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Course of Neuropsychiatric Symptoms After Introduction and Removal of Nonsteroidal Anti-Inflammatory Drugs: A Pediatric Observational Study
Abstract
Objective:
Accumulating evidence suggests that anti-inflammatory interventions can modulate neuropsychiatric symptoms. Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is characterized by an abrupt and dramatic onset of obsessive-compulsive (OC) symptoms and/or severely restrictive food intake and at least two coinciding, equally debilitating neuropsychiatric symptoms. When associated with group A Streptococcus, the syndrome is labeled Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections (PANDAS). Here, we describe the course of neuropsychiatric symptoms in patients diagnosed with PANS and PANDAS after introduction or removal of nonsteroidal anti-inflammatory drugs (NSAIDs).
Study design:
We reviewed the electronic medical records (EMR) of 218 consecutive patients evaluated in our Stanford PANS Clinic for patients who met strict PANS or PANDAS research criteria and received NSAIDs for arthritis, pain, and/or psychiatric symptoms. We describe neuropsychiatric symptoms that were noted in the EMR before, during, and after NSAIDs were introduced or removed as the sole change in pharmacologic treatment.
Results:
Seventy-seven patients were included in the current study. Of the 52 trials in which NSAID addition was the sole change in treatment, 16 (31%) coincided with an improvement in patients' neuropsychiatric symptoms. Of the 57 trials in which removal of NSAID treatment was the sole change in treatment, 20 (35%) coincided with escalation in patients' neuropsychiatric symptoms. Thirty patients (39%) experienced side effects, mainly mild gastrointestinal symptoms, which self-resolved after removal of NSAID, reduction of dose, or change in NSAID.
Conclusions:
Improvement in neuropsychiatric symptoms was evident in roughly one-third of NSAID treatment trials. A randomized clinical trial will be necessary to confirm whether NSAIDs are successful in reducing neuropsychiatric symptoms in youth with PANS.
... After searching the abstracts and applying the eligibility criteria on identified potential abstracts, eight articles published between January 2010 and November 2020 were included in the present systematic review, involving 31,204 OCD patients from different countries. Out of the eight studies [15][16][17][18][19][20][21][22], five were randomized controlled studies [16,17,[20][21][22], while two studies were retrospective [15,19], and one study was a total-population multigenerational family cohort study [18]. Furthermore, the pediatric population was examined in three papers [17,19,20], while the adult population was examined in four articles [15,16,21,22], and both adults and pediatrics were examined in one multi-generation study [18]. ...
... After searching the abstracts and applying the eligibility criteria on identified potential abstracts, eight articles published between January 2010 and November 2020 were included in the present systematic review, involving 31,204 OCD patients from different countries. Out of the eight studies [15][16][17][18][19][20][21][22], five were randomized controlled studies [16,17,[20][21][22], while two studies were retrospective [15,19], and one study was a total-population multigenerational family cohort study [18]. Furthermore, the pediatric population was examined in three papers [17,19,20], while the adult population was examined in four articles [15,16,21,22], and both adults and pediatrics were examined in one multi-generation study [18]. ...
... Out of the eight studies [15][16][17][18][19][20][21][22], five were randomized controlled studies [16,17,[20][21][22], while two studies were retrospective [15,19], and one study was a total-population multigenerational family cohort study [18]. Furthermore, the pediatric population was examined in three papers [17,19,20], while the adult population was examined in four articles [15,16,21,22], and both adults and pediatrics were examined in one multi-generation study [18]. ...
Obsessive-compulsive disorder (OCD) is a common mental illness that can significantly impair the patients' quality of life. Recent studies have shown that patients with this condition usually suffer from inflammatory or rheumatological comorbidities. However, the association between OCD's etiology and inflammation is still controversial. This review aims to explore the correlation between OCD and rheumatological as well as inflammatory disorders based on studies conducted in the last decade. A total of eight articles that were deemed eligible were included in the final assessment, involving 31,204 OCD patients from various countries. The most significant inflammatory biomarkers examined were tumor necrosis factor-alpha (TNF-α), interleukins, neutrophil-to-lymphocyte ratio (NLR), and cytokines. We concluded that the pathophysiology and etiology of OCD are strongly correlated with inflammatory biomarkers. This finding warrants future studies on the efficacy of anti-inflammatory agents to treat OCD, particularly in the early stages of the disease.
... If symptoms continue beyond 2 weeks (especially if the symptoms are worsening and/or impairing function), oral nonsteroidal antiinflammatory drugs (NSAIDs) may be helpful, as tolerated (Table 3 and Appendix Table A1) (Brown et al. 2017b;Spartz et al. 2017). Although the therapeutic mechanisms in PANS are presumed to be Application of corticosteroids late into the disease often requires higher dosing and/or more prolonged tapers. ...
... Clinical trials have also shown benefit of NSAIDs in schizophrenia, bipolar disorder, and depression (Müller et al. 2004;Abbasi et al. 2012;Arabzadeh et al. 2015). In a recent retrospective study of consecutive patients trialed on NSAIDs, approximately one-third of the patients were reported to have improvement in some or all PANS symptoms and an additional one-third of the patients had deterioration after the NSAID was discontinued, suggesting possible efficacy (Spartz et al. 2017). In another retrospective study, NSAID use was associated with shorter duration of PANS flares compared with untreated flares (Brown et al. 2017b). ...
... If discontinuation of the NSAIDs results in recrudescence of symptoms, the medications can be restarted and continued for another 6 weeks or longer. Some patients have remained on NSAIDs chronically when continued benefit is demonstrated with on/off trials (Spartz et al. 2017). It is the authors' experience that NSAIDs can be used safely in the long term if standard precautions are taken (Appendix Table A1). ...
Introduction
Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is a clinically heterogeneous disorder with a number of different etiologies and disease mechanisms. Inflammatory and postinfectious autoimmune presentations of PANS occur frequently, with some clinical series documenting immune abnormalities in 75%–80% of patients. Thus, comprehensive treatment protocols must include immunological interventions, but their use should be reserved only for PANS cases in which the symptoms represent underlying neuroinflammation or postinfectious autoimmunity, as seen in the PANDAS subgroup (Pediatric Autoimmune Neuropsychiatric Disorders associated with Streptococcal infections).
Methods
The PANS Research Consortium (PRC) immunomodulatory task force is comprised of immunologists, rheumatologists, neurologists, infectious disease experts, general pediatricians, psychiatrists, nurse practitioners, and basic scientists with expertise in neuroimmunology and PANS-related animal models. Preliminary treatment guidelines were created in the Spring of 2014 at the National Institute of Health and refined over the ensuing 2 years over conference calls and a shared web-based document. Seven pediatric mental health practitioners, with expertise in diagnosing and monitoring patients with PANS, were consulted to create categories in disease severity and critically review final recommendations. All authors played a role in creating these guidelines. The views of all authors were incorporated and all authors gave final approval of these guidelines.
Results
Separate guidelines were created for the use of immunomodulatory therapies in PANS patients with (1) mild, (2) moderate-to-severe, and (3) extreme/life-threatening severity. For mildly impairing PANS, the most appropriate therapy may be “tincture of time” combined with cognitive behavioral therapy and other supportive therapies. If symptoms persist, nonsteroidal anti-inflammatory drugs and/or short oral corticosteroid bursts are recommended. For moderate-to-severe PANS, oral or intravenous corticosteroids may be sufficient. However, intravenous immunoglobulin (IVIG) is often the preferred treatment for these patients by most PRC members. For more severe or chronic presentations, prolonged corticosteroid courses (with taper) or repeated high-dose corticosteroids may be indicated. For PANS with extreme and life-threatening impairment, therapeutic plasma exchange is the first-line therapy given either alone or in combination with IVIG, high-dose intravenous corticosteroids, and/or rituximab.
Conclusions
These recommendations will help guide the use of anti-inflammatory and immunomodulatory therapy in the treatment of PANS.
... Consensus guidelines for immunomodulatory interventions have been developed, recommending therapies depending on disease severity and course . The use of nonsteroidal antiinflammatory drugs (NSAIDs) is included in these recommendations which are based on clinical experience, as there are limited reports on the efficacy of NSAIDs in PANS (Spartz et al. 2017). ...
... When our PANS clinic opened in September 2012, clinicians initially prescribed NSAIDs for arthritis and pain, as this is the standard of care for juvenile arthritis. Interestingly, in addition to improvement in joint pain, temporal associations between NSAID introduction and psychiatric symptom improvement were noted (Spartz et al. 2017). These observations are congruent with burgeoning anecdotal experiences shared between parents of affected youth in online PANS/PANDAS forums. ...
