Scleritis Therapy

Ultrasound biomicroscopy in scleritis

To evaluate demographic characteristics, clinical features, systemic disease associations, visual outcomes, and treatment modalities of patients with episcleritis and scleritis in an Italian tertiary care referral center. Data from 25 patients with episcleritis and from 85 patients with scleritis followed from 2003 to 2012 were retrospectively evaluated. The main outcome measures were demographics, ocular disease characteristics, presence of systemic associated disease, treatment regimen, and follow-up period. Episcleritis and scleritis were found bilaterally in 24% and 31% of patients, respectively (p<0.521). The episcleritis was diffuse in 15 and focal in 10 patients, while the scleritis was diffuse in 49, nodular in 28, necrotizing in 6, and posterior in 2 patients. Anterior uveitis (4% vs 31%; p<0.006), peripheral ulcerative keratitis (0% vs 14%; p<0.167), ocular hypertension (0% vs 7%; p<0.333), and a decrease in visual acuity (4% vs 19%; p<0.112) were encountered as ocular complications in patients with episcleritis and patients with scleritis, respectively. An associated systemic disease was found in 20% and 52% of patients with episcleritis and patients with scleritis (p<0.004). Among patients with episcleritis, 76% required topical corticosteroid treatment to achieve disease resolution, 16% oral nonsteroidal anti-inflammatory drugs (NSAIDs), and 8% antivirals; 39% of patients with scleritis required systemic NSAIDs, 12% oral corticosteroids, 34% immunosuppressive drugs, and 15% antibiotics or antivirals. The importance of differentiating scleritis from episcleritis is remarkable given the significant difference in the degree of ocular complications and associated systemic diseases between these ocular conditions. Prompt diagnosis, systemic assessment, and treatment are fundamental in all patients with scleral inflammation.

Objective To evaluate the clinical characteristics,the associated systemic diseases,the treatment outcomes and prognostic factors of the patients with scleritis and episcleritis.Methods Medical records were retrospectively reviewed for 79 patients with scleritis and episcleritis who presented between 2006 and 2012.Forty-eight patients were female and 31 were male.The mean age at presentation was 47.3±18.7 years old (ranged 16～69 years).The clinical features,the best corrected visual acuity,the systemic disease association,the treatment outcomes and ocular complications were analyzed.The main treatments included the topical or systemic nonsteroidal anti-inflammatory drugs and corticosteroids.Some patients were treated with additional immunosuppressive agents.Results Of the 79 patients,the unilateral involvement occurred in 61 patients (77.2％) and bilateral involvement in 18 patients (22.8％).There was a slight predominance of women (60.8％).There were 11 cases (13.9％) with episcleritis and 68 cases (86.1％) with scleritis.Among the scleritis,there were 37 cases (46.8％) with diffuse anterior scleritis,15 cases (19.0％) with nodular anterior scleritis,4 cases (5.1％) with necrotising anterior scleritis and 12 cases (15.2％) with posterior scleritis.There were 25 cases (31.6％) combined with anterior uveitis,16 cases (20.3％) with ocular hypertension and 23 cases (29.1％) associated with systemic diseases.Thirty-six cases (45.6％) of patients were treated with systemic corticosteroids and 16 cases (20.3％) were combined with immunosuppressive agents.The visual outcomes were generally good in most patients,the risk factors for the poorer visual outcomes included necrotizing scleritis (OR=4.01,P ＜0.01),degree of scleral inflammation of more than level 3 (OR=2.24,P ＜0.01),posterior scleritis (OR=2.13,P ＜0.05),association with systemic disease (OR=1.57,P ＜0.05) and combined with anterior uveitis (OR=1.25,P ＜0.05).Conclusions Scleritis is a form of recurrent ocular inflammation frequently associated with systemic autoimmune diseases.Most of the episcleritis and some anterior scleritis are achieved the good prognostic visual outcomes.Some of the refractory patients need to receive the oral corticosteroids or immunosuppressive drugs to control the recurrent inflammation. Key words: Scleritis; Episcleritis; Immunosuppressive therapy

Non steroidal anti-inflammatory drugs (NSAIDs) are still the most commonly used remedies for rheumatic diseases. But NSAIDs produce serious adverse effects, the most important being gastric injury up to gastric ulceration and renal damage. Several strategies have been adopted in order to avoid these shortcomings, especially gastrointestinal toxicity. So, non steroidal anti-inflammatory drugs have been associated with gastroprotective agents that counteract the damaging effects of prostaglandin synthesis suppression: however, a combination therapy introduces problems of pharmacokinetics, toxicity, and patient s compliance. Also incorporation of a nitric oxide (NO)-generating moiety into the molecule of several NSAIDs was shown to greatly attenuate their ulcerogenic activity: however, several findings suggest a possible involvement of NO in the pathogenesis of arthritis and subsequent tissue destruction. A most promising approach seemed to be the preparation of novel NSAIDs, specific for the inducible isoform of cyclooxygenase (COX-2): they appear to be devoid of gastrointestinal toxicity, in that they spare mucosal prostaglandin synthesis. However, a number of recent studies raised serious questions about the two central tenets that support this approach, namely that the prostaglandins that mediate inflammation and pain are produced solely via COX-2 and that the prostaglandins that are important in gastrointestinal and renal function are produced solely via COX-1. So, increasing evidence shows that COX-2 (not only COX-1) also plays a physiological role in several body functions and that, conversely, COX-1 (not only COX-2) may also be induced at sites of inflammation. Moreover, COX-2 selective NSAIDs have lost the cardiovascular protective effects of non-selective NSAIDs, effects which are mediated through COX-1 inhibition (in addition, COX-2 has a role in sustaining vascular prostacyclin production). The products generated by the 5-lipoxygenase pathway (leukotrienes) are particularly important in inflammation: indeed, leukotrienes increase microvascular permeability and are potent chemotactic agents; moreover, inhibition of 5-lipoxygenase indirectly reduces the expression of TNF-alpha (a cytokine that plays a key role in inflammation). This explains the efforts to obtain drugs able to inhibit both 5-lipoxygenase and cyclooxygenases: the so-called dual acting anti-inflammatory drugs. Such compounds retain the activity of classical NSAIDs, while avoiding their main drawbacks, in that curtailed production of gastroprotective prostaglandins is associated with a concurrent curtailed production of the gastro-damaging and bronchoconstrictive leukotrienes. Moreover, thanks to their mechanism of action, dual acting anti-inflammatory drugs could not merely alleviate symptoms of rheumatic diseases, but might also satisfy, at least in part, the criteria of curative drugs. Indeed, leukotrienes are pro-inflammatory, increase microvascular permeability, are potent chemotactic agents and attract eosinophils, neutrophils and monocytes into the synovium. Finally, recent data strongly suggest that dual inhibitors may have specific protective activity also in neurodegeneration.

A review of anaphylaxis in a clinic over three years was performed. A co-factor for anaphylaxis stood out as a commonality to all reactions. All five patients had a non steroidal anti-inflammatory drug (NSAID) 24 hours prior to immunotherapy. Among symptoms, urticaria was the commonest; others included cough, angioedema, dyspnea, nausea, vomiting, hypotension and tachycardia. The symptoms appeared within 5 minutes to two hours post-injection. All reactions resolved after few hours. In all cases, NSAID use pre-injection was the only common factor. Two patients also had moderate exercise post-injection, but previous immunotherapy was without incident. All but one patient were administered epinephrine in clinic and recovered without significant morbidity, some were also given cetirizine as adjunct treatment and all were observed until symptoms resolved. While two patients stopped immunotherapy, three patients continued without incident and are now on maintenance dose. The one patient who did not receive epinephrine presented to a walk in clinic for her reaction and received antihistamine treatment alone. NSAID use, although overlooked in the literature, is a common cofactor in anaphylaxis in response to immunotherapy. At Torontoallergists™, a clinic with three allergists in practice, 5 such cases among approximately 3 600 injections in the last three years were noted after extensive chart review. Therefore an NSAID was associated with anaphylaxis in 0.0014% of the immunotherapy injections, whereas two cases of anaphylaxis involved NSAID and exercise involvement. No cases implicating other risk factors or co-factors for anaphylaxis during immunotherapy, such as dosage errors, or injection during asthma exacerbation were present [1]. It is speculated that aspirin and other NSAIDS lower the threshold for anaphylaxis after allergen injections through their COX-inhibiting mechanism of action [2]. The COX pathway synthesizes, from arachidonic acids, prostaglandin D2 and E2, are repressors of inflammatory mediator release from basophils and mast cells [3]. Therefore, NSAIDS increases the likelihood of anaphylaxis after immunotherapy by suppression of prostaglandin D2 and E2, which would normally inhibit histamine release. Supporting this mechanism is Marone et al’s study where higher concentration of NSAIDS and more inhibition of COX activity correlated with higher release of histamine [2]. However, in spite of the data about NSAID acting as a co-factor for anaphylaxis, NSAID avoidance around immunotherapy cannot be found in practice parameters from the AAAAI, ACAAI, and CSACI [4,5]. Therefore, as a patient safety precaution, we highly encourage NSAIDS avoidance to be included for future immunotherapy practice guidelines. We welcome other centers to corroborate.

Anti-inflammatory analgesics and drugs used in rheumatoid arthritis and gout

Néphropathie interstitielle avec syndrome néphrotique induite par le pirprofène

Researchers have found dramatically elevated cyclooxygenase-2 (COX-2) expression in a striking number of malignant and premalignant conditions. Epidemiological evidence is in favour of aspirin and non steroidal anti-inflammatory drugs (NSAIDs) preventing certain tumors. More than 100 years after aspirin, an inhibitor of cyclooxygenase-1 and -2, was first used for the treatment of rheumatic diseases, analogues were developed for the same and other inclinations that now are available for clinical use. These new drugs were designed to specifically inhibit cyclooxygenase-2. They are thought having equal efficacy, but significantly fewer gastrointestinal side effects than the non steroidal anti-inflammatory drugs that nonspecifically inhibit the cyclooxygenase enzymes. After the selective cyclooxygenase-2 inhibitor celexocib has been licensed in the USA for the chemoprevention of colorectal cancer, there is hope in this new class of agents to prevent other cancers as well. Epidemiological studies suggest a decreased incidence of cancers of the colon, rectum, oesophagus, and stomach in regular users of non steroidal anti-inflammatory drugs; while the evidence from observational studies for other tumors is not yet strong enough, the broad range of clinical trials that are currently under their way will help establish the drugs' effectiveness in preventing or treating a variety of different types of cancer.

Clinical Characteristics of a Large Cohort of Patients with Scleritis and Episcleritis

Non- Steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed category of drugs. NSAIDs are the main cause of allergic reactions both in adults and children. Hypersensitivity reactions due to NSAIDs involve 0.3% to 0.5% of the overall population. Among the different types of NSAIDs induced hypersensitivity reactions, urticaria and angioedema are the most common. Angioedema can be of two types, allergic(IgE) &amp; Nonallergic( Non IgE) mediated. Allergic angioedema is immune mediated but non allergic angioedema mimic immune mediated allergic reaction without underlying evidence of immunological mechanism which can cause diagnostic difficulties for the clinician. Distinguishing immune-mediated and non-immune-mediated reactions can be difficult, so careful evaluation is needed. Pathomechanism of NSAIDs induced non allergic angioedema is based on cysteniyl leukotrienes and bradykinin pathway in which NSAIDs block cyclo oxygenase pathway and directs the lipoxygenase pathway and generates leukotrienes which result in the development of angioedema. NSAIDs induced allergic angioedema is quite frequent and NSAIDs induced nonallergic angioedema are quite rare.The detailed information of these reactions is necessary to decrease morbidity and mortality associated with the reactions.The early recognition and discontinuation of suspected drug should be done in order to avoid further complications. Here, we report a case of a patient with non allergic angioedema in association with use of Ketorolac.

Computation-based drug repositioning approaches that automatically search vast amounts of genomic-chemical-phenotypic data for tens of thousands of drugs and diseases can greatly speed up the traditional drug-discovery process. To date, systematic and comprehensive computation-based approaches to identify and validate drug repositioning candidates for High-grade serous ovarian cancer (HGSOC) have not been undertaken. Using a novel computational drug-repositioning platform (Drug-Predict) with HGSOC gene expression dataset from The Cancer Genome Atlas (TCGA) as the input, we have uncovered that Non-steroidal anti-inflammatory drugs (NSAIDs) could be potential candidates for Drug repositioning in HGSOC. Given that numerous epidemiological studies have shown that regular intake of NSAIDs in women is associated with decreased incidence of ovarian cancer, we assessed whether NSAIDs could have chemo-adjuvant applications in HGSOC and have identified Indomethacin as a novel chemo-adjuvant in HGSOC. Indomethacin decreased survival of primary HGSOC tumor cells and interestingly, cisplatin resistant ovarian tumor cells (derived from primary HGSOC PDX models) exhibited significantly higher cell death upon Indomethacin treatment suggesting that Indomethacin could exert chemo-adjuvant effects in HGSOC. Accordingly, Indomethacin treatment induced chemo-sensitivity in cisplatin resistant HGSOC tumor cells and combo treatment with Indomethacin and cisplatin exerted synergistic cell death as compared to individual drugs alone. Furthermore, Indomethacin decreased stem-like properties and induced chemo-sensitivity in ALDHhigh cisplatin-resistant tumor-initiating cells (TICs) thus suggesting that the chemo-adjuvant effect of the drug is mediated by decrease in TIC properties in HGSOC cells. Mechanistically, we found that Indomethacin inhibits Wnt/β-catenin signaling by degrading β-catenin and β-catenin modulation inversely affected Indomethacin functioning in HGSOC. Our study is the first report describing functional effects of an NSAID in patient-derived HGSOC models and demonstrates that combining novel computational predictions with experimental validation has potential in identifying viable drug candidates and moving them into patient trials efficiently and cost-effectively. Since NSAIDs are in routine clinical use in gynecological settings and have acceptable safety profile, this discovery provides with a potentially rapid and cost-effective translational opportunity for testing NSAIDs as chemo-adjuvants in patient trials in HGSOC. Citation Format: Anil Belur Nagaraj, QuanQiu Wang, Olga Kovalenko, Peronne Joseph, Yang Chen, Rong Xu and Analisa DiFeo. PHARMACOLOGIC ANALYSIS OF HIGH–GRADE SEROUS OVARIAN CANCER TCGA DATASET IDENTIFIES A NOVEL CHEMO–ADJUVANT ROLE FOR NON–STEROIDAL ANTI–INFLAMMATORY DRUGS (NSAIDS) [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-081.

BackgroundMany older people have chronic knee pain. Both topical and oral non- steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat this. Oral NSAIDS are effective, at least in the short term, but can have severe adverse effects. Topical NSAIDs also appear to be effective, at least in the short term. One might expect topical NSAIDs both to be less effective and to have fewer adverse effects than oral NSAIDs. If topical NSAIDs have fewer adverse effects this may outweigh both the reduction in effectiveness and the higher cost of topical compared to oral treatment. Patient preferences may influence the comparative effectiveness of drugs delivered via different routes.MethodsTOIB is a randomised trial comparing topical and oral ibuprofen, with a parallel patient preference study. We are recruiting people aged 50 or over with chronic knee pain, from 27 MRC General Practice Research Framework practices across the UK. We are seeking to recruit 283 participants to the RCT and 379 to the PPS. Participants will be followed up for up to two years (with the majority reaching one year). Outcomes will be assessed by postal questionnaire, nurse examination, laboratory tests and medical record searches at one and two years or the end of the study.DiscussionThis study will provide new evidence on the overall costs and benefits of treating chronic knee pain with either oral or topical ibuprofen. The use of a patient preference design is unusual, but will allow us to explore how preference influences response to a medication. In addition, it will provide more information on adverse events. This study will provide evidence to inform primary care practitioners, and possibly influence practice.

Objetivo: Correlacionar achados da biomicroscopia ultra-sonica (UBM) com tipos de esclerite anterior. Metodos: Foram avaliados seis pacientes encaminhados ao Setor de Ultra-som do Departamento de Oftalmologia da Universidade Federal de Sao Paulo - Escola Paulista de Medicina, com suspeita clinica de esclerite anterior, utilizando-se o ultra-som de alta frequencia (transdutor de 50 MHz) para elucidacao das alteracoes histopatologicas encontradas na esclerite anterior. Resultados: Pacientes com esclerite nodular apresentaram lesao escleral bem delimitada, homogenea, hiporrefletiva, com espessamento localizado e hiporrefletividade dos tecidos adjacentes. Pacientes com esclerite difusa apresentaram espessamento escleral heterogeneo, de aspecto moteado. Pacientes com esclerite necrotizante apresentaram perda de tecido com afinamento escleral e alteracoes vitreas adjacentes. Conclusao: A biomicroscopia ultra-sonica e excelente metodo nao-invasivo para se diferenciar os tecidos oculares acometidos durante o processo de esclerite anterior, auxiliando o profissional no diagnostico e, consequentemente, no tratamento das lesoes.

Non steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed drugs; in the US alone there are over 110 million prescriptions annually [1]. However, their use is limited by their gastrointestinal (GI) side-effects, which is an issue particularly in the elderly where the risk for GI complications is elevated and –70% take an NSAID (including aspirin) at least once weekly [2–4]. The occurrence of complicated GI events due to NSAIDs in patients with arthritis is 1–1.5% yearly (i.e., only perforation, ulceration and bleeding) [1]. When considering the large number of patients consuming NSAIDs, this translates into a considerable health care problem. Other risk factors associated with NSAID-induced GI complications are history of previous ulcers, concomitant anticoagulation or corticosteroid use and high dose NSAIDs [3]. Use of low-dose aspirin approximately doubles the risk of bleeding in patients taking NSAIDs [3–4].

Background : The prevalence of erosive esophagitis tends to increase recently. It induces higher medical expense, loss of working time, and decreases quality of life. However the study on risk factors of erosive esophagitis scarcely reported in Indonesia. This study aimed to find the association between age, sex, smoking, alcohol drinking, body mass index, hiatal hernia, the use of non steroidal anti-inflammatory drugs (NSAID), and drugs that decrease lower esophageal sphincter (LES) tone with the occurrence of erosive esophagitis in dyspeptic patients. Method: A case-control study was conducted on patients with dyspepsia who underwent upper gastrointestinal endoscopy procedure and had been interviewed to determine risk factors for erosive esophagitis in July - September 2008. The association between risk factors and the occurrence of erosive esophagitis were analyzed using Chi-square, which subsequently revealed p < 0.25, this variable included in multivariate analysis. Result: There were 135 patients fulfilled criteria; 45 patients as cases and 90 patients as controls. The association was found between the occurrence of erosive esophagitis in dyspeptic patients and smoking more than 15 cigarette/day (OR 15.43; p = 0.00; CI 95% 4.77-49.88), the use of NSAID (OR 9.49; p = 0.00; CI 95% 2.77-32.53) and the consumption of drugs that decrease LES tone (OR 3.56; p = 0.02; CI 95% 1.26-10.02). Conclusion: Smoking more than 15 cigarettes/day, use of NSAID and drugs that decrease LES tone is a risk factors for the occurrence of erosive esophagitis. Keywords: erosive esophagitis, NSAID, smoking, drugs that decrease LES tone