Mortality in patients with rheumatoid arthritis-associated interstitial lung disease treated with an anti-tumor necrosis factor agent

BACKGROUND/AIMS: To evaluate the impact on mortality of anti-tumor necrosis factor (anti-TNF) treatment of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). METHODS: We retrospectively reviewed the medical records of 100 RA-ILD patients who visited our tertiary care medical center between 2004 and 2011, identified those treated with an anti-TNF agent, divided patients into non-survivor and survivor groups and evaluated their clinical characteristics and causes of death. RESULTS: A total of 24 RA-ILD patients received anti-TNF therapy, of whom six died (25%). Mean age at initiation of anti-TNF therapy was significantly higher in the nonsurvivor versus survivor group (76 years [range, 66 to 85] vs. 64 years [range, 50 to 81], respectively; p = 0.043). The mean duration of anti-TNF treatment in the non-survivor group was shorter (7 months [range, 2 to 14] vs. 23 months [range, 2 to 58], respectively; p = 0.030). The duration of anti-TNF therapy in all nonsurviving patients was < 12 months. Pulmonary function test results at ILD diagnosis, and cumulative doses of disease-modifying drugs and steroids, did not differ between groups. Five of the six deaths (83%) were related to lung disease, including two diffuse alveolar hemorrhages, two cases of acute exacerbation of ILD, and one of pneumonia. The sixth patient died of septic shock following septic arthritis of the knee. CONCLUSIONS: Lung complications can occur within months of initial anti-TNF treatment in older RA-ILD patients; therefore, anti-TNF therapy should be used with caution in these patients.

TNF-alpha Inhibitor Treatment in an Ankylosing Spondylitis Patient with Secondary Amyloidosis that Manifest with Diarrhea: A Case Report / 대한내과학회지

Secondary amyloidosis (Amyloid A amyloidosis) occurs when serum amyloid S accumulates in various tissues and organs. It often accompanies chronic inflammatory disease, especially rheumatoid arthritis, as well as ankylosing spondylitis (AS) and Crohn's disease. Although amyloid deposits were reported in 7% of the abdominal fatty tissue samples from AS patients, most of the patients had no symptoms. In a large study, 1.1% of 730 patients with AS were diagnosed with amyloidosis. Most of them showed renal involvement, while none had gastrointestinal symptoms. In South Korea, only a few cases of gastrointestinal involvement of secondary amyloidosis have been reported in AS patients, and there is no report on the effect of a tumor necrosis factor (TNF)-alpha inhibitor. We report a case of secondary amyloidosis in an AS patient who improved with the TNF-alpha inhibitor etanercept.

A Case of Varicelliform Zoster in a Patient Treated with Etanercept for Ankylosing Spondylitis

Tumor necrosis factor-alpha (TNF-alpha) inhibitors are increasingly used in treatment of inflammatory disorders because of their immunomodulatory efficacy. Increased risk of infection is an adverse effect of anti-TNF-alpha therapy. The incidence rate and severity of herpes zoster is significantly higher in patients on anti-TNF-alpha therapy than in the general population. The clinical presentation of varicella zoster virus infection is also often atypical in these patients. We experienced a patient who presented with a disseminated varicelliform rash while on etanercept therapy for ankylosing spondylitis.

The use of biologics for severe psoriasis

Psoriasis is a life-long chronic relapsing dermatosis that shows waxing and waning of disease despite of a lot of conventional treatment. Severe psoriasis, usually defined by a psoriasis area and severity index (PASI) score of more than 10 and an area of involved skin of more than 10%, is a typical indication for biologic therapy. TNF-alpha inhibitors (etanercept, infliximab, and adalimumab) and an IL-12/23 inhibitor (ustekinumab) are the major biologics currently available for psoriasis. After the introduction of biologic treatment, many patients with severe psoriasis experience dramatic improvement of their disease without many side effects and are able to maintain a long-term remission period. Long-term follow up of the side effects of currently available biologics reveals no increase in adverse events compared with non-psoriatic individuals. However, the high cost of psoriasis biologics is a major remaining hurdle for the prescription of these agents to patients with severe psoriasis.

Etanercept for steroid-refractory acute graft versus host disease following allogeneic hematopoietic stem cell transplantation

BACKGROUND/AIMS: The treatment for steroid-refractory acute graft versus host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT) needs to be standardized. We report our clinical experience with etanercept for steroid-refractory acute GVHD. METHODS: Eighteen patients who underwent allo-SCT and presented with steroid-refractory acute GVHD at Ajou University Hospital were studied retrospectively. They were given 25 mg of etanercept subcutaneously twice weekly for 4 weeks. The clinical responses were evaluated with regard to the severity of acute GVHD. RESULTS: The median patient age was 43.5 years. Using nonparametric tests, etanercept had a down-grading effect on acute GVHD (p = 0.005), although no patient experienced complete remission. Partial responses were seen in 80%, 17%, and 57% of grade II to IV patients, respectively. Skin and gut GVHD were well controlled with etanercept, whereas hepatic GVHD was not. Four patients died of fatal infections. No factors affecting the clinical outcome of etanercept were identified. CONCLUSIONS: Etanercept has a modest effect on steroid-refractory acute GVHD after allo-SCT, with tolerable side effects.

Early effects of tumor necrosis factor inhibition on bone homeostasis after soluble tumor necrosis factor receptor use

BACKGROUND/AIMS: Our aim was to assess whether short-term treatment with soluble tumor necrosis factor (TNF) receptor affects circulating markers of bone metabolism in rheumatoid arthritis (RA) patients. METHODS: Thirty-three active RA patients, treated with oral disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids for > 6 months, were administered etanercept for 12 weeks. Serum levels of bone metabolism markers were compared among patients treated with DMARDs at baseline and after etanercept treatment, normal controls and naive RA patients not previously treated with DMARDs (both age- and gender-matched). RESULTS: Bone-specific alkaline phosphatase (BSALP) and serum c-telopeptide (CTX)-1 levels were lower in RA patients treated with DMARDs than in DMARD-naive RA patients. After 12 weeks of etanercept treatment, serum CTX-1 and sclerostin levels increased. In patients whose DAS28 improved, the sclerostin level increased from 1.67 +/- 2.12 pg/mL at baseline to 2.51 +/- 3.03 pg/mL, which was statistically significant (p = 0.021). Increases in sclerostin levels after etanercept treatment were positively correlated with those of serum CTX-1 (r = 0.775), as were those of BSALP (r = 0.755). CONCLUSIONS: RA patients treated with DMARDs showed depressed bone metabolism compared to naive RA patients. Increases in serum CTX-1 and sclerostin levels after short-term etanercept treatment suggest reconstitution of bone metabolism homeostasis.

Descripción del estado de salud y calidad de vida en pacientes tratados con etanercept dentro de un programa de atención para artritis reumatoide en un centro especializado en Colombi / Description of health status and quality of life in rheumatoid arthritis patients treated with etanercept in a care program in a Colombian specialist center

Resumen Objetivo: Realizar un análisis descriptivo de la actividad de la enfermedad medida por DAS28, de la funcionalidad medida por HAQ (Health Assessment Questionnaire) y escala de depresión, tras un año de seguimiento en un programa de gerenciamiento de la enfermedad «Evaluación día¼, para pacientes colombianos con artritis reumatoide que iniciaron tratamiento con etanercept (Enbrel®). Materiales y métodos: Se diseñó un programa como parte del manejo integral de la enfermedad que comprendía cuatro visitas e incluía paraclínicos, evaluación por reumatólogo, psicólogo, terapeuta físico y ocupacional, y clinimetría. Resultados: Se incluyeron 91 sujetos. Al ingreso del programa, 42 pacientes (80.7%) fueron clasificados con actividad moderada y grave. Al año, la remisión fue alcanzada en 25%. El número de pacientes que presentaron una reducción mayor de 1.2 en el DAS28, respecto al inicio del tratamiento, fue de 19 (37.5%). La medida promedio de HAQ al inicio fue 1,07 y mejoró al disminuir a 0,96 en el último control, aunque en 11 de los individuos (13,5%) no se realizó la medición. Al ingreso del programa, 33.3% de los pacientes, tenía algún grado de depresión mayor de acuerdo con la escala de Zung y al año de la observación sólo la presentaba el 21.9%. Conclusiones: La descripción de estos programas de gerenciamiento es importante para contar con data propia de los pacientes colombianos con artritis reumatoide y brindar el manejo integral que se requiere en las enfermedades crónicas. Los resultados obtenidos parecen corresponder a los descritos en otras observaciones.

Abstract Objective: We conducted a descriptive analysis of rheumatoid arthritis activity according to DAS28, and functionality with HAQ (Health Assessment Questionnaire), and depression scales after one year of follow-up, in a disease management program «Evaluación día¼ for Colombian patients whom started treatment with etanercept. Methods: We designed a program as part of an integral disease management. It involved four visits, including: lab tests, questionnaires, and clinical evaluation by rheumatologist, psychologist, physical and occupational therapist. Results: 91 patients were included. At the beginning of the program, 80.7% of the individuals were classified in moderate and severe disease activity. At the end of follow-up, disease remission by DAS28 was reached in 25% of the patients. The number of patients who experienced DAS28 reduction more than 1.2 points was 19 (37.5%). HAQ average at baseline was 1.07 and improved to 0.96 at the end of the follow-up. At baseline, 33.3% of patients had a mayor depression according to Zung Score and, after one year, this score was present in 21.9% of the patients. Conclusions: The description of this disease management program is important for the understanding of rheumatoid arthritis in Colombia and it may offer an integral treatment, which is necessary in all chronic diseases. The results found in this analysis seem to be similar as described in other observations.

Optimization of the culture temperature of recombinant CHO-DG44 cells expressing tumor necrosis factor receptor-Fc / 中国药学杂志

OBJECTIVE: To optimize the culture temperature of recombinant CHO-DG44 cells expressing tumor necrosis factor receptor-Fc fusion protein and to determine the bioactivity of expressed protein at the best culture temperature. METHODS: Recombinant CHO cells were batchly cultured at three different temperatures (37°C, 37°C shifting to 31°C and 31°C). Samples were daily tested for cell densities, viabilities, glucose concentration, lactic acid concentration and TNFR-Fc fusion protein concentration, then the best culture temperature was chosen to scale up the fermentation volume (10, 50, 200 mL, and 2 L). TNFR-Fc fusion protein was purified with Protein A affinity chromatography, determined for relative molecular mass, purity and neutralizing activity by SDS-PAGE, SE-HPLC and WST-8 separately. RESULTS: The culture condition of 37°C shifting to 31°C resulted in the maximum viable cell density, high viability and long culture time of the cells as well as high TNFR-Fc protein productivity, and this culture procedure could be successfully applied to the scale-up of recombinant CHO cells. The purified fusion protein, with a relative molecular mass about 150 000, reached the purity of more than 93% and neutralized the cytotoxic effect of TNFα. CONCLUSION: Compared to the traditional culture temperature of 37°C, the culture temperature of 37°C shifting to 31°C can obviously improve the TNFR-Fc fusion protein output by recombinant CHO-DG44 cells. And this technique can be applied to scale-up, which will lay a foundation of large scale industrial production.

Uveítis y terapia anti-TNF / Uveitis and anti-TNF therapy

La uveítis es responsable de la pérdida visual hasta del 10% de la población mundial y es la segunda causa de ceguera tratable en personas de edad productiva, después de la retinopatía diabética. El tratamiento de la uveítis no infecciosa depende de su severidad; existe un alto porcentaje (hasta el 40%) de casos refractarios a inmunosupresores y esteroides a dosis altas. El factor de necrosis tumoral (TNF) es una citoquina fundamental en la patogénesis de la uveítis no infecciosa; su bloqueo selectivo con anticuerpos monoclonales y proteínas de fusión ha demostrado, en series de casos, estudios abiertos y pequeños estudios clínicos aleatorizados, eficacia y seguridad en casos idiopáticos y asociados a enfermedades autoinmunes, en la prevención de recaídas, ahorro de esteroides y pronóstico visual a largo plazo. Sin embargo, se han descrito efectos paradójicos, como la inducción de uveítis asociada al uso de proteínas de fusión contra TNF, como etanercept. Se pretende hacer una revisión exhaustiva de la literatura para determinar el papel de los agentes anti-TNF en el tratamiento de la uveítis no infecciosa refractaria.

Uveitis is responsible for visual loss of up to 10% of world population and is the second leading cause of treatable blindness in people of working age, after diabetic retinopathy. The treatment of noninfectious uveitis depends on its severity; there is a high percentage (up to 40%) of cases refractory to immunosuppressants and high-dose corticosteroids. Tumor necrosis factor (TNF) is a key cytokine in the pathogenesis of noninfectious uveitis. Several case reports, open trials and small randomized controlled trials with selective blocking of TNF with monoclonal antibodies (infliximab and adalimumab) and fusion proteins (etanercept) have shown efficacy in the treatment of refractory uveitis, in idiopathic and associated with autoimmune diseases, in preventing relapses, steroid-sparing effect and improvement of long-term visual prognosis. However, there are some reports of paradoxical effects, such as induction of uveitis associated with the use of etanercept. We performed a thorough review of the literature to determine the role of anti-TNF agents in the treatment of refractory non-infectious uveitis.

Anti-TNFalpha Treatment for Two Cases of Acute Generalized Exanthematous Pustulosis Caused by Rhus Hypersensitivity / 대한내과학회지

Acute generalized exanthematous pustulosis (AGEP) is characterized by the rapid occurrence of many sterile, nonfollicular pustules on an edematous erythema accompanied by leucocytosis and fever. It is usually attributed to drugs, including herbal medications such as rhus in Korea. We report two cases of AGEP due to rhus hypersensitivity treated with anti-tumor necrosis factor (TNF)-alpha. The patients developed a generalized erythematous rash and edema, particularly on the face, with high fever and leukocytosis several days after ingesting rhus chicken or contacting rhus extract. Following treatment with a systemic steroid, the skin rash spread to the entire body and pustules arose on an edematous erythema. After stopping the systemic steroid and administering a subcutaneous injection of Etanercept, the pustular rashes, fever, and edema improved within 4 days. These results suggest that anti-TNF-alpha treatment may be effective for rapidly improving AGEP.

Safety and Clinical Responses in Ankylosing Spondylitis after Three Months of Etanercept Therapy

We aimed to evaluate the safety and clinical responses in Korean ankylosing spondylitis (AS) patients after three months of etanercept therapy. AS patients satisfying the Modified New York Criteria were enrolled. They were assessed for safety and clinical responses at enrollment and after three months of etanercept therapy. A total of 124 patients completed the study. After three months, the rate of ASsessment in AS International Working Group 20% improvement (ASAS 20) response was 79.8%. The rates of ASAS 40 and ASAS 5/6 responses were 58.5 and 62.8%, respectively. Significant improvement of Korean version of Bath AS Disease Activity Index (KBASDAI) (p<0.0001), Bath AS Functional Activity Index (BASFI) (p<0.0001), and Bath AS Metrology Index (BASMI) (p=0.0009) were achieved after three months. Quality of life was also significantly improved after three months, as demonstrated by scores for SF-36 (p<0.0001) and EQ-5D (p<0.0001). Erythrocyte sedimentation rate and C-reactive protein were significantly decreased (p<0.0001, p<0.0001, respectively). None of the patients developed tuberculosis and there were no serious adverse event. AS patients with inadequate response to conventional therapy showed significant clinical improvement without serious adverse events after three months of etanercept therapy.

Adenoviral Pneumonia During Etanercept Treatment in a Patient with Rheumatoid Arthritis

Inhibitors of tumor necrosis factor-alpha (TNF-alpha) have been approved for treating rheumatoid arthritis. As one of the biological response modifiers, etanercept has also been used in the treatment of psoriatic arthritis and inflammatory bowel disease. While etanercept is effective, certain infectious complications, such as tuberculosis, fungus, and cytomegalovirus, have been reported. We report the first Korean case of adenoviral pneumonia in a 55-year-old female who developed disseminated adenoviral infection following etanercept treatment, which resolved after anti-TNF-alpha discontinuation.

Etanercept-Induced Systemic Lupus Erythematosus in a Patient with Rheumatoid Arthritis

Tumor necrosis factor (TNF) is known to play a critical role in the pathogenesis of rheumatoid arthritis (RA). Etanercept is a recombinant soluble fusion protein of TNF type II receptor and IgG, which acts as a specific TNF- antagonist. Anti-TNF-therapy has been an important advance in the treatment of RA. However, induction of autoantibodies in some proportion of patients treated with TNF inhibitors raised concerns for development of systemic autoimmune diseases such as systemic lupus erythematosus (SLE). Although new autoantibody formation is common with anti-TNF therapy, there are only rare reports of overt SLE, most of which manifested without major organ involvement and resolved shortly after discontinuation of the therapy. We describe a 55-yr-old Korean woman who developed overt life threatening SLE complicated by pneumonia and tuberculosis following etanercept treatment for RA. This case is to our knowledge, the first report of etanercept-induced SLE in Korea.