... Wide variability in flare duration was observed in this study, which may be explained by the heterogeneity of the patient and flare groups with respect to disease severity, disease trajectory at the time of NSAID introduction, and flare trigger (i.e., bacterial, viral, etc.). Some patients in our clinic experience a dramatic and rapid response to NSAIDs, whereas others exhibit no response to NSAIDs (Spartz et al. 2017). Variability in response is also observed within individual patients; an individual may exhibit littleto-no response to an initial NSAID trial, but may respond to NSAIDs in a future milder flare (Spartz et al. 2017). ...
Introduction:
Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is characterized by the sudden onset of severe obsessive-compulsive symptoms and/or eating restriction along with at least two coinciding neuropsychiatric symptoms. When associated with group A Streptococcus, the syndrome is labeled Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections (PANDAS). An abnormal immune response to infection and subsequent neuroinflammation is postulated to play an etiologic role. We evaluated the impact of nonsteroidal anti-inflammatory drug (NSAID) treatment on flare duration in PANS/PANDAS.
Methods:
Patient inclusion criteria: Patients were included if they had at least one neuropsychiatric deterioration ("flare") that met strict PANS/PANDAS research criteria and for which flare duration could be assessed. Flare inclusion criteria: Any flare that started before October 15, 2016 was included and followed until the flare resolved or until the end of our data collection (November 1, 2016). Flare exclusion criteria: Flares were excluded if they were incompletely resolved, treated with aggressive immunomodulation, or treated with NSAIDs late (>30 days of flare onset). Ninety-five patients met study inclusion criteria and collectively experienced 390 flares that met flare criteria. Data were analyzed using multilevel linear models, adjusting for demographics, disease, and treatment covariates.
Results:
NSAID use was associated with a significantly shorter flare duration. Flares not treated with NSAIDs had a mean duration of approximately 12.2 weeks (95% CI: 9.3-15.1). Flares that occurred while the child was on NSAID maintenance therapy were approximately 4 weeks shorter than flares not managed with NSAIDs (95% CI: 1.85-6.24; p < 0.0001). Flares treated with NSAIDs within 30 days of flare onset were approximately 2.6 weeks shorter than flares not managed with NSAIDs (95% CI: 0.43-4.68; p = 0.02). Flares treated prophylactically and those treated early with NSAIDs did not differ in duration (p = 0.26). Among the flares that received NSAID treatment within the first 30 days, earlier intervention was modestly associated with shorter flare durations (i.e., for each day that NSAID treatment was delayed, flare duration increased by 0.18 weeks; 95% CI: 0.03-0.33; p = 0.02), though it was not statistically significant after controlling for covariates (p = 0.06).
Conclusion:
NSAIDs given prophylactically or within 30 days of flare onset may shorten neuropsychiatric symptom duration in patients with new-onset and relapsing/remitting PANS and PANDAS. A randomized placebo-control clinical trial of NSAIDs in PANS is warranted to formally assess treatment efficacy.
... Despite the few reports on their efficacy in PANS, 131 the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is encompassed into the consensus guidelines for immunomodulatory interventions. 33 NSAIDs have been mainly proposed as prophylaxis in patients with new-onset and relapsing/remitting PANS, within 30 days of flare onset, assuming that they are able to shorten the symptom duration. ...
... Instead, in other countries, especially in North America, the role of immunomodulatory and antiinflammatory therapies is more relevant, according to the importance that the immunological and inflammatory aspects of the disease assumed in the last years. Consistently, a large body of research reports a significant benefit of immunomodulatory/anti-inflammatory treatments, in most cases, 90,126,131,134,138,151,152 suggesting a guarantee of immunomodulatory treatment in all patients. A larger number of studies are available on IVIG treatment (see Table 3) compared to the number of studies on single steroids and NSAIDs. ...
Pediatric acute-onset neuropsychiatric syndrome (PANS) features a heterogeneous constellation of acute obsessive-compulsive disorder (OCD), eating restriction, cognitive, behavioral and/or affective symptoms, often followed by a chronic course with cognitive deterioration. An immune-mediated etiology is advocated in which the CNS is hit by different pathogen-driven (auto)immune responses. This narrative review focused on recent clinical (ie, diagnostic criteria, pre-existing neurodevelopmental disorders, neuroimaging) and pathophysiological (ie, CSF, serum, genetic and autoimmune findings) aspects of PANS. We also summarized recent points to facilitate practitioners with the disease management. Relevant literature was obtained from PubMed database which included only English-written, full-text clinical studies, case reports, and reviews. Among a total of 1005 articles, 205 were pertinent to study inclusion. Expert opinions are converging on PANS as the effect of post-infectious events or stressors leading to "brain inflammation", as it is well-established for anti-neuronal psychosis. Interestingly, differentiating PANS from either autoimmune encephalitides and Sydenham's chorea or from alleged "pure" psychiatric disorders (OCD, tics, Tourette's syndrome), reveals several overlaps and more analogies than differences. Our review highlights the need for a comprehensive algorithm to help both patients during their acute distressing phase and physicians during their treatment decision. A full agreement on the hierarchy of each therapeutical intervention is missing owing to the limited number of randomized controlled trials. The current approach to PANS treatment emphasizes immunomodulation/anti-inflammatory treatments in association with both psychotropic and cognitive-behavioral therapies, while antibiotics are suggested when an active bacterial infection is established. A dimensional view, taking into account the multifactorial origin of psychiatric disorders, should suggest neuro-inflammation as a possible shared substrate of different psychiatric phenotypes. Hence, PANS and PANS-related disorders should be considered as a conceptual framework describing the etiological and phenotypical complexity of many psychiatric disorders.
... Antibiotics (penicillin V, azithromycin), anti-inflammatory drugs (cyclooxygenase (COX) inhibitors, corticosteroids), immunomodulating treatments (intravenous immunoglobulin -IVIG. plasma exchange) are the most applied treatment singularly or in association [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. ...
... Among the various diagnostic hypotheses reported in the literature, streptococcal and other infections have been shown to trigger the development of symptoms such as OCD, tics and behavioral disturbances [2,3,5]. Therefore, numerous studies have been performed on neurological outcomes in PANDAS patients undergoing medical or surgical treatments, with the principle of adenotonsillar infection as the primary target [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]32,33]. Pavone et al. examined whether adenotonsillectomy could impact both disease remission and affect the clinical course, streptococcal antibody titers, neuronal antibodies, or the clinical severity of the obsessive-compulsive disorder (OCD) [13]. ...
Background:
Several treatment options have been proposed for pediatric acute-onset neuropsychiatric syndrome/pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANS/PANDAS). Still, no clear therapeutic protocol has been recognized to prevent these neuropsychiatric diseases. The study aims to report on the literature evidence and different treatment strategies related to these disorders.
Methods:
We analyzed the last 20 years' English language literature and performed a comprehensive review of the PANS/PANDAS treatment, including studies reporting OCD outcomes post-treatment follow-up.
Results:
We covered 11 articles in our systematic literature review for a total of 473 patients, of which four studies included 129 surgical subjects and seven papers with 326 medically treated patients. Pooled outcomes analysis, surgical and medical treatment reported an OCD reduction, but no statistical significance was obtained (p < 0.05 for both).
Conclusions:
Surgical therapy in selected patients can lead to promising results, although further evidence is needed. On the other hand, the role of medical therapy remains controversial, often due to the lack of univocal curative protocols and variable responses depending on the drug used and the timing of administration. Therefore, further investigations are necessary to clarify the most appropriate therapeutic procedure.
... Furthermore, treatment of PANDAS (described below) is not identical to OCD treatment. Prophylactic antibiotics or antibiotic treatment, anti-inflammatory treatment, and immunoglobulin, indicated in PANDAS treatment, are not prescribed in "idiopathic OCD" [118,[120][121][122][123][124][125]. Therefore, it would be important to recognize and adequately treat PANDAS within a personalized medical setting. ...
... However, if streptococcal infection is still present during acute episodes of PANDAS, antibiotics are considered as the best treatment [167,168]. Finally, corticosteroid and nonsteroidal anti-inflammatory drugs (NSAIDs) do appear to be effective [120][121][122]126] (Table 5). ...
Obsessive–compulsive disorder (OCD) affects about 2% of the general population, for which several etiological factors were identified. Important among these is immunological dysfunction. This review aims to show how immunology can inform specific etiological factors, and how distinguishing between these etiologies is important from a personalized treatment perspective. We found discrepancies concerning cytokines, raising the hypothesis of specific immunological etiological factors. Antibody studies support the existence of a potential autoimmune etiological factor. Infections may also provoke OCD symptoms, and therefore, could be considered as specific etiological factors with specific immunological impairments. Finally, we underline the importance of distinguishing between different etiological factors since some specific treatments already exist in the context of immunological factors for the improvement of classic treatments.
... Treatments noted in the case reports included antibiotics and tonsillectomy to address the infectious agent; IVIG, TPE, corticosteroids, NSAID and anti-CD20 monoclonal antibodies for immunomodulation; and psychotropic medications and CBT for psychiatric symptoms. In the 6 case series, the authors evaluated the response to antibiotics (Murphy and Pichichero, 2002), antibiotics in combination with tonsillectomy (Demesh et al., 2015), TPE alone or in combination with antibiotics (Beşiroǧlu et al., 2007;Latimer et al., 2015), treatment of sinusitis (Mahony et al., 2017) and NSAID (Spartz et al., 2017). Our systematic review of case reports is presented in Supplementary Table S1. ...
... One large case series has evaluated the use of NSAID in PANS (Spartz et al., 2017). This study was based on the same sample of the first 218 consecutivepatients treated at the Stanford PANS clinic as Brown et al., (2017b). ...
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are a subtype of acute-onset obsessive-compulsive disorder (OCD) thought to be caused by an autoimmune response to group A streptococcal infection. Based on this proposed pathophysiology, alternative treatments for acute-onset OCD have been introduced, including antibiotics and immunomodulatory interventions. However, the literature on treatment of PANDAS is diverse, and clinical consensus regarding optimal treatment strategy is lacking. We conducted a systematic review of articles in PubMed, Cochrane Library, and Scopus that addressed treatment for PANDAS and related disorders. Twelve research studies involving the following treatments met inclusion criteria: penicillin, azithromycin, intravenous immunoglobulin, plasma exchange, tonsillectomy, cognitive behavior therapy, NSAID and corticosteroids. In addition, 65 case reports in which patients received immunomodulatory treatments, antibiotics, and/or psychotropics were identified. We determined that rigorously conducted research regarding treatments for PANDAS is scarce, and published studies have a high risk of bias. Further research is needed in which promising treatment strategies for PANDAS and other variants of OCD with proposed autoimmune etiology are rigorously investigated.
... The capsular thickening seen in these patients is likely reflective of the psoriatic arthritis subtype and possibly relates to the connection between GAS and psoriasis [14]. NSAIDs are the first line for childhood arthritis and have been shown to reduce PANS flare duration and symptoms [15,16]. However, when patients have significant capsular or synovial thickening on imaging and ongoing pain and stiffness despite NSAID therapy, we often escalate treatment to include disease-modifying antirheumatic drugs. ...
Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections (PANDAS), Sydenham chorea and other post-infectious psychiatric deteriorations are thought to be caused by inflammatory/autoimmune mechanisms, likely involving the basal ganglia based on imaging studies. Patients have a relapsing-remitting course and some develop severe refractory psychiatric disease. We found that 55/193 (28%) of consecutive patients meeting PANS criteria developed chronic arthritis and 25/121 (21%) of those with related psychiatric deteriorations developed chronic arthritis. Here we describe 7 of these patients in detail and one sibling. Many of our patients often have "dry" arthritis (no effusions found on physical exam), but subtle effusions detected by imaging and features of spondyloarthritis, enthesitis, and synovitis. Joint capsule thickening, not previously reported in children, is a common finding in the presented cases and in psoriatic arthritis in adults. Due to the severity of psychiatric symptoms in some cases, which often overshadow joint symptoms, and concomitant sensory dysregulation (making the physical exam unreliable in the absence of effusions), we rely on imaging to improve sensitivity and specificity of the arthritis classification. We also report the immunomodulatory treatments of these 7 patients (initially non-steroidal anti-inflammatory drugs and disease-modifying anti-rheumatic drugs with escalation to biologic medications) and note any coincidental changes to their arthritis and psychiatric symptoms while on immunomodulation. Conclusion: Patients with overlapping psychiatric syndromes and arthritis may have a unifying cause and pose unique challenges; a multi-disciplinary team can utilize imaging to tailor and coordinate treatment for this patient population.
... Treatment studies represent another approach to validate the immune-mediated etiology using anti-microbials (109,110), non-steroidal anti-inflammatory agents such as naproxen sodium (111) and cyclo-oxygenase inhibitors such as celecoxib (112,113), but these studies involved several psychiatric disorders, suggesting a non-specific effect. However, one study reported an improvement in OCD symptoms specifically (114). ...
There appear to be two peaks of incidence of Obsessive Compulsive Disorder (OCD), one with a pre-adolescent onset and another in early adulthood. As new cases are added, the cumulative prevalence of OCD increases, but the great majority of cases have an onset in youth. The notion that early onset OCD represents a unique developmental subtype of the disorder has been considered by many researchers based on several specific age-related factors. Ascertainment and early intervention in affected youth is critical to abbreviate the functional impairments associated with untreated illness. In this paper we review the clinical, familial and translational biomarker correlates seen in early onset OCD that support the notion of a developmental subtype and discuss implications for research and treatment aimed at this cohort. The importance of cognitive, academic and social development tasks of childhood and adolescence, illness-specific and familial factors, and immune-mediated inflammatory factors are discussed, with their implications for management.
... 83 Despite early investigations suggested a positive effect of antibiotics on PANS patients, current literature did not support their use but showed promising effects of the non-steroidal antiinflammatory drugs (NSAID). 84,85 Thus, antiinflammatory agents have also been investigated on adults with OCD. Here, we will review current literature on antiinflammatory agents for adults with OCD. ...
Treatment-resistance is a frequent condition for obsessive-compulsive disorder (OCD). Over the past decades, a lot of effort has been made to address this issue, and several augmentation strategies of serotonergic drugs have been investigated. Antidopaminergic drugs are considered the first choice as augmentation strategy for treatment-resistant OCD patients, but they seem to work only for a subset of patients, and none of them have been officially approved for OCD. Recently, the role of glutamate and inflammation in OCD pathophysiology clearly emerged, and this has led to several investigations on glutamatergic and anti-inflammatory agents. Results seem promising but still inconclusive. Probiotic interventions (considered to modulate the immune systems and the brain activity) are gaining attention in several psychiatric fields but are still at their early stages in the OCD field. Research on new treatment approaches for OCD is moving forward, and more than one hundred interventional trials are ongoing around the world. While the vast majority of these trials involve neuromodulation and psychotherapeutic approaches, only a small proportion (around 20%) involve the investigation of new pharmacological approaches (tolcapone, nabilone, psilocybin, troriluzole, nitrous oxide, rituximab, naproxen, and immunoglobulins). Here, we provide a comprehensive review of investigational and experimental drugs to treat OCD.
... Immunomodulatory therapy represents a new field of investigation in OCD. While treatment with antimicrobials has delivered inconsistent results (Burchi and Pallanti, 2018), other immunological modulators, such as celecoxib* (Shalbafan et al., 2015) and nonspecific nonsteroidal anti-inflammatory drugs (Spartz et al., 2017), have produced some positive findings, the latter only in a subset of young people. Thus, evidence of the usefulness of this approach in OCD remains insufficient. ...
In this position statement, developed by The International College of Obsessive-Compulsive Spectrum Disorders, a group of international experts responds to recent developments in the evidence-based management of obsessive-compulsive disorder (OCD). The article presents those selected therapeutic advances judged to be of utmost relevance to the treatment of OCD, based on new and emerging evidence from clinical and translational science. Areas covered include refinement in the methods of clinical assessment, the importance of early intervention based on new staging models and the need to provide sustained well-being involving effective relapse prevention. The relative benefits of psychological, pharmacological and somatic treatments are reviewed and novel treatment strategies for difficult to treat OCD, including neurostimulation, as well as new areas for research such as problematic internet use, novel digital interventions, immunological therapies, pharmacogenetics and novel forms of psychotherapy are discussed.
... Clinical practice guidelines for the treatment of children with pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) recommend the use of naproxen before celecoxib because of its "greater potency" (35), despite clinical studies showing benefit of adjunctive celecoxib in OCD (36,37) and pre-clinical data demonstrating celecoxibmediated enhancement of the serotonergic effects of fluoxetine in a rat model of anxiety (38). Moreover, observational studies have focused on NSAIDs as a class in children with PANS/PANDAS (39,40). Given the significance of different COX isoforms and their unknown relative "potencies" in the CNS, careful attention must be given to selection and evaluation of specific NSAIDs. ...
... So far, it is unknown why the examined patients present different therapeutic effects of NSAIDs. However, both prophylactic and early usage of NSAIDs is associated with the shorter duration of the exacerbation of PANDAS symptoms [196]. Because of the wide range of the results which are available at the actual state of knowledge, nevertheless, additional research trials should be done to specify the role of NSAIDs application in PANDAS patients. ...
The objective of this paper is to review and summarize conclusions from the available literature regarding Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). The authors have independently reviewed articles from 1977 onwards, primarily focusing on the etiopathology, symptoms, differentiation between similar psychiatric conditions, immunological reactions, alterations in the nervous system and gut microbiota, genetics, and the available treatment for PANDAS. Recent research indicates that PANDAS patients show noticeable alterations within the structures of the central nervous system, including caudate, putamen, globus pallidus, and striatum, as well as bilateral and lentiform nuclei. Likewise, the presence of autoantibodies that interact with basal ganglia was observed in PANDAS patients. Several studies also suggest a relationship between the presence of obsessive-compulsive disorders like PANDAS and alterations to the gut microbiota. Further, genetic predispositions—including variations in the MBL gene and TNF-α—seem to be relevant regarding PANDAS syndrome. Even though the literature is still scarce, the authors have attempted to provide a thorough insight into the PANDAS syndrome, bearing in mind the diagnostic difficulties of this condition.
... Indeed, NSAID may be effective in 23% of patients diagnosed with PANS [71]. Ibuprofen in addition to antibiotics may improve psychiatric symptoms according to case reports [77]. Forty-two percent of PANS subjects may respond to NSAID [78] which may also shorten the duration of the OCD symptoms among patients with PANS [79]. ...
Purpose of Review
Here, we propose to review the immuno-inflammatory hypothesis in OCD given the concurrent incidence of autoimmune comorbidities, infectious stigma, and raised levels of inflammatory markers in a significant subset of patients. A better understanding of the immune dysfunction in OCD may allow stratifying the patients in order to design personalized pharmaco/psychotherapeutic strategies.
Recent Findings
A persistent low-grade inflammation involving both innate and adaptive immune system with coexisting autoimmune morbidities and stigma of infectious events has been prominently observed in OCD. Hence, specific treatments targeting inflammation/infection are a feasible alternative in OCD.
Summary
This review highlights that OCD is associated with low-grade inflammation, neural antibodies, and neuro-inflammatory and auto-immune disorders. In some subset of OCD patients, autoimmunity is likely triggered by specific bacterial, viral, or parasitic agents with overlapping surface epitopes in CNS. Hence, subset-profiling in OCD is warranted to benefit from distinct immune-targeted treatment modalities.
... Clinical data of well-characterized PANS patients are still limited and more evidence is needed to support the current treatment routines that have been developed mainly according to clinical experience, case reports, and case series. Previous research has suggested that immunomodulatory and/or anti-inflammatory treatments may be beneficial in some cases, but evidence is inconclusive Farhood et al. 2016;Williams et al. 2016;Brown et al. 2017aBrown et al. , 2017bSpartz et al. 2017;Sigra et al. 2018). Definitive clinical trials are sorely needed to guide clinical decision-making. ...
Objectives:
Pediatric acute-onset neuropsychiatric syndrome (PANS) is a descriptive clinical entity defined by the abrupt onset of psychiatric and somatic symptoms leading to significant loss of function. Data on well-characterized PANS patients are limited, biomarkers have yet to be identified, and a solid evidence base to guide treatment is lacking. In this study, we present our experience of a systematic evaluation of the first 45 patients included in a Swedish cohort.
Methods:
During the period 2014-2018, our clinic received 100 referrals regarding suspected PANS. All patients underwent a standardized psychiatric/medical evaluation by a child/adolescent psychiatrist and a clinical psychologist or a nurse. Those with severe symptoms were also assessed by a pediatric neurologist and a pediatric rheumatologist. Laboratory tests were obtained at different time points in an attempt to capture an active disease state.
Results:
Of the 100 referrals, 45 met strict PANS criteria and consented to participate in a long-term follow-up study. The median age at intake was 7.2 years (range 3.0-13.1) and 56% were male. Ninety-three percent fulfilled both criteria for acute/atypical onset of PANS symptoms and having had an infection in relation to onset. Sixteen percent had an onset of an autoimmune or inflammatory disorder in temporal relation to the onset of PANS-related symptoms. The most common onset symptoms were obsessive-compulsive disorder (89%), anxiety (78%), and emotional lability (71%). Twenty-four percent had a preexisting autoimmune disease (AD) and 18% a preexisting psychiatric/neuropsychiatric diagnosis. Sixty-four percent of biological relatives had at least one psychiatric disorder and 76% at least one AD or inflammatory disorder. Complement activation (37%), leukopenia (20%), positive antinuclear antibodies (17%), and elevated thyroid antibodies (11%) were the most common laboratory findings.
Conclusions:
In our PANS cohort, there was a strong indication of an association with AD. Further work is needed to establish whether any of the potential biomarkers identified will be clinically useful. Long-term follow-up of these patients using the Swedish national registers will enable a deeper understanding of the course of this patient group.
... Although some studies demonstrated that OCD symptoms have improved with plasma exchange, intravenous immunoglobulin and antibiotic prophylaxis (e.g., Snider et al., 2005 ), the use of antibiotics and immunoglobulins for early and acute onset OCD patients remains controversial Williams et al., 2016 ).Additional evidence hints at a potential therapeutic role for anti-inflammatory agents ( Spartz et al., 2017 ). Interestingly, SSRIs (a first line OCD treatment) have been shown to exert several immunological effects, such as reduced lymphocyte proliferation, alteration of cytokine secretion and induction of apoptosis ( Gobin et al., 2014 ). ...
Obsessive-compulsive disorder (OCD) is common, emerges early in life and tends to run a chronic, impairing course. Despite the availability of effective treatments, the duration of untreated illness (DUI) is high (up to around 10 years in adults) and is associated with considerable suffering for the individual and their families. This consensus statement represents the views of an international group of expert clinicians, including child and adult psychiatrists, psychologists and neuroscientists, working both in high and low and middle income countries, as well as those with the experience of living with OCD. The statement draws together evidence from epidemiological, clinical, health economic and brain imaging studies documenting the negative impact associated with treatment delay on clinical outcomes, and supporting the importance of early clinical intervention. It draws parallels between OCD and other disorders for which early intervention is recognized as beneficial, such as psychotic disorders and impulsive-compulsive disorders associated with problematic usage of the Internet, for which early intervention may prevent the development of later addictive disorders. It also generates new heuristics for exploring the brain-based mechanisms moderating the ‘toxic’ effect of an extended DUI in OCD. The statement concludes that there is a global unmet need for early intervention services for OC related disorders to reduce the unnecessary suffering and costly disability associated with under-treatment. New clinical staging models for OCD that may be used to facilitate primary, secondary and tertiary prevention within this context are proposed.
The etiology of severe mental illnesses (SMIs) of the schizophrenic and affective spectra still appears to be rather obscure. However, a small, emerging subgroup can now be diagnosed as autoimmune psychoses (AP), often presenting as schizophrenia-like psychosis, and can be successfully treated with various immune-modulatory treatments. These recent insights match the longer, previously defined, mild encephalitis hypothesis. Recently published consensus AP diagnostic criteria are comparable with autoimmune encephalitis criteria and are mainly based on the presence of neuronal autoantibodies in cerebrospinal fluid (CSF). Other forms of autoimmune-mediated psychiatric syndromes may present in context with systemic autoimmune diseases and yet unknown underlying causes. The frequent prevalence of minor CSF pathologies and postmortem findings of low-grade neuroinflammatory processes in a considerable subgroup of SMIs remains an intriguing challenge for further etiology-focused research, which should include immunogenetics, the role of infections and of the blood-brain barrier, and potentially, various types of immune-pathology beyond the important paraclinical methods, such as CSF diagnostics and neuroimaging.KeywordsSchizophreniaPsychosisAffective spectrumAutoimmune psychosisAutoimmune encephalitisMild encephalitisCSFBlood brain barrier
Tourette syndrome (TS) is now recognized as a common neurodevelopmental disorder affecting children and adults. It has gained increasingly public awareness and scientific interest worldwide. Knowledge of its clinical presentation and available treatment approaches has increased dramatically over the last two decades. Tourette Syndrome offers a unique, comprehensive, and up-to-date overview of TS. The volume highlights the latest findings regarding clinical presentation, underlying genetic, epigenetic, immunological, and neurobiological causal mechanisms, and state-of-the-art therapies. Importantly, in this digital world of ours and given the ongoing pandemic, this volume also provides a detailed review of the latest available multifaceted and multidisciplinary treatment options including psychoeducational and cognitive-behavioral interventions, many of which can now be accessed online. More than 50 leading scientists and expert clinicians from across the globe authored the chapters. Readers can also access videotaped presentations recorded by several of these scholars. Fortunately, several of these presentations include individuals with TS and related conditions who have graciously volunteered to discuss their life’s journey. This volume is a useful source for a wide audience of scholars and clinicians, all of whom will have access to what is known so far on TS and related conditions within their area of expertise. It provides readers an opportunity to expand and update their knowledge base in other areas of science and advocacy. Families and health professionals will also have access to updates from a broad range of advocacy associations and organizations all around the world that are dedicated to improving lives of individuals with TS.
Objectives:
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) is characterized by the sudden onset of obsessive-compulsive disorder (OCD) and other neurobehavioral symptoms following group A streptococcal infection. The cardinal neuropsychiatric symptoms are believed to reflect an aberrant autoimmune or inflammatory response that may selectively disrupt basal ganglia function. The investigators examined whether neuropsychological skills associated with frontostriatal networks (executive functions and motor skills) are affected in patients with PANDAS following resolution of acute symptoms and the degree to which there are persistent social, emotional, and academic difficulties.
Methods:
Twenty-seven patients ages 6-14 years (mean age=9.63 years [SD=1.78]; male, N=22) completed neuropsychological testing as part of routine clinical care. Performances on measures of intellectual ability, executive function, motor skills, and academic skills are reported, as well as parent-reported emotional, behavioral, and social skills.
Results:
On neuropsychological measures, patients exhibited average intellectual functioning with relative and mild difficulties in skills supporting cognitive efficiency, including attentional regulation, inhibitory control, and processing speed. Dexterity was normal but graphomotor skills were reduced. Core reading, math, and writing skills were within expectations, but reading and math fluency were reduced, and the majority of patients received special education services or accommodations. Parents reported high levels of concern about anxiety, depression, inattention, hyperactivity, and social skills.
Conclusions:
These findings indicated relative difficulties with aspects of executive and motor functions. Although evaluations were performed following the resolution of acute symptoms, ongoing and significant academic difficulties and emotional, behavioral, and social concerns were targets for clinical intervention and support.
Background
Obsessive Compulsive Disorder (OCD) is considered as a serious disabling psychiatric disorder, influencing 2-3% of the total general population, with an unknown etiology.
Methods
A comprehensive literature search in electronic databases was performed to investigate treatments targeting inflammation in patients suffering from OCD.
Results
The recent studies display that inflammation processes and the dysfunction of the immune system are likely to play a role in the pathophysiology of OCD, indicating that the disturbances in neurotransmitters such as serotonin and dopamine cannot be alone involved in the development of OCD. Therefore, it seems that medications with antiinflammatory effects have the potential to be evaluated as a new therapeutic strategy for OCD. However, this issue can be studied closely if OCD etiological factors are thoroughly understood. The present review study aims at gathering all obtained results concerning new treatments targeting inflammation in OCD patients. Reviewing the conducted studies shows that the use of agents with anti-inflammatory properties including some NSAIDs, Minocycline and Atorvastatin could lead to promising and intriguing results in the treatment of OCD. Curcumin, also showed good efficacy in the reduction of OCD-like behavior when it has been used in an animal model. However, there is still no definitive and conclusive evidence for any of the medications proposed.
Conclusion
more future studies are needed to investigate antiinflammatory treatment strategies for OCD and its other subtypes such as Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS), and Pediatric Autoimmune Neuropsychiatric Disorder associated with Streptococcal infection (PANDAS).
PANS, or Pediatric Acute-onset Neuropsychiatric Syndrome, is characterized by the sudden onset of obsessive-compulsive syndrome and accompanied by anxiety, emotional lability and other symptoms. PANDAS, or Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections, is a subtype of PANS. Modern data on PANS/PANDAS etiology, pathogenesis, diagnostics and management is presented in this article. Therapeutic decisions on using anti-inflammatory and immunotropic therapy including non-steroidal anti-inflammatory drugs, glucocorticoids, intravenous immunoglobulin, plasmapheresis, rituximab and mycophenolate mofetil are analysed.
Introduction: Only 40–60% of obsessive-compulsive patients respond to first line treatments, such as selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioral therapy. Several second-line treatments have been investigated in the last two decades, and most of them seem to work, at least in a subset of patients. However, since there is still a lack of treatment predictors, the treatment of obsessive-compulsive disorder (OCD) is still empirical and non-evidence based.
Areas covered: In this paper, we review current and up-and-coming pharmacotherapy for OCD in adults, focusing on two emerging fields of research, inflammation and glutamate systems, since they have attracted the greatest attention in recent years in OCD pharmacological research.
Expert opinion: Most of the investigated second-line agents seem to work at least in a subset of patients with OCD. These results raise an open question: what works for who? In our opinion, this question should be answered in a precision medicine perspective or, in other words, individualizing diagnostic processes and treatment approaches. In a precision medicine approach, OCD treatment should be sub-type specific, phase specific, multimodal and sequential, and, more importantly, dimensional.
Introduction
Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is a clinically heterogeneous disorder with a number of different etiologies and disease mechanisms. Inflammatory and postinfectious autoimmune presentations of PANS occur frequently, with some clinical series documenting immune abnormalities in 75%–80% of patients. Thus, comprehensive treatment protocols must include immunological interventions, but their use should be reserved only for PANS cases in which the symptoms represent underlying neuroinflammation or postinfectious autoimmunity, as seen in the PANDAS subgroup (Pediatric Autoimmune Neuropsychiatric Disorders associated with Streptococcal infections).
Methods
The PANS Research Consortium (PRC) immunomodulatory task force is comprised of immunologists, rheumatologists, neurologists, infectious disease experts, general pediatricians, psychiatrists, nurse practitioners, and basic scientists with expertise in neuroimmunology and PANS-related animal models. Preliminary treatment guidelines were created in the Spring of 2014 at the National Institute of Health and refined over the ensuing 2 years over conference calls and a shared web-based document. Seven pediatric mental health practitioners, with expertise in diagnosing and monitoring patients with PANS, were consulted to create categories in disease severity and critically review final recommendations. All authors played a role in creating these guidelines. The views of all authors were incorporated and all authors gave final approval of these guidelines.
Results
Separate guidelines were created for the use of immunomodulatory therapies in PANS patients with (1) mild, (2) moderate-to-severe, and (3) extreme/life-threatening severity. For mildly impairing PANS, the most appropriate therapy may be “tincture of time” combined with cognitive behavioral therapy and other supportive therapies. If symptoms persist, nonsteroidal anti-inflammatory drugs and/or short oral corticosteroid bursts are recommended. For moderate-to-severe PANS, oral or intravenous corticosteroids may be sufficient. However, intravenous immunoglobulin (IVIG) is often the preferred treatment for these patients by most PRC members. For more severe or chronic presentations, prolonged corticosteroid courses (with taper) or repeated high-dose corticosteroids may be indicated. For PANS with extreme and life-threatening impairment, therapeutic plasma exchange is the first-line therapy given either alone or in combination with IVIG, high-dose intravenous corticosteroids, and/or rituximab.
Conclusions
These recommendations will help guide the use of anti-inflammatory and immunomodulatory therapy in the treatment of PANS.
Neuropsychiatric systemic lupus erythematosus (NPSLE) is a generic definition referring to a series of neurological and psychiatric symptoms directly related to systemic lupus erythematosus (SLE). NPSLE includes heterogeneous and rare neuropsychiatric (NP) manifestations involving both the central and peripheral nervous system. Due to the lack of a gold standard, the attribution of NP symptoms to SLE represents a clinical challenge that obligates the strict exclusion of any other potential cause. In the acute setting, management of these patients does not differ from other non-SLE subjects presenting with the same NP manifestation. Afterwards, an individualized therapeutic strategy, depending on the presenting manifestation and severity of symptoms, must be started. Clinical trials in NPSLE are scarce and most of the data are extracted from case series and case reports. High-dose glucocorticoids and intravenous cyclophosphamide remain the cornerstone for patients with severe symptoms that are thought to reflect inflammation or an underlying autoimmune process. Rituximab, intravenous immunoglobulins, or plasmapheresis may be used if response is not achieved. When patients present with mild to moderate NP manifestations, or when maintenance therapy is warranted, azathioprine and mycophenolate may be considered. When symptoms are thought to reflect a thrombotic underlying process, anticoagulation and antiplatelet agents are the mainstay of therapy, especially if antiphospholipid antibodies or antiphospholipid syndrome are present. Recent trials on SLE using new biologicals, based on newly understood SLE mechanisms, have shown promising results. Based on what we currently know about its pathogenesis, it is tempting to speculate how these new therapies may affect the management of NPSLE patients. This article provides a comprehensive and critical review of the literature on the epidemiology, pathophysiology, diagnosis, and management of NPSLE. We describe the most common pharmacological treatments used in NPSLE, based on both a literature search and our expert opinion. The extent to which new drugs in the advanced development of SLE, or the blockade of new targets, may impact future treatment of NPSLE will also be discussed.
Acute rheumatic fever (ARF) is the result of an autoimmune response to pharyngitis caused by infection with group A Streptococcus. The long-term damage to cardiac valves caused by ARF, which can result from a single severe episode or from multiple recurrent episodes of the illness, is known as rheumatic heart disease (RHD) and is a notable cause of morbidity and mortality in resource-poor settings around the world. Although our understanding of disease pathogenesis has advanced in recent years, this has not led to dramatic improvements in diagnostic approaches, which are still reliant on clinical features using the Jones Criteria, or treatment practices. Indeed, penicillin has been the mainstay of treatment for decades and there is no other treatment that has been proven to alter the likelihood or the severity of RHD after an episode of ARF. Recent advances — including the use of echocardiographic diagnosis in those with ARF and in screening for early detection of RHD, progress in developing group A streptococcal vaccines and an increased focus on the lived experience of those with RHD and the need to improve quality of life — give cause for optimism that progress will be made in coming years against this neglected disease that affects populations around the world, but is a particular issue for those living in poverty.
Group A streptococcal (GAS) infection induces the production of Abs that cross-react with host neuronal proteins, and these anti-GAS mimetic Abs are associated with autoimmune diseases of the CNS. However, the mechanisms that allow these Abs to cross the blood-brain barrier (BBB) and induce neuropathology remain unresolved. We have previously shown that GAS infection in mouse models induces a robust Th17 response in nasal-associated lymphoid tissue (NALT). Here, we identified GAS-specific Th17 cells in tonsils of humans naturally exposed to GAS, prompting us to explore whether GAS-specific CD4+ T cells home to mouse brains following i.n. infection. Intranasal challenge of repeatedly GAS-inoculated mice promoted migration of GAS-specific Th17 cells from NALT into the brain, BBB breakdown, serum IgG deposition, microglial activation, and loss of excitatory synaptic proteins under conditions in which no viable bacteria were detected in CNS tissue. CD4+ T cells were predominantly located in the olfactory bulb (OB) and in other brain regions that receive direct input from the OB. Together, these findings provide insight into the immunopathology of neuropsychiatric complications that are associated with GAS infections and suggest that crosstalk between the CNS and cellular immunity may be a general mechanism by which infectious agents exacerbate symptoms associated with other CNS autoimmune disorders.
Repeated exposure to Group-A β-Haemolytic Streptococcus (GAS) may constitute a vulnerability factor in the onset and course of pediatric motor disturbances. GAS infections/colonization can stimulate the production of antibodies, which may cross the blood brain barrier, target selected brain areas (e.g. basal ganglia), and exacerbate motor alterations. Here, we exposed developing SJL male mice to four injections with a GAS homogenate and evaluated the following domains: motor coordination; general locomotion; repetitive behaviors; perseverative responses; and sensorimotor gating (pre-pulse inhibition, PPI). To demonstrate that behavioral changes were associated with immune-mediated brain alterations, we analyzed, in selected brain areas, the presence of infiltrates and microglial activation (immunohistochemistry), monoamines (HPLC), and brain metabolites (in vivo Magnetic Resonance Spectroscopy). GAS-exposed mice showed increased repetitive and perseverative behaviors, impaired PPI, and reduced concentrations of serotonin in prefrontal cortex, a brain area linked to the behavioral domains investigated, wherein they also showed remarkable elevations in lactate. Active inflammatory processes were substantiated by the observation of infiltrates and microglial activation in the white matter of the anterior diencephalon. These data support the hypothesis that repeated GAS exposure may elicit inflammatory responses in brain areas involved in motor control and perseverative behavior, and result in phenotypic abnormalities.
Objectives
Recent research has focused on the inflammatory cascade as a key culprit in the etiology of bipolar disorder. We hypothesized that celecoxib, via its anti-inflammatory properties, may have a therapeutic role in mood disorder.Methods
Forty-six inpatients with the diagnosis of acute bipolar mania without psychotic features participated in a parallel, randomized, double-blind, placebo-controlled trial, and underwent six weeks of treatment with either celecoxib (400 mg daily) or placebo as an adjunctive treatment to sodium valproate. Patients were evaluated using the Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HDRS). The primary outcome measure with respect to efficacy was the mean decrease in YMRS score from baseline to the study endpoint, which was compared between the two groups.ResultsA significant difference was observed in the change in YMRS scores on Day 42 compared to baseline in the two groups (p < 0.001). The changes at the endpoint compared to baseline were −29.78 ± 21.78 (mean ± standard deviation) and −21.78 ± 7.16 for the celecoxib and placebo groups, respectively. A significantly higher remission rate was observed in the celecoxib group (87.0%) than the placebo group (43.5%) at Week 6 (p = 0.005). General linear model repeated measures demonstrated a significant effect for the time × treatment interaction on the YMRS scores [F(2.27,99.98) = 6.67, p = 0.001].Conclusions
Celecoxib is an effective adjuvant therapy in the treatment of manic episodes (without psychotic features) of bipolar mood disorder. The mood-stabilizing role of the drug might be mediated via its action on the inflammatory cascade.
This study aimed to assess long-term safety and developmental data on juvenile idiopathic arthritis (JIA) patients treated in routine clinical practice with celecoxib or nonselective nonsteroidal anti-inflammatory drugs (nsNSAIDs).
Children aged ≥2 to <18 years with rheumatoid-factor–positive or –negative polyarthritis, persistent or extended oligoarthritis, or systemic arthritis were enrolled into this prospective, observational, multicenter standard-of-care registry. Eligible patients were newly or recently prescribed (≤6 months) an nsNSAID or celecoxib. Enrolled patients were followed to the end of the study, whether they remained on the original NSAID, switched, or discontinued therapy altogether. All adverse events (AEs) regardless of severity were captured in the database.
A total of 274 patients (nsNSAID, n = 219; celecoxib, n = 55) were observed for 410 patient-years of observation. Naproxen, meloxicam, and nabumetone were the most frequently used nsNSAIDs. At baseline, the celecoxib group was older, had a numerically longer median time since diagnosis, and a numerically higher proportion of patients with a history of gastrointestinal-related NSAID intolerance. AEs reported were those frequently observed with NSAID treatment and were similar across groups (nsNSAIDs: 52.0%; celecoxib: 52.9%). Twelve unique patients experienced a total of 18 serious AEs; the most frequent were infections, and none was attributed to NSAID use.
The safety profile of celecoxib and nsNSAIDs appears similar overall. The results from this registry, ongoing pharmacovigilance, and the phase 3 trial that led to the approval of celecoxib for children with JIA provide evidence that the benefit-risk for celecoxib treatment in JIA remains positive.
Trial registration
ClinicalTrials.gov identifier NCT00688545.
How autoantibodies target the brain and lead to disease in disorders such as Sydenham chorea (SC) is not known. SC is characterized by autoantibodies against the brain and is the main neurologic manifestation of streptococcal-induced rheumatic fever. Previously, our novel SC-derived mAb 24.3.1 was found to recognize streptococcal and brain Ags. To investigate in vivo targets of human mAb 24.3.1, VH/VL genes were expressed in B cells of transgenic (Tg) mice as functional chimeric human VH 24.3.1-mouse C-region IgG1(a) autoantibody. Chimeric human-mouse IgG1(a) autoantibody colocalized with tyrosine hydroxylase in the basal ganglia within dopaminergic neurons in vivo in VH 24.3.1 Tg mice. Both human mAb 24.3.1 and IgG1(a) in Tg sera were found to react with human dopamine D2 receptor (D2R). Reactivity of chorea-derived mAb 24.3.1 or SC IgG with D2R was confirmed by dose-dependent inhibitory signaling of D2R as a potential consequence of targeting dopaminergic neurons, reaction with surface-exposed FLAG epitope-tagged D2R, and blocking of Ab reactivity by an extracellular D2R peptide. IgG from SC and a related subset of streptococcal-associated behavioral disorders called "pediatric autoimmune neuropsychiatric disorder associated with streptococci" (PANDAS) with small choreiform movements reacted in ELISA with D2R. Reaction with FLAG-tagged D2R distinguished SC from PANDAS, whereas sera from both SC and PANDAS induced inhibitory signaling of D2R on transfected cells comparably to dopamine. In this study, we define a mechanism by which the brain may be altered by Ab in movement and behavioral disorders.
Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is a newly defined disease in neuropsychiatry and occurs with an autoimmune mechanism after Group A Beta Hemolytic Streptococcus (GABHS) infection. Tumor necrosis factor (TNF), encoded by TNF-α gene has an important role in the apoptotic mechanisms of autoimmune diseases. Recently, TNF-α polymorphisms and autoimmune/psychiatric disorders have been reported to be related. In this regard, we focused on to investigate a possible relation between the TNF-α gene promoter region-308 G/A and - 850 C/T polymorphisms and PANDAS.
In this study, ages of PANDAS patient and control groups were ranging from 4 years to 12-year-old. Patient group includes childhood onset PANDAS patients (n = 42) and control group includes healthy children (n = 58). Diagnoses have been carried out according to Diagnostic and Statistical Manual of Mental Disorder (DSM-IV) criteria with Affective Disorders and Schizophrenia-Present and Lifetime (KSAD-S-PL) and Children Yale-Brown Obsessive Compulsive Scale Moreover, PANDAS criteria established by the American National Psychiatry Institute have been employed for diagnoses. For identifying polymorphisms; Polymerase Chain Reaction, Restriction Fragment Length Polymorphism and Polyacrylamid Gel Electrophoresis were used.
For -308 polymorphism, 37 of 42 PANDAS patients' results and for -850 C/T polymorphism, 38 of 42 PANDAS patients' results were obtained. According to our statistical analysis there is a positive relationship between PANDAS patients for -308 G/A polymorphism but not for -850 C/T polymorphism. There is no positive relationship between -308 G/A polymorphism and antistrep-tolysin O (ASO) titers and no relationship between -850 C/T polymorphism and ASO titers. We found, however, positive relationship between genders of patients (boys) and the disease. According to our results, we propose that the AA polymorphism of -308 G/A polymorphism can be used as a molecular indicator for PANDAS.
Group A streptococcal (GAS) infections and autoimmunity are associated with the onset of a spectrum of neuropsychiatric disorders in children, with the prototypical disorder being Sydenham chorea (SC). Our aim was to develop an animal model that resembled the behavioral, pharmacological, and immunological abnormalities of SC and other streptococcal-related neuropsychiatric disorders. Male Lewis rats exposed to GAS antigen exhibited motor symptoms (impaired food manipulation and beam walking) and compulsive behavior (increased induced-grooming). These symptoms were alleviated by the D2 blocker haloperidol and the selective serotonin reuptake inhibitor paroxetine, respectively, drugs that are used to treat motor symptoms and compulsions in streptococcal-related neuropsychiatric disorders. Streptococcal exposure resulted in antibody deposition in the striatum, thalamus, and frontal cortex, and concomitant alterations in dopamine and glutamate levels in cortex and basal ganglia, consistent with the known pathophysiology of SC and related neuropsychiatric disorders. Autoantibodies (IgG) of GAS rats reacted with tubulin and caused elevated calcium/calmodulin-dependent protein kinase II signaling in SK-N-SH neuronal cells, as previously found with sera from SC and related neuropsychiatric disorders. Our new animal model translates directly to human disease and led us to discover autoantibodies targeted against dopamine D1 and D2 receptors in the rat model as well as in SC and other streptococcal-related neuropsychiatric disorders.
Streptococcal infections can induce obsessive-compulsive and tic disorders. In children, this syndrome, frequently associated with disturbances in attention, learning and mood, has been designated pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). Autoantibodies recognizing central nervous system (CNS) epitopes are found in sera of most PANDAS subjects, but may not be unique to this neuropsychiatric subset. In support of a humoral immune mechanism, clinical improvement often follows plasmapheresis or intravenous immunoglobulin. We recently described a PANDAS mouse model wherein repetitive behaviors correlate with peripheral anti-CNS antibodies and immune deposits in brain following streptococcal immunization. These antibodies are directed against group A beta-hemolytic streptococcus matrix (M) protein and cross-react with molecular targets complement C4 protein and alpha-2-macroglobulin in brain. Here we show additional deficits in motor coordination, learning/memory and social interaction in PANDAS mice, replicating more complex aspects of human disease. Furthermore, we demonstrate for the first time that humoral immunity is necessary and sufficient to induce the syndrome through experiments wherein naive mice are transfused with immunoglobulin G (IgG) from PANDAS mice. Depletion of IgG from donor sera abrogates behavior changes. These functional disturbances link to the autoimmunity-related IgG1 subclass but are not attributable to differences in cytokine profiles. The mode of disrupting blood-brain barrier integrity differentially affects the ultimate CNS distribution of these antibodies and is shown to be an additional important determinant of neuropsychiatric outcomes. This work provides insights into PANDAS pathogenesis and may lead to new strategies for identification and treatment of children at risk for autoimmune brain disorders.
Microenvironment molecular cues direct T helper (Th) cell differentiation; however, Th17 fate determination is still imprecisely understood in humans. To assess the role of prostaglandin E(2) (PGE(2)) in Th expansion, we activated peripheral blood mononuclear cells by CD3 cross-linking. In the presence of exogenous PGE(2), peripheral blood mononuclear cells produced higher interleukin-17 (IL-17), C-C chemokine ligand 20 (CCL20)/macrophage inflammatory protein 3alpha (MIP-3alpha), CXC chemokine ligand 8 (CXCL8)/IL-8, and lower interferon-gamma and IL-22 levels than in control cultures. Exogenous PGE(2) and IL-23 synergized in inducing IL-17, whereas indomethacin and IL-23 blockade drastically reduced IL-17 but not interferon-gamma production. Furthermore, IL-1 but not tumor necrosis factor was absolutely required for IL-17 production. PGE(2) doubled the frequency of CD4+ T cells producing IL-17 and within the CD4+ subset enhanced C-C chemokine receptor 6 (CCR6) and CCR4 while decreasing CXC chemokine receptor 3 (CXCR3) expression. Furthermore, in CD4+ T-cell lines, the production of IL-17 segregated with the CCR6+ subset. In the presence of CCR6+ compared with CXCR3+ Th cells, monocytes/macrophages produced much higher levels of matrix metalloproteinase-1, -3, and -9 but similar levels of CXCL10 and IL-1beta. These results identify PGE(2) and IL-23 as participating in the expansion of CD4+ T cells endowed with high IL-17 production capacity, which in turn favors monocyte production of mediators important for host defense and tissue destruction.
Cyclooxygenase (COX), known to exist in two isoforms, COX-1 and COX-2, is a key enzyme in prostaglandin synthesis and the target for most nonsteroidal anti-inflammatory drugs. In this study, we show that human T lymphocytes express the COX-2 isoenzyme. COX-2 mRNA and protein were induced in both Jurkat and purified T cells stimulated by TCR/CD3 or PMA activation. COX-2 mRNA was induced very early after activation and superinduced by protein synthesis inhibitors, whereas it was inhibited by the immunosuppressive drug cyclosporin A, identifying it as an early T cell activation gene. Interestingly, treatment with COX-2-specific inhibitors such as NS398 or Celecoxib severely diminished early and late events of T cell activation, including CD25 and CD71 cell surface expression, IL-2, TNF-alpha, and IFN-gamma production and cell proliferation, but not the expression of CD69, an immediate early gene. COX-2 inhibitors also abolished induced transcription of reporter genes driven by IL-2 and TNF-alpha promoters. Moreover, induced transcription from NF-kappaB- and NF-AT-dependent enhancers was also inhibited. These results may have important implications in anti-inflammatory therapy and open a new field on COX-2-selective nonsteroidal anti-inflammatory drugs as modulators of the immune activation.
Behçet's disease (BD) is a multisystem disease with unknown etiology. Until today, the role of emotional stress and the real incidence of psychiatric symptoms in this disease have not been clarified yet.
In this study, we aimed to evaluate the general psychological profile of the patients diagnosed as having BD as well as their depression and anxiety levels in order to investigate the psychiatric aspects of this disease.
Twenty-three patients with BD and 17 patients with chronic plaque-type psoriasis who made up the control group were examined by the Beck Depression (BDI), Beck Anxiety (BAI) and Brief Symptom Inventories (BSI).
The mean BDI score of the BD group was 11.69 +/- 6.93, and the corresponding value was 9.11 +/- 7.34 for the psoriasis group. The mean BAI score of the BD group was 21.39 + 13.68 and this level was 12.41 +/- 10.70 for psoriasis patients. The mean BSI score of the BD group was 61.30 +/- 43.66 and it was 30.41 +/- 28.77 for the control group. The mean BDI, BAI and BSI scores of the patients diagnosed as having BD were significantly higher than those of the control group (F = 0.234, F = 0.508, F = 0.549 and p < 0.05).
BDI, BAI and BSI scales are useful to evaluate the psychiatric aspects of BD. The results of our study revealed that the collaboration of a dermatologist and psychiatrist is essential for the follow-up of patients with BD.
A syndrome of motoric and neuropsychiatric symptoms comprising various elements, including chorea, hyperactivity, tics, emotional lability, and obsessive-compulsive symptoms, can occur in association with group A beta-hemolytic streptococcal (GABHS) infection. We tested the hypothesis that an immune response to GABHS can result in behavioral abnormalities. Female SJL/J mice were immunized and boosted with a GABHS homogenate in Freund's adjuvant, whereas controls received Freund's adjuvant alone. When sera from GABHS-immunized mice were tested for immunoreactivity to mouse brain, a subset was found to be immunoreactive to several brain regions, including deep cerebellar nuclei (DCN), globus pallidus, and thalamus. GABHS-immunized mice having serum immunoreactivity to DCN also had increased IgG deposits in DCN and exhibited increased rearing behavior in open-field and hole-board tests compared with controls and with GABHS-immunized mice lacking serum anti-DCN antibodies. Rearing and ambulatory behavior were correlated with IgG deposits in the DCN and with serum immunoreactivity to GABHS proteins in Western blot. In addition, serum from a GABHS mouse reacted with normal mouse cerebellum in nondenaturing Western blots and immunoprecipitated C4 complement protein and alpha-2-macroglobulin. These results are consistent with the hypothesis that immune response to GABHS can result in motoric and behavioral disturbances and suggest that anti-GABHS antibodies cross-reactive with brain components may play a role in their pathophysiology.
Increased permeability of the blood-brain barrier (BBB) is important in neurological disorders. Neuroinflammation is associated with increased BBB breakdown and brain injury. Tumor necrosis factor (TNF)-alpha is involved in BBB injury and edema formation through a mechanism involving matrix metalloproteinase (MMP) up-regulation. There is emerging evidence indicating that cyclooxygenase (COX) inhibition limits BBB disruption following ischemic stroke and bacterial meningitis, but the mechanisms involved are not known. We used intracerebral injection of TNF-alpha to study the effect of COX inhibition on TNF-alpha-induced BBB breakdown, MMP expression/activity, and oxidative stress. BBB disruption was evaluated by the uptake of (14)C-sucrose into the brain and by magnetic resonance imaging utilizing gadolinium-diethylenetriaminepentaacetic acid as a paramagnetic contrast agent. Using selective inhibitors of each COX isoform, we found that COX-1 activity is more important than COX-2 in BBB opening. TNF-alpha induced a significant up-regulation of gelatinase B (MMP-9), stromelysin-1 (MMP-3), and COX-2. In addition, TNF-alpha significantly depleted glutathione as compared with saline. Indomethacin (10 mg/kg i.p.), an inhibitor of COX-1 and COX-2, reduced BBB damage at 24 h. Indomethacin significantly attenuated MMP-9 and MMP-3 expression and activation and prevented the loss of endogenous radical scavenging capacity following intracerebral injection of TNF-alpha. Our results show for the first time that BBB disruption during neuroinflammation can be significantly reduced by administration of COX inhibitors. Modulation of COX in brain injury by COX inhibitors or agents modulating prostaglandin E(2) formation/signaling may be useful in clinical settings associated with BBB disruption.
The microenvironment of the brain requires tight regulation for proper neuronal function. Protecting the central nervous system (CNS) from the varying concentrations of ions, proteins, and toxins in the periphery is the dynamically regulated blood-brain barrier (BBB). Recent studies have demonstrated significant modulation of the BBB in a number of diseases and physiological states, including pain. This study expands on previous explorations of acute and chronic pain-induced effects on the function and molecular cytoarchitecture of the barrier. It describes the role of cyclooxygenase (COX) up-regulation by blocking with diclofenac (30 mg/kg, i.p.), and it examines the variation in BBB regulation through various brain regions. Edema and hyperalgesia were induced by lambda-carrageenan and attenuated by the additional administration of diclofenac. Examination of unidirectional [14C]sucrose permeability with multitime in situ perfusion studies demonstrated that lambda-carrageenan significantly increased cerebral permeability and decreased brainstem permeability. There were no significant changes in any of the other brain regions examined. These permeability changes correlated with up- and down-regulation of the tight junction (TJ) protein claudin-5 in the cerebrum and brainstem, respectively. Diclofenac administration attenuated the cerebral permeability uptake as well as the claudin-5 up-regulation. In addition, diclofenac reversed the lowered permeability in the brainstem, but it did not attenuate TJ protein expression. These studies demonstrate the complex regulation of the BBB occurring during inflammatory pain and the role of COX in this process. An understanding of BBB regulation during pain states is critically important for pharmacotherapy, and it holds great promise for new therapies to treat central nervous system pathologies.
Streptococcus pyogenes infections have been associated with two autoimmune diseases of the CNS: Sydenham's chorea (SC) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus infections (PANDAS). Despite the high frequency of pharyngeal streptococcus infections among children, only a small fraction develops SC or PANDAS. This suggests that several factors in combination are necessary to trigger autoimmune complications: specific S. pyogenes strains that induce a strong immune response toward the host nervous system; genetic susceptibility that predispose children toward an autoimmune response involving movement or tic symptoms; and multiple infections of the throat or tonsils that lead to a robust Th17 cellular and humoral immune response when untreated. In this review, we summarize the evidence for each factor and propose that all must be met for the requisite neurovascular pathology and behavioral deficits found in SC/PANDAS.
Introduction: A growing body of evidence implicates inflammatory cascades in the pathophysiology of obsessive-compulsive disorder (OCD), making this pathway a target for development of novel treatments. Methods: 50 outpatients with moderate to severe OCD participated in the trial, and underwent 10 weeks of treatment with either celecoxib (200 mg twice daily) or placebo as an adjuvant to fluvoxamine. Participants were investigated using Yale-Brown Obsessive Compulsive Scale (Y-BOCS). The main outcome measure was to assess the efficacy of celecoxib in improving the OCD symptoms. Results: General linear model repeated measures demonstrated significant effect for time × treatment interaction on the Y-BOCS total scores [F (1.38, 66.34)=6.91, p=0.005]. Kaplan-Meier estimation with log-rank test demonstrated significantly more rapid response in the celecoxib group than the placebo group (p<0.001). There was no significant difference in adverse event frequencies between the groups. Discussion: The results of the current study suggest that celecoxib could be a tolerable and effective adjunctive treatment for more rapid and more satisfying improvements in OCD symptoms.
© Georg Thieme Verlag KG Stuttgart · New York.
Abrupt, dramatic onset obsessive-compulsive disorder (OCD) and/or eating restriction with at least two coinciding symptoms (anxiety, mood dysregulation, irritability/aggression/oppositionality, behavioral regression, cognitive deterioration, sensory or motor abnormalities, or somatic symptoms) defines pediatric acute-onset neuropsychiatric syndrome (PANS). Descriptions of clinical data in such youth are limited.
We reviewed charts of 53 consecutive patients evaluated in our PANS Clinic; 47 met PANS symptom criteria but not all met the requirement for "acute onset." Patients meeting full criteria for PANS were compared with patients who had a subacute/insidious onset of symptoms.
Nineteen of 47 (40%) patients in the study had acute onset of symptoms. In these patients, autoimmune/inflammatory diseases and psychiatric disