Objective
To analyze the factors associated with response to anti–tumor necrosis factor (anti‐TNF) treatment and compare the efficacy and safety of infliximab (IFX) and adalimumab (ADA) in patients ...with refractory noninfectious uveitis.
Methods
This was a multicenter observational study of 160 patients (39% men and 61% women; median age 31 years interquartile range 21–42) with uveitis that had been refractory to other therapies, who were treated with anti‐TNF (IFX 5 mg/kg at weeks 0, 2, 6, and then every 5–6 weeks n = 98 or ADA 40 mg every 2 weeks n = 62). Factors associated with complete response were assessed by multivariate analysis. Efficacy and safety of IFX versus ADA were compared using a propensity score approach with baseline characteristics taken into account. Subdistribution hazard ratios (SHRs) and 95% confidence intervals (95% CIs) were calculated.
Results
The main etiologies of uveitis included Behçet's disease (BD) (36%), juvenile idiopathic arthritis (22%), spondyloarthropathy (10%), and sarcoidosis (6%). The overall response rate at 6 and 12 months was 87% (26% with complete response) and 93% (28% with complete response), respectively. The median time to complete response was 2 months. In multivariate analysis, BD and occurrence of >5 uveitis flares before anti‐TNF initiation were associated with complete response to anti‐TNF (SHR 2.52 95% CI 1.35–4.71, P = 0.004 and SHR 1.97 95% CI 1.02–3.84, P = 0.045, respectively). Side effects were reported in 28% of patients, including serious adverse events in 13%. IFX and ADA did not differ significantly in terms of occurrence of complete response (SHR 0.65 95% CI 0.25–1.71, P = 0.39), serious side effects (SHR 0.22 95% CI 0.04–1.25, P = 0.089), or event‐free survival (SHR 0.55 95% CI 0.28–1.08, P = 0.083).
Conclusion
Anti‐TNF treatment is highly effective in refractory inflammatory uveitis. BD is associated with increased odds of response. IFX and ADA appear to be equivalent in terms of efficacy.
In Vivo Tissue Engineering of Human Airways Martinod, Emmanuel; Paquet, Joseph; Dutau, Hervé ...
The Annals of thoracic surgery,
05/2017, Volume:
103, Issue:
5
Journal Article
Peer reviewed
Open access
Airway transplantation remains a major challenge in thoracic surgery. Based on our previous laboratory work, we developed the techniques required to bioengineer a tracheal substitute in vivo using ...cryopreserved aortic allografts as biological matrices (Replacement of the Airways and/or the Pulmonary Vessels Using a Cryopreserved Arterial Allograft TRACHEOBRONCART Study, NCT01331863). We present here 2 patients who had a definitive tracheostomy for complex laryngotracheal stenoses refractory to conventional therapy.
According to our protocol, a stented gender-mismatched -80°C cryopreserved aortic allograft was used for airway reconstruction. Follow-up assessments were done at regular intervals using clinical, imaging, and endoscopic evaluations. Immunohistochemical and XX/XY chimerism studies were performed at time of stent removal using graft biopsy specimens. Chemotactic and angiogenic properties of implanted matrices were also investigated.
At a maximal follow-up of 5 years and 7 months, the patients were breathing and speaking normally, without tracheostomy or stent. Regeneration of cartilage within the aortic grafts was demonstrated by positive immunodetection of type II collagen and markers specific for Sox9. Chimerism study from samples of neotissues demonstrated that regenerated cartilage came from recipient cells. The remaining viable matrix cells released a functionally relevant amount of proangiogenic, chemoattractant, proinflammatory/immunomodulatory cytokines, and growth factors.
This report documents the feasibility of in vivo tissue engineering for long-term functional airway transplantation in humans.
Abstract Introduction The off-label use of TNF antagonists in refractory sarcoidosis is increasingly reported but data on their efficacy and safety are still insufficient. Objective To report on ...efficacy and safety of TNF antagonists in severe and refractory sarcoidosis. Methods Examination of retrospective demographic, clinical, therapeutic, and adverse event data on 132 sarcoidosis patients (58% women; mean (min-max) age 45.5 (14–78) years) given TNF antagonists (mainly infliximab, 91%) and investigation of response-linked factors. Results The overall clinical response (complete and partial) rate was 64%. TNF-antagonist efficacy (i.e., significant decrease of the ePOST score) was noted in cases with neurologic, heart, skin, and upper respiratory tract involvements. No significant difference in efficacy was found between anti-TNF used alone and TNF with immunosuppressant. The use of anti-TNF allowed reducing prednisone dosage at end of follow-up (p<0.001). Adverse events were observed in 52% of the patients; they included infections (36%) and allergic reactions (8%) and required treatment interruption in 31 cases (23%). When TNF antagonists were interrupted, 13 patients experienced relapses within 14 months on average (median follow-up: 20.5 months). Conclusion TNF antagonists were efficacious in about two-thirds of patients with severe/refractory sarcoidosis but their use led to a high rate of adverse events.
The goal of this work was to assess the safety and efficacy of biologics (ie, tumor necrosis factor-α antagonists and tocilizumab) in patients with Takayasu arteritis.
This was a retrospective, ...multicenter study of the characteristics and outcomes of 49 patients with Takayasu arteritis (80% female; median age, 42 years 20-55 years treated by tumor necrosis factor-α antagonists 80% or tocilizumab 20%) and fulfilling American College of Rheumatology or Ishikawa criteria. Factors associated with complete response were assessed. Eighty-eight percent of patients with Takayasu arteritis were inadequately controlled with or were intolerant to conventional immunosuppressive therapy (median number, 3 1-5). Overall response (ie, complete and partial) to biological-targeted treatments at 6 and 12 months was 75% and 83%, respectively. There were significantly lower C-reactive protein levels at the initiation of biological-targeted treatments (22 mg/L 10-46 mg/L versus 58 mg/L 26-76 mg/L; P=0.006) and a trend toward fewer immunosuppressants drugs used before biologics (P=0.054) in responders (ie, complete or partial responders) relative to nonresponders to biological-targeted treatments. C-reactive protein levels and daily prednisone dose significantly decreased after 12 months of biological-targeted treatments (30 versus 6 mg/L P<0.05 and 15 versus 7.5 mg P<0.05 at baseline and 12 months, respectively). The 3-year relapse-free survival was 90.9% (83.5%-99%) over the biological treatment period compared with 58.7% (43.3%-79.7%; P=0.0025) with disease-modifying antirheumatic drugs. No difference in efficacy was found between tumor necrosis factor-α antagonists and tocilizumab. After a median follow-up of 24 months (2-95 months), 21% of patients experienced adverse effects, with biological-targeted treatments discontinued in 6.6% of cases.
This nationwide study shows a high efficacy of biological-targeted treatments in refractory patients with Takayasu arteritis with an acceptable safety profile.
Pulmonary fibrosis (PF) is an uncommon manifestation observed in patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), particularly microscopic polyangiitis (MPA). ...While patients with PF associated with AAV seem to have a worse prognosis, these patients have been described only in case reports or small retrospective case series. In this retrospective multicenter study, we report the main features and long-term outcomes of patients with PF associated with AAV, fulfilling the American College of Rheumatology criteria and/or Chapel Hill definitions. Forty-nine patients (30 men 61%; median age at diagnosis of AAV, 68 interquartile range, 58-73 years) with PF associated with AAV were identified. Forty (81.6%) patients had MPA and 9 (18.4%) had granulomatosis with polyangiitis. The diagnosis of PF preceded the onset of vasculitis in 22 (45%) patients. Usual interstitial pneumonia was the main radiologic pattern (n = 18, 43%). ANCA were mostly of antimyeloperoxidase specificity (88%). All patients were treated with glucocorticoids as induction therapy, combined with cyclophosphamide (CYC) (n = 36, 73.5%) or rituximab (RTX) (n = 1, 2%). Factors associated with mortality included occurrence of chronic respiratory insufficiency (hazard ratio HR, 7.44; 95% confidence interval CI, 1.6-34.5; p = 0.003), induction therapy with glucocorticoids alone (HR, 2.94; CI, 1.05-8.33; p = 0.04), and initial weigh loss (HR, 2.83; CI, 1.05-7.65; p = 0.041). The 3-year survival rate in patients treated with glucocorticoids alone or combined with an immunosuppressant (CYC or RTX) as induction therapy was 64% (95% CI, 41-99) and 94% (95% CI, 86-100), respectively (p = 0.03). After a median follow-up of 48 months interquartile range, 14-88 mo, 18 (37%) patients died, including 11 related to respiratory insufficiency. PF is a rare manifestation of AAV with a very poor prognosis. Induction therapy with CYC might improve the outcome.
Abstract
Objective
Orbital mass is a rare and sight-threatening manifestation of ANCA-associated vasculitides, which remains a therapeutic challenge. We aimed to describe the presentation, ...therapeutic management and outcome of ANCA-associated vasculitides-related orbital mass.
Methods
We conducted a French nationwide retrospective study of patients with orbital mass in the setting of ANCA-associated vasculitides according to ACR criteria and/or Chapel Hill Consensus Conference definitions.
Results
Fifty-nine patients 33 women, median age 46 (range 7–90) years were included. Fifty-six (95%) patients had granulomatosis with polyangiitis, two eosinophilic granulomatosis with polyangiitis and one microscopic polyangiitis. Orbital mass was unilateral in 47 (80%) cases, and seemed to develop from ENT involvement in most cases. Orbital mass biopsy was available in 32 (54%) patients, showing lymphoplasmacytic infiltration in 65%, fibrosis in 55%, granulomas in 48% and vasculitis in 36%. All patients but one received glucocorticoids as first-line therapy associated with immunosuppressive agents in 82%, mainly cyclophosphamide. Response to therapy was noted in 52% of patients treated with cyclophosphamide compared with 91% of those treated with rituximab. Twenty-seven (46%) patients required a second-line therapy because of relapse (59%) or refractory course (41%). Sequelae included visual impairment in 28%, with definitive blindness in 17%. Refractory course was associated with PR3-ANCA positivity, visual loss and contiguous pachymeningitis.
Conclusion
Orbital mass is associated with refractory course and high frequency of sequelae, especially blindness. Refractory course is associated with PR3-ANCA positivity, visual loss and contiguous pachymeningitis.
Converging evidence that G-CSF, the hemopoietic growth factor of the myeloid lineage, also exerts anti-inflammatory and pro-Th2 effects, prompted us to evaluate its direct therapeutic potential in ...autoimmune diseases. Here we report a novel activity of G-CSF in experimental allergic encephalomyelitis, a murine model for multiple sclerosis, driven by Th1-oriented autoaggressive cells. A short 7-day treatment with G-CSF, initiated at the onset of clinical signs, provided durable protection from experimental autoimmune encephalomyelitis. G-CSF-treated mice displayed limited demyelination, reduced recruitment of T cells to the CNS, and very discrete autoimmune inflammation, as well as barely detectable CNS mRNA levels of cytokines and chemokines. In the periphery, G-CSF treatment triggered an imbalance in the production by macrophages as well as autoreactive splenocytes of macrophage inflammatory protein-1alpha and monocyte chemoattractant protein-1, the prototypical pro-Th1 and pro-Th2 CC chemokines, respectively. This chemokine imbalance was associated with an immune deviation of the autoreactive response, with reduced IFN-gamma and increased IL-4 and TGF-beta1 levels. Moreover, G-CSF limited the production of TNF-alpha, a cytokine also associated with early CNS infiltration and neurological deficit. These findings support the potential application of G-CSF in the treatment of human autoimmune diseases such as multiple sclerosis, taking advantage of the wide clinical favorable experience with this molecule.
Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare disease, defined by the association of idiopathic acute TINU. The aim of our work was to determine the characteristics of adult TINU ...syndrome in France, and to assess factors (including treatment) influencing medium-term prognosis.We conducted a nationwide study including 20 French hospitals. Clinical, laboratory, and renal histopathologic data of 41 biopsy-proven TINU syndromes were retrospectively collected. The patients were diagnosed between January 1, 1999 and December 1, 2015.Twenty-five females and 16 males were included (F/M ratio: 1.6:1). The median age at disease onset was 46.8 years (range 16.8-77.4) with a median serum creatinine level at 207 μmol/L (range 100-1687) and a median estimated glomerular filtration rate (eGFR) at 27 mL/min per 1.73 m (range 2-73). Twenty-nine patients (71%) had a bilateral anterior uveitis and 24 (59%) had deterioration in general health at presentation. Moderate proteinuria was found in 32 patients (78%) (median proteinuria 0.52 g/24 h; range 0.10-2.10), aseptic leukocyturia in 25/36 patients (70%). The evaluation of renal biopsies revealed 41 patients (100%) with an acute tubulointerstitial nephritis, 19/39 patients (49%) with light to moderate fibrosis and 5 patients (12%) with an acute tubular necrosis. Thirty-six patients (88%) were treated with oral corticosteroids. After 1 year of follow-up, the median eGFR was 76 mL/min per 1.73 m (range 17-119) and 32% of the patients suffered from moderate to severe chronic kidney disease. Serum creatinine (P < 0.001, r = -0.54), serum bicarbonate and phosphate levels (respectively, P = 0.01, r = 0.53; and P = 0.04, r = 0.46), and age (P = 0.03, r = -0.37) at the 1st symptoms were associated with eGFR after 1 year. During the 1st year 40% of patients had uveitis relapses. The use of oral corticosteroids was not associated with a better kidney function but was associated with fewer uveitis relapses (P = 0.44 and 0.02, respectively).In our study, 32% of patients were suffering from moderate to severe chronic kidney disease after 1 year of follow-up, and 40% had uveitis relapses during this follow-up. This work also suggests that oral corticosteroids are effective for the treatment of TINU syndrome's uveitis.
The efficacy of intravenous immunoglobulins (IVIg) in patients with autoimmune diseases (AID) has been known for several decades. Majority of these patients received IVIg in hospital. A retrospective ...study was conducted in 22 centers in France to evaluate the feasibility of the administration of Tegeline, an IVIg from LFB Biomedicaments, and assess its safety at home, compared to in hospital, in patients with AID. The included patients were at least 18 years old, suffering from AID, and treated with at least 1 cycle of Tegeline at home after receiving 3 consecutive cycles of hospital-based treatment with Tegeline at a dose between 1 and 2 g/kg/cycle. Forty-six patients with AID, in most cases immune-mediated neuropathies, received a total of 138 cycles of Tegeline in hospital and then 323 at home. Forty-five drug-related adverse events occurred in 17 patients who received their cycles at home compared to 24 adverse events in hospital in 15 patients. Serious adverse events occurred in 3 patients during home treatment, but they were not life-threatening and did not lead to discontinuation of Tegeline. Forty-five patients continued their treatment with Tegeline at home or in hospital; 39 (84.8%) were still receiving home treatment at the end of the study. In conclusion, the study demonstrates the good safety profile of Tegeline administered at home at high doses in patients with AID who are eligible for home administration of Tegeline.
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