Childhood-Onset Non-Infectious Uveitis in the "Biologic Era". Results From Spanish Multicenter Multidisciplinary Real-World Clinical Settings.

OBJECTIVE: To characterize and describe clinical experience with childhood-onset non-infectious uveitis. STUDY DESIGN: A multicenter retrospective multidisciplinary national web-based registry of 507 patients from 21 hospitals was analyzed. Cases were grouped as immune disease-associated (IMDu), idiopathic (IDIu) or ophthalmologically distinct. Characteristics of juvenile idiopathic arthritis-associated (non-HLA-B27-related) uveitis (JIAu), IDIu, and pars planitis (PP) were compared. RESULTS: IMDu (62.3%) and JIAu (51.9%) predominated in young females; and IDIu (22.7%) and PP (13.6%) in older children, without sex imbalance. Ocular complications occurred in 45.3% of cases (posterior synechiae [28%], cataracts [16%], band keratopathy [14%], ocular hypertension [11%] and cystoid macular edema [10%]) and were associated with synthetic (86%) and biologic (65%) disease-modifying antirheumatic drug (DMARD) use. Subgroups were significantly associated (p < 0.05) with different characteristics. JIAu was typically anterior (98%), insidious (75%), in ANA-positive (69%), young females (82%) with fewer complications (31%), better visual outcomes, and later use of uveitis-effective biologics. In contrast, IDIu was characteristically anterior (87%) or panuveitic (12.1%), with acute onset (60%) and more complications at onset (59%: synechiae [31%] and cataracts [9.6%]) and less DMARD use, while PP is intermediate, and was mostly bilateral (72.5%), persistent (86.5%) and chronic (86.8%), with more complications (70%; mainly posterior segment and cataracts at last visit), impaired visual acuity at onset, and greater systemic (81.2%), subtenon (29.1%) and intravitreal (10.1%) steroid use. CONCLUSION: Prognosis of childhood uveitis has improved in the "biologic era," particularly in JIAu. Early referral and DMARD therapy may reduce steroid use and improve outcomes, especially in PP and IDIu.

Clinical and immunological study of Tofacitinib and Baricitinib in refractory Blau syndrome: case report and literature review.

Blau syndrome (BS) is an autoinflammatory disorder characterized by non-caseating granulomatous dermatitis, arthritis, and uveitis. We present a case of refractory and severe BS that was treated with the Janus kinase inhibitors (JAKINIBS), Tofacitinib (TOFA) and then Baricitinib (BARI). Our aim was to describe the clinical and immunological outcomes after treatment with JAKINIBS. Blood tests and serum samples were obtained during follow-up with TOFA and BARI. We assessed their effects on clinical outcomes, acute phase reactants, absolute lymphocyte counts (ALCs), lymphocyte subset counts, immunoglobulins, and cytokine levels. A review of the literature on the use of JAKINIBS for the treatment of uveitis and sarcoidosis was also conducted. TOFA led to a rapid and maintained disease control and a steroid-sparing effect. A decrease from baseline was observed in ALC, CD3+, CD4+, CD8+, and natural killer (NK) cell counts. B-cells were stable. Serum levels of interleukin (IL)-4 and tumor necrosis factor alpha (TNF-α) increased, whereas IL-2, IL-6, IL-10, and IL-17 maintained stable. TOFA was discontinued after 19 months due to significant lymphopenia. The initiation of BARI allowed maintaining adequate control of disease activity with an adequate safety profile. The literature review showed seven patients with uveitis and five with sarcoidosis treated with JAKINIBS. No cases of BS treated with JAKINIBS were found. We report the successful use of JAKINIBS in a patient with refractory and severe BS.

Intravenous methylprednisolone induces rapid improvement in non-infectious uveitis: a multicentre study of 112 patients.

OBJECTIVES: Rapid control of intraocular inflammation in non-infectious uveitis (NIU) is mandatory to avoid irreversible structural and functional damage. In this study, we assessed the efficacy and safety of intravenous methylprednisolone (IVMP) pulses in the treatment of NIU. METHODS: A retrospective case series of 112 patients who received IVMP for the treatment of NIU, either isolated or associated with different underlying diseases, was studied. Intraocular inflammation (anterior chamber cells and vitritis) was the primary outcome measure. Secondary outcome measures were macular thickness and best corrected visual acuity (BCVA). Patients were assessed at baseline visit, and at days 2-5, 7, 15 and 30 after initiation of IVMP pulse therapy. RESULTS: A total of 112 patients (mean age 42±14.5 yrs) were assessed. An underlying immune-mediated disease was diagnosed in 73 patients. Inflammatory ocular patterns were panuveitis (n=68), posterior uveitis (n=30), anterior uveitis (AU) (n=12), and intermediate uveitis (n=2). Additionally, patients presented cystoid macular oedema (CME) (n=50), retinal vasculitis (n=37), and exudative retinal detachment (n=31). Therapies used before IVMP included intraocular glucocorticoids (n=4), high-dose oral systemic glucocorticoids (n=77), and conventional (n=107) or biologic (n=40) immunosuppressive drugs. IVMP dose ranged from 80 to 1,000 mg/day for 3-5 consecutive days. Improvement was observed in AU, vitritis, BCVA, CME, and retinal vasculitis. At first month evaluation, total remission was achieved in 19 patients. Side effects of IVMP were respiratory infections (n=3), uncontrolled hyperglycaemia (n=1), herpes zoster (n=1), and oral candidiasis (n=1). CONCLUSIONS: IVMP pulse therapy was effective and safe, and achieved rapid control of NIU.

Epidemiology of sarcoidosis in northern Spain, 1999-2019: A population-based study.

BACKGROUND: The incidence of sarcoidosis varies widely worldwide. The aim of this study was to estimate the incidence of sarcoidosis in a population-based cohort from northern Spain. METHODS: Patients diagnosed with sarcoidosis at Marqués de Valdecilla University Hospital, corresponding to the central Cantabria that encompasses Santander city and the surroundings, between January 1999 and December 2019were assessed. The diagnosis of sarcoidosis was established according to ATS/ERS/WASOG criteria as follows: compatible clinical and radiological presentation, histopathologic confirmation, and exclusion of other granulomatous diseases. Demographic and clinical data were collected. The incidence of sarcoidosis between 1999-2019 was estimated by sex, age, and year of diagnosis. RESULTS: A total of 234 patients were included, with a male/female ratio of 0.81. The mean age of the cohort at diagnosis was 48.43 ± 14.83 years and 129 (55.1%) were women. Incidence during the period of study was 3.58 per 100,000 populations (95% confidence interval: 3.13 - 4.07). No gender predominance was observed. An increase in age at diagnosis over time was found in the linear regression analysis. Thoracic affection was found in 180 patients (76.9%). Most common extra-thoracic areas affected were skin (34.2%), joints (30.8%) and eyes (15.4%). CONCLUSIONS: The incidence of sarcoidosis estimated in this study was similar to that of other Mediterranean countries. No gender predominance was observed. Consistent with previous studies, male presented an incidence peak 10 years earlier than female. A second peak between ages 60-69 years was identified in both sexes.

Long-term Follow-up and Optimization of Infliximab in Refractory Uveitis Due to Behçet Disease: National Study of 103 White Patients.

OBJECTIVE: In a large series of White patients with refractory uveitis due to Behçet disease (BD) being treated with infliximab (IFX), we assessed (1) long-term efficacy and safety of IFX, and (2) IFX optimization when ocular remission was achieved. METHODS: Our multicenter study of IFX-treated patients with BD uveitis refractory to conventional immunosuppressant agents treated 103 patients/185 affected eyes with IFX as first biologic therapy in the following intervals: 3-5 mg/kg intravenous at 0, 2, 6, and then every 4-8 weeks. The main outcome variables were analyzed at baseline, first week, first month, sixth month, first year, and second year of IFX therapy. After remission, based on a shared decision between patient and clinician, IFX optimization was performed. Efficacy, safety, and cost of IFX therapy were evaluated. RESULTS: In the whole series (n = 103), main outcome variables showed a rapid and maintained improvement, reaching remission in 78 patients after a mean IFX duration of 31.5 months. Serious adverse events were observed in 9 patients: infusion reactions (n = 4), tuberculosis (n = 1), Mycobacterium avium pneumonia (n = 1), severe oral ulcers (n = 1), palmoplantar psoriasis (n = 1), and colon carcinoma (n = 1). In the optimization subanalysis, the comparative study between optimized and nonoptimized groups showed (1) no differences in clinical characteristics at baseline, (2) similar maintained improvement in most ocular outcomes, (3) lower severe adverse events, and (4) lower mean IFX costs in the optimized group (€4826.52 vs €9854.13 per patient/yr). CONCLUSION: IFX seems to be effective and relatively safe in White patients with refractory BD uveitis. IFX optimization is effective, safe, and cost-effective.

Biologic therapy in severe and refractory peripheral ulcerative keratitis (PUK). Multicenter study of 34 patients.

PURPOSE: We assessed the efficacy and safety of biologic therapy in severe and refractory Peripheral Ulcerative Keratitis (PUK). DESIGN: Open-label multicenter study of biologic-treated patients with severe PUK refractory to conventional immunosuppressive drugs. SUBJECTS: We studied 34 patients (44 affected eyes) (24 women/10 men; mean age, 55.26±17.4 years). PUK was associated with a well-defined condition in 29 of them (rheumatoid arthritis [n = 20], psoriatic arthritis [n = 2], inflammatory bowel disease [n = 2], Behçet disease [n = 1], granulomatosis with polyangiitis [n = 1], microscopic polyangiitis [n = 1], systemic lupus erythematosus [n = 1] and axial spondyloarthritis [n = 1]). Besides topical and oral systemic glucocorticoids, patients had received: methylprednisolone pulses [n = 9], and conventional immunosuppressive drugs, mainly methotrexate [n = 18], and leflunomide [n = 7]. Eleven patients had required ocular surgery prior to biologic therapy. METHODS: Following biologic therapy, baseline main outcomes were compared with those found at 1st week, 1st and 6th months and 1st year. MAIN OUTCOME MEASURES: Efficacy and safety of biologic therapy. Efficacy was analyzed by the assessment of corneal inflammation (corneal thinning, central keratolysis and ocular perforation); other causes of ocular surface inflammation (scleritis, episcleritis); intraocular inflammation (uveitis); visual acuity and glucocorticoid sparing effect. RESULTS: The first biologic agents used were anti-TNFα drugs (n = 25); adalimumab (n = 16), infliximab (n = 8), etanercept (n = 1), and non-TNFα agents (n = 9); rituximab (n = 7), tocilizumab (n = 1) belimumab (n = 1) and abatacept (n = 1). During the follow-up, switching to a second biologic agent was required in 12 of the 25 (48%) patients treated with anti-TNFα drugs. However, no switching was required in those undergoing biologic therapy different from anti-TNFα agents. The main outcome variables showed a rapid and maintained improvement after a mean follow-up of 23.7 ± 20 months. Major adverse effects were tachyphylaxis, relapsing respiratory infections, supraventricular tachycardia, pulmonary tuberculosis and death, one each. CONCLUSIONS: Biologic therapy is effective and relatively safe in patients with severe and refractory PUK. Non-anti-TNFα agents appear to be effective in these patients.

Anti-IL6-Receptor Tocilizumab in Refractory and Noninfectious Uveitic Cystoid Macular Edema: Multicenter Study of 25 Patients.

PURPOSE: Cystoid macular edema (CME) is a leading cause of blindness. This study assessed the efficacy and safety of tocilizumab (TCZ) in refractory CME. DESIGN: Retrospective case series. METHODS: Patients with CME secondary to noninfectious uveitis who had inadequate response to corticosteroids and at least 1 conventional immunosuppressive drug, and in most cases to other biological agents, were studied. CME was defined as central retinal thickness greater than 300 µm. The primary outcome measure was macular thickness. Intraocular inflammation, best-corrected visual acuity (BCVA), and corticosteroid-sparing effect were also analyzed. RESULTS: A total of 25 patients (mean ± standard deviation age 33.6 ± 18.9 years; 17 women) with CME were assessed. Underlying diseases associated with uveitis-related CME are juvenile idiopathic arthritis (n = 9), Behçet disease (n = 7), birdshot retinochoroidopathy (n = 4), idiopathic (n = 4), and sarcoidosis (n = 1). The ocular patterns were panuveitis (n = 9), anterior uveitis (n = 7), posterior uveitis (n = 5), and intermediate uveitis (n = 4). Most patients had CME in both eyes (n = 24). TCZ was used in monotherapy (n = 11) or combined with conventional immunosuppressive drugs. Regardless of the underlying disease, compared to baseline, a statistically significant improvement in macular thickness (415.7 ± 177.2 vs 259.1 ± 499.5 µm; P = .00009) and BCVA (0.39 ± 0.31 vs 0.54 ± 0.33; P = .0002) was obtained, allowing us to reduce the daily dose of prednisone (15.9 ± 13.6 mg/day vs 3.1 ± 2.3 mg/day; P = .002) after 12 months of therapy. Remission was achieved in 14 patients. Only minor side effects were observed after a mean follow-up of 12.7 ± 8.34 months. CONCLUSION: Macular thickness is reduced following administration of TCZ in refractory uveitis-related CME.

Successful Optimization of Adalimumab Therapy in Refractory Uveitis Due to Behçet's Disease.

PURPOSE: To assess efficacy, safety, and cost-effectiveness of adalimumab (ADA) therapy optimization in a large series of patients with uveitis due to Behçet disease (BD) who achieved remission after the use of this biologic agent. DESIGN: Open-label multicenter study of ADA-treated patients with BD uveitis refractory to conventional immunosuppressants. SUBJECTS: Sixty-five of 74 patients with uveitis due to BD, who achieved remission after a median ADA duration of 6 (range, 3-12) months. ADA was optimized in 23 (35.4%) of them. This biologic agent was maintained at a dose of 40 mg/subcutaneously/2 weeks in the remaining 42 patients. METHODS: After remission, based on a shared decision between the patient and the treating physician, ADA was optimized. When agreement between patient and physician was reached, optimization was performed by prolonging the ADA dosing interval progressively. Comparison between optimized and nonoptimized patients was performed. MAIN OUTCOME MEASURES: Efficacy, safety, and cost-effectiveness in optimized and nonoptimized groups. To determine efficacy, intraocular inflammation (anterior chamber cells, vitritis, and retinal vasculitis), macular thickness, visual acuity, and the sparing effect of glucocorticoids were assessed. RESULTS: No demographic or ocular differences were found at the time of ADA onset between the optimized and the nonoptimized groups. Most ocular outcomes were similar after a mean ± standard deviation follow-up of 34.7±13.3 and 26±21.3 months in the optimized and nonoptimized groups, respectively. However, relevant adverse effects were only seen in the nonoptimized group (lymphoma, pneumonia, severe local reaction at the injection site, and bacteremia by Escherichia coli, 1 each). Moreover, the mean ADA treatment costs were lower in the optimized group than in the nonoptimized group (6101.25 euros/patient/year vs. 12 339.48; P < 0.01). CONCLUSION: ADA optimization in BD uveitis refractory to conventional therapy is effective, safe, and cost-effective.

Anti-interleukin 6 receptor tocilizumab in refractory uveitis associated with Behçet's disease: multicentre retrospective study.

Objective: To assess the efficacy of tocilizumab (TCZ) in refractory uveitis of Behçet's disease (BD). Methods: Multicentre study of patients with BD-associated uveitis. Patients were refractory to conventional and biologic immunosuppressive drugs. The main outcome measures were intraocular inflammation, macular thickness, visual acuity and corticosteroid-sparing effects. Results: We studied 11 patients (7 men) (20 affected eyes); median age 35 years. Uveitis was bilateral in nine patients. The patterns of ocular involvement were panuveitis (n = 8, with retinal vasculitis in 4), anterior uveitis (n = 2) and posterior uveitis (n = 1). Cystoid macular oedema was present in seven patients. The clinical course was recurrent (n = 7) or chronic (n = 4). Before TCZ, patients had received systemic corticosteroids, conventional immunosuppressants and the following biologic agents: adalimumab (n = 8), infliximab (n = 4), canakimumab (n = 1), golimumab (n = 3), etanercept (n = 1). TCZ was used as monotherapy or combined with conventional immunosuppressants at 8 mg/kg/i.v./4 weeks (n = 10) or 162 mg/s.c./week (n = 1). At TCZ onset the following extraocular manifestations were present: oral and/or genital ulcers (n = 7), arthritis (n = 4), folliculitis/pseudofolliculitis (n = 4), erythema nodosum (n = 2), livedo reticularis (n = 1) and neurological involvement (n = 2). TCZ yielded rapid and maintained improvement in all ocular parameters of the patients, with complete remission in eight of them. However, this was not the case for the extraocular manifestations, since TCZ was only effective in three of them. After a mean (s.d.) follow-up of 9.5 (8.05) months, TCZ was withdrawn in two cases, due to a severe infusion reaction and arthritis impairment, respectively. Conclusion: TCZ could be a therapeutic option in patients with BD and refractory uveitis.

Thrombocytopenia as a thrombotic risk factor in patients with antiphospholipid antibodies without disease criteria. / Trombocitopenia como factor de riesgo trombótico en pacientes con anticuerpos antifosfolipídicos sin criterios de enfermedad.

INTRODUCTION: The antiphospholipid syndrome (APS) is an acquired immune disorder defined by the presence of thrombosis (arterial and/or venous) and/or pregnancy morbidity along with the presence of positive antiphospholipid antibodies (aPL). There is a clear relationship between aPL and some events not included in the clinical criteria, including haematologic. OBJECTIVES: a) to study the probability of developing clinical APS in patients with positive aPL and thrombopenia; b) to identify potential risk factors for thrombosis, and c) to study the association between thrombocytopenia and aPL. METHODS: A retrospective study of 138 patients with positive aPL without fulfilling clinical criteria for APS. Thrombocytopenia was defined as a platelet count≤100,000/µl. Patients with other causes of thrombocytopenia were excluded. RESULTS: Seventeen of the 138 (12%) patients in the study had thrombocytopenia. The mean platelet count was 60,000/µl. The risk of developing thrombocytopenia was higher in smokers (OR 2.8; P=.044), in those with lupus anticoagulant (OR 13.5; P<.001) and those with higher burden of aPL (OR 50.8; P<.001). After a mean follow-up of 146±60.3 months, 5 patients with thrombocytopenia (29.4%) developed thrombosis. CONCLUSIONS: In our series, the incidence of thrombocytopenia is 12%. aPL-positive patients who develop thrombocytopenia have a potential risk of developing thrombosis. Tobacco could be a risk factor for thrombocytopenia. Autoantibodies load is a risk factor for the development of thrombocytopenia.

Efficacy of Anti-IL6-Receptor Tocilizumab in Refractory Cystoid Macular Edema of Birdshot Retinochoroidopathy Report of Two Cases and Literature Review.

PURPOSE: To evaluate tocilizumab (TCZ) efficacy in severe and refractory birdshot chorioretinopathy (BSCR). METHODS: Assessment of BSCR patients refractory to conventional immunosuppressive and anti-TNF-α drugs who underwent TCZ therapy. RESULTS: Two HLA-A29 positive patients (man/37 years and woman/38 years; four affected eyes) with BSCR were studied. They had a chronic bilateral posterior uveitis. Patient 1 had been treated with intraocular and oral corticosteroids, cyclosporine A, and infliximab whereas Patient 2 received intravenous methylprednisolone pulses, cyclosporine A, azathioprine, and adalimumab. At TCZ onset they had macular edema (four eyes); visual acuity (VA) impairment (four eyes); vitritis (one eye); and diffuse angiographic signs of vasculitis (periphlebitis) (two eyes). Improvement of VA and OCT was observed following TCZ therapy in both patients. After a follow-up of 18 months (Patient 1) and 10 months (Patient 2), respectively, a corticosteroid sparing effect without any adverse effects was achieved in both cases. CONCLUSIONS: TCZ was effective in two patients with BSCR refractory to anti-TNF-α agents.

Anti-Interleukin-6 Receptor Tocilizumab for Severe Juvenile Idiopathic Arthritis-Associated Uveitis Refractory to Anti-Tumor Necrosis Factor Therapy: A Multicenter Study of Twenty-Five Patients.

OBJECTIVE: To assess the efficacy of tocilizumab (TCZ) for the treatment of juvenile idiopathic arthritis (JIA)-associated uveitis. METHODS: We conducted a multicenter study of patients with JIA-associated uveitis that was refractory to conventional immunosuppressive drugs and anti-tumor necrosis factor (anti-TNF) agents. RESULTS: We assessed 25 patients (21 female; 47 affected eyes) with a mean ± SD age of 18.5 ± 8.3 years. Uveitis was bilateral in 22 patients. Cystoid macular edema was present in 9 patients. Ocular sequelae found at initiation of TCZ included cataracts (n = 13), glaucoma (n = 7), synechiae (n = 10), band keratopathy (n = 12), maculopathy (n = 9), and amblyopia (n = 5). Before TCZ, patients had received corticosteroids, conventional immunosuppressive drugs, and biologic agents (median 2 [range 1-5]), including adalimumab (n = 24), etanercept (n = 8), infliximab (n = 7), abatacept (n = 6), rituximab (n = 2), anakinra (n = 1), and golimumab (n = 1). Patients received 8 mg/kg TCZ intravenously every 4 weeks in most cases. TCZ yielded rapid and maintained improvement in all ocular parameters. After 6 months of therapy, 79.2% of patients showed improvement in anterior chamber cell numbers, and 88.2% showed improvement after 1 year. Central macular thickness measured by optical coherence tomography in patients with cystoid macular edema decreased from a mean ± SD of 401.7 ± 86.8 µm to 259.1 ± 39.5 µm after 6 months of TCZ (P = 0.012). The best-corrected visual acuity increased from 0.56 ± 0.35 to 0.64 ± 0.32 (P < 0.01). After a median follow-up of 12 months, visual improvement persisted, and complete remission of uveitis was observed in 19 of 25 patients. Significant reduction in the prednisone dosage was also achieved. The main adverse effects were severe autoimmune thrombocytopenia in 1 patient, pneumonia and then autoimmune anemia and thrombocytopenia in 1 patient, and viral conjunctivitis and bullous impetigo in 1 patient. CONCLUSION: TCZ appears to be a useful therapy for severe refractory JIA-associated uveitis.