología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Antirreumáticos/administración & dosificación , Antirreumáticos/efectos adversos , Colchicina/uso terapéutico , Quimioterapia Combinada , Femenino , Humanos , Proteína Antagonista del Receptor de Interleucina 1/administración & dosificación , Proteína Antagonista del Receptor de Interleucina 1/efectos adversos , Masculino , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVES: The diagnosis of familial Mediterranean fever (FMF) can be missed or delayed even in countries where FMF prevalence is high. In this study we investigated the presentation pattern, the frequency of misdiagnosis and the duration of diagnostic delay and its underlying causes in a large cohort followed by a single tertiary centre in Turkey. METHODS: We studied 197 (118 F, 79 M) consecutive patients with FMF (median age: 34 years [IQR: 27-44]). The median registry year of the patients was 2006 [IQR: 2001-2011]. A standardised questionnaire was used to assess age at first symptom, date at diagnosis, previous diagnosis and treatments before the FMF diagnosis. RESULTS: A total of 167 (84%) patients were misdiagnosed and 56 (28%) underwent surgical operations before FMF diagnosis. The most common mis-diagnoses were appendicitis (55%) and acute rheumatic fever (ARF) (45%). The median duration of diagnostic delay was 11 years. Joint attacks were observed to start at a significantly younger age (median age: 3 years) than abdominal attacks (median age: 12 years). Early onset with solo joint attacks, without usual peritonitis attacks and being a carrier of M694V were found to be significantly associated with ARF misdiagnosis. CONCLUSIONS: Misdiagnosis frequency is still significantly high and diagnostic delay is long even in a cohort of patients registered after year 2000 in Turkey. Atypical presentation with solo joint attacks, especially among patients with early onset, seems to play a significant role in misdiagnosis and delay in diagnosis.
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Fiebre Mediterránea Familiar , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , Diagnóstico Tardío , Errores Diagnósticos , Fiebre Mediterránea Familiar/diagnóstico , Femenino , Humanos , Masculino , Turquía , Adulto JovenRESUMEN
OBJECTIVES: Polyarteritis nodosa is a necrotising vasculitis of predominantly medium size vessels. The present study aimed to summarise the characteristics of PAN patients, and also analyse the trend of decreasing PAN frequency in the last 25 years. METHODS: PAN patients followed up between 1990 and 2015 were included. The demographics, clinical findings and outcomes were retrospectively evaluated. RESULTS: One hundred thirty-three patients, including 66 children, were enrolled in the study. Among 133 patients, 86 (64.7%) had fever, 108 (81.2%) had skin involvement, 54 (40.6%) had renal involvement, 43 (32.3%) had neurological involvement, 32 (24.1%) had gastrointestinal involvement, 10 (7.5%) had cardiac involvement, 6 (4.5%) had pulmonary involvement. The median (minimum-maximum) leukocyte count, erythrocyte sedimentation rate and C-reactive protein levels at the time of diagnosis were 10400 (6100-32000)/mm3, 58 (2-132) mm/h and 5.22 (0-46) mg/dL, respectively. All patients were ANCA negative. Hepatitis serology was analysed in 121 patients and found positive in 13 of them. MEFV mutations were screened among 65 patients, 24 of them had mutations in at least one allele. Biopsy was performed in 109 patients and angiography was performed in 92 patients. The number of PAN patients declined significantly after 2010. 9 patients were re-categorised as DADA2 after 2014 and no patient were diagnosed with FMF+PAN after 2008. CONCLUSIONS: Our results suggest a decrease in PAN in our country which may be due to improved healthcare and dissecting mimicking diseases. Further prospective studies with prolonged follow-up could help us to better understand the disease characteristics.
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Poliarteritis Nudosa , Adenosina Desaminasa , Adolescente , Adulto , Sedimentación Sanguínea , Niño , Progresión de la Enfermedad , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular , Masculino , Persona de Mediana Edad , Poliarteritis Nudosa/diagnóstico , Poliarteritis Nudosa/epidemiología , Estudios Prospectivos , Pirina , Estudios RetrospectivosRESUMEN
The second affiliation of the corresponding author Eda Tahir Turanli was incorrectly published as Istanbul Medeniyet University instead of Istanbul Technical University.
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Systemic autoinflammatory diseases (sAIDs) are a heterogeneous group of disorders, having monogenic inherited forms with overlapping clinical manifestations. More than half of patients do not carry any pathogenic variant in formerly associated disease genes. Here, we report a cross-sectional study on targeted Next-Generation Sequencing (NGS) screening in patients with suspected sAIDs to determine the diagnostic utility of genetic screening. Fifteen autoinflammation/immune-related genes (ADA2-CARD14-IL10RA-LPIN2-MEFV-MVK-NLRC4-NLRP12-NLRP3-NOD2-PLCG2-PSTPIP1-SLC29A3-TMEM173-TNFRSF1A) were used to screen 196 subjects from adult/pediatric clinics, each with an initial clinical suspicion of one or more sAID diagnosis with the exclusion of typical familial Mediterranean fever (FMF) patients. Following the genetic screening, 140 patients (71.4%) were clinically followed-up and re-evaluated. Fifty rare variants in 41 patients (20.9%) were classified as pathogenic or likely pathogenic and 32 of those variants were located on the MEFV gene. We detected pathogenic or likely pathogenic variants compatible with the final diagnoses and inheritance patterns in 14/140 (10%) of patients for the following sAIDs: familial Mediterranean fever (n = 7), deficiency of adenosine deaminase 2 (n = 2), mevalonate kinase deficiency (n = 2), Muckle-Wells syndrome (n = 1), Majeed syndrome (n = 1), and STING-associated vasculopathy with onset in infancy (n = 1). Targeted NGS panels have impact on diagnosing rare monogenic sAIDs for a group of patients. We suggest that MEFV gene screening should be first-tier genetic testing especially in regions with high carrier rates. Clinical utility of multi-gene testing in sAIDs was as low as expected, but extensive genome-wide familial analyses in combination with exome screening would enlighten additional genetic factors causing disease.
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Pruebas Genéticas , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Secuenciación de Nucleótidos de Alto Rendimiento , Proteínas Adaptadoras Transductoras de Señales/genética , Adenosina Desaminasa/deficiencia , Adenosina Desaminasa/genética , Adolescente , Adulto , Agammaglobulinemia/diagnóstico , Agammaglobulinemia/genética , Anemia Diseritropoyética Congénita/diagnóstico , Anemia Diseritropoyética Congénita/genética , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas de Unión al Calcio/genética , Niño , Preescolar , Síndromes Periódicos Asociados a Criopirina/diagnóstico , Síndromes Periódicos Asociados a Criopirina/genética , Proteínas del Citoesqueleto/genética , Fiebre Mediterránea Familiar/diagnóstico , Fiebre Mediterránea Familiar/genética , Femenino , Enfermedades Autoinflamatorias Hereditarias/genética , Humanos , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Masculino , Deficiencia de Mevalonato Quinasa/diagnóstico , Deficiencia de Mevalonato Quinasa/genética , Persona de Mediana Edad , Proteínas de Transporte de Nucleósidos/genética , Osteomielitis/diagnóstico , Osteomielitis/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Pirina/genética , Análisis de Secuencia de ADN , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/genética , Adulto JovenRESUMEN
Deficiency of adenosine deaminase type 2 (DADA2) is a rare form of autoinflammatory disorder with limited reported cases. In this paper, we have presented the clinico-immunological, radiological and genetic characteristics of five surviving and three deceased childhood-onset DADA2 patients. We aimed to compare surviving and deceased patients in terms of clinical features and treatment modalities. Moreover, we have evaluated the causes of death in our DADA2 subjects together with the previously reported cases. Demographic features, clinical characteristics, imaging findings, mutations and pharmacological treatments of DADA2 subjects were noted from patient records of pediatric and adult rheumatology clinics in a retrospective and longitudinal nature. Eight patients from seven families were enrolled. While five of them were surviving, three of them had died due to various reasons. Median age of the patients at disease onset and diagnosis was 7 years (range 0.5-13 years) and 14 years (range 5-27 years), respectively. The main clinical manifestations were cutaneous findings (7/8), recurrent low-grade fever (6/8), neurological involvement (6/8) and gastrointestinal involvement (5/8). All patients had increased acute phase reactants at presentation and also during the disease flares. Until the diagnosis of DADA2 was confirmed, five patients have been followed-up with the diagnosis of PAN: two patients both with PAN and FMF, and one patient with CAPS and vasculitis. Demographic, clinical, neurological features and genetic mutations did not differ in surviving and deceased DADA2 patients. Deceased and surviving subjects differed in terms of treatment modalities after the diagnosis of DADA2. Anti-TNF alpha treatment has been initiated in five surviving patients as soon as the diagnosis of DADA2 was established. However, three patients who have died were not able to use sufficient doses of anti-TNF alpha treatment; in one case due to reluctance of patient and in two cases due to establishment of the definite diagnosis by genetic analysis at the same time with the last fatal DADA2 episode. Despite limited number of patients, this case series for the first time compares the phenotypic, genotypic and medication differences between surviving and deceased DADA2 patients. Anti-TNF alpha treatment seems to be efficient and lifesaving in DADA2 patients.
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Adenosina Desaminasa/deficiencia , Agammaglobulinemia/diagnóstico , Productos Biológicos/uso terapéutico , Inmunodeficiencia Combinada Grave/diagnóstico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adenosina Desaminasa/genética , Adolescente , Adulto , Agammaglobulinemia/diagnóstico por imagen , Agammaglobulinemia/tratamiento farmacológico , Agammaglobulinemia/genética , Edad de Inicio , Niño , Preescolar , Genotipo , Humanos , Lactante , Angiografía por Resonancia Magnética , Inmunodeficiencia Combinada Grave/diagnóstico por imagen , Inmunodeficiencia Combinada Grave/tratamiento farmacológico , Inmunodeficiencia Combinada Grave/genética , Adulto JovenRESUMEN
Rituximab (RTX) is becoming a standard treatment for patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) but heterogeneity exists regarding its use. We present our uncontrolled experience with RTX in patients with refractory AAV and also the results of a systematic review of non-randomized studies on RTX in AAV patients. We retrospectively reviewed the records of AAV patients treated with RTX following an inadequate response to immunosuppressives between 2011 and 2015. The systematic review covered all English articles listed in PubMed until June 2017. There were 25 AAV patients (21 GPA, four unclassified) treated with RTX (median 2, IQR 1-3 courses; median follow-up 24, IQR 17-50 months). The kidney and the lung were the most commonly affected organs, observed in 14 and 16 patients, respectively. Complete remission rate was 72% at month 6 and 88% at month 12. Two patients had died and three serious adverse events occurred. The systematic review included 56 studies on 1422 patients with the majority being on refractory or relapsing disease. There was wide variability regarding disease characteristics, endpoints, concomitant immunosuppressives and RTX schedule. Most studies reported > 80% complete or partial remission rates with the lowest response (37.5%) for granulomatous lesions. The relapse rate was 30%. Infections and infusion reactions were the main adverse events. Our experience with RTX in refractory AAV is in line with the literature in terms of efficacy and safety. The systematic review underlines many uncertainties on its optimal use.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Rituximab/uso terapéutico , Adulto , Anciano , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/sangre , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/mortalidad , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Biomarcadores/sangre , Femenino , Humanos , Factores Inmunológicos/efectos adversos , Masculino , Persona de Mediana Edad , Inducción de Remisión , Estudios Retrospectivos , Rituximab/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenAsunto(s)
COVID-19 , Fiebre Mediterránea Familiar , Formación de Anticuerpos , COVID-19/prevención & control , Vacunas contra la COVID-19/uso terapéutico , Fiebre Mediterránea Familiar/tratamiento farmacológico , Fiebre Mediterránea Familiar/genética , Humanos , Interleucina-1 , ARN Mensajero , SARS-CoV-2RESUMEN
Objective: To provide outcome data concerning pregnancies exposed to the Interleukin-1 (IL-1) inhibitors prior to conception in both men and women, during pregnancy and breast feeding. Methods: Retrospective data were collected from members of the International Society for Systemic Autoinflammatory diseases and collated in a single centre. A uniform data collection sheet was used to obtain standardized data including maternal age and diagnosis, type, duration of and response to IL-1 blockade, pregnancy duration, delivery, mode of feeding and neonatal development. Results: There were 31 maternal-exposed pregnancies from seven countries and we report the first data on paternal exposure: six to anakinra and five to canakinumab, with no negative outcomes. We also report the first data on canakinumab-exposed pregnancies: eight pregnancies that resulted in the delivery of seven healthy infants of normal gestational age and birthweight. There were 23 anakinra-exposed pregnancies resulting in the birth of 21 healthy infants, and one baby with unilateral renal agenesis and ectopic neurohypophysis. There were two first trimester miscarriages affecting a mother with active disease. There were no serious neonatal infections. Fourteen infants were breast fed with no complications. There were no reports of developmental delay, with follow-up of up to 10 years (median 18 months). Conclusion: This series substantially increases the published experience of IL-1 blockade and reproduction including the first data on canakinumab and on paternal exposure to these agents. Data are generally reassuring, although the case of renal agenesis is the second reported in an anakinra-exposed pregnancy.
Asunto(s)
Antirreumáticos/efectos adversos , Enfermedades Autoinmunes/tratamiento farmacológico , Interleucina-1/antagonistas & inhibidores , Exposición Materna/efectos adversos , Exposición Paterna/efectos adversos , Adulto , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Enfermedades Autoinmunes/complicaciones , Peso al Nacer , Lactancia Materna/efectos adversos , Femenino , Edad Gestacional , Humanos , Recién Nacido , Proteína Antagonista del Receptor de Interleucina 1/efectos adversos , Masculino , Embarazo , Resultado del Embarazo , Estudios Retrospectivos , Adulto JovenRESUMEN
OBJECTIVES: No MEFV mutations are detected in approximately 10% of the patients with clinical FMF in populations where the disease is highly prevalent. Causative mutations were searched in other genes in two such families with "MEFV negative clinical FMF". METHODS: Father and daughter of family A had attacks of fever, abdominal pain and AA amyloidosis. The two sibs of family B complained of febrile episodes with abdominal pain and arthritis. The patients were clinically investigated. Exome analysis in the daughter in family A and linkage analysis and candidate gene sequencing for the members of family B were performed. All patients were re-evaluated in the light of the genetic findings. RESULTS: In the daughter in family A, filtering of the exome file for variants in 25 autoimmune/inflammatory disease-related genes revealed two heterozygous missense variants in TNFRSF1A, novel p.Cys72Phe and frequent p.Arg121Gln. In family B, novel, homozygous missense p.Cys161Arg in MVK was identified. A clinical re-evaluation of the patients revealed a phenotype consistent with FMF rather than TRAPS in family A and an overlap of FMF with HIDS in family B. CONCLUSIONS: In high risk populations of FMF a proportion of patients without MEFV mutations may carry causative mutations in other genes, and the clinical findings may not be fully consistent with the phenotype expected of the mutation identified but rather resemble FMF or an overlap syndrome.
Asunto(s)
Fiebre Mediterránea Familiar/genética , Fiebre/genética , Enfermedades Autoinflamatorias Hereditarias/genética , Heterocigoto , Homocigoto , Deficiencia de Mevalonato Quinasa/genética , Mutación Missense , Proteínas del Tejido Nervioso/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Adolescente , Niño , Análisis Mutacional de ADN , Diagnóstico Diferencial , Fiebre Mediterránea Familiar/diagnóstico , Fiebre Mediterránea Familiar/epidemiología , Fiebre Mediterránea Familiar/inmunología , Femenino , Fiebre/diagnóstico , Fiebre/epidemiología , Fiebre/inmunología , Predisposición Genética a la Enfermedad , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Enfermedades Autoinflamatorias Hereditarias/epidemiología , Enfermedades Autoinflamatorias Hereditarias/inmunología , Herencia , Humanos , Masculino , Deficiencia de Mevalonato Quinasa/diagnóstico , Deficiencia de Mevalonato Quinasa/epidemiología , Deficiencia de Mevalonato Quinasa/inmunología , Persona de Mediana Edad , Linaje , Fenotipo , Valor Predictivo de las Pruebas , Prevalencia , Pirina/genética , Factores de Riesgo , Turquía/epidemiología , Adulto JovenRESUMEN
OBECTIVES: Menstruation triggers several conditions such as migraine, recurrent aphthous stomatitis and acne vulgaris in healthy individuals. There is evidence that Behçet's syndrome (BS) and familial Mediterranean fever (FMF) may exacerbate during menstruation. The aim is to assess whether BS and FMF patients experience menstrual flares. METHODS: Females of reproductive age with BS and FMF seen consecutively at the outpatient clinic of Cerrahpasa Medical Faculty at Istanbul, as well as apparently healthy hospital workers were studied using a standardised questionnaire. BS patients were asked whether they experienced increased skin-mucosa lesions during the menstrual period. A similar questionnaire assessing this time the frequency of abdominal pain, chest pain and fever attacks was given to the patients with FMF. The healthy controls received both questionnaires. RESULTS: A total of 200 BS patients, 240 FMF patients and 250 healthy controls were studied. The most commonly reported symptom among both BS patients (51%) and healthy controls (62%) was the acneiform lesion. At least 79% patients with FMF reported attacks with menstruation, notably abdominal pain which, majority thought, could be differentiated from dysmenorrhea. Additionally, 76% of healthy controls reported having abdominal pain consistent most probably with dysmenorrhea. CONCLUSIONS: This survey showed that, in 68% of the patients with BS at least one skin mucosa lesion was exacerbated with menstruation, this was most commonly acneiform lesion. Menstruation had a slightly stronger effect on FMF, triggering at least one symptom in 79%. The main limitation of the study was the self-reported assessment methodology.
Asunto(s)
Síndrome de Behçet/fisiopatología , Fiebre Mediterránea Familiar/fisiopatología , Menstruación , Dolor Abdominal/etiología , Dolor Abdominal/fisiopatología , Acné Vulgar/etiología , Acné Vulgar/fisiopatología , Adulto , Síndrome de Behçet/complicaciones , Síndrome de Behçet/diagnóstico , Estudios de Casos y Controles , Progresión de la Enfermedad , Dismenorrea/etiología , Dismenorrea/fisiopatología , Fiebre Mediterránea Familiar/diagnóstico , Femenino , Enfermedades de los Genitales Femeninos/etiología , Enfermedades de los Genitales Femeninos/fisiopatología , Humanos , Úlceras Bucales/etiología , Úlceras Bucales/fisiopatología , Factores de Riesgo , Factores Sexuales , Encuestas y Cuestionarios , TurquíaRESUMEN
OBJECTIVE: To develop widely accepted international severity score for children and adult patients with familial Mediterranean fever (FMF) that can be easily applied, in research and clinical practice. METHODS: Candidate severity criteria were suggested by several FMF expert physicians. After three rounds of Delphi survey, the candidate criteria, defined by the survey, were discussed by experts in a consensus meeting. Each expert brought data of clinical manifestations, laboratory findings and physician's global assessments (PGAs) of minimum 20 patients from their centres. We used the PGAs for disease severity as a gold standard. Logistic regression analysis was used to evaluate the predicting value of each item, and receiver operating characteristic curve analysis was performed to demonstrate the success of the criteria set. RESULTS: A total of 281 patients consist of 162 children and 119 adults with FMF were enrolled and available for validity analysis: Nine domains were included in the final core set of variables for the evaluation of disease severity in FMF. The International Severity Score for FMF (ISSF) may reach a maximum of 10 if all items are maximally scored. The threshold values to determine: severe disease ≥6, intermediate disease 3-5, mild disease ≤2. Area under the curve was calculated as 0.825 for this set in the whole group. CONCLUSIONS: The initial validity of ISSF both in children and adult with FMF was demonstrated. We anticipate that it will provide a robust tool to objectively define disease severity for clinical trials, future research as well as for therapeutic decisions in managing patients with FMF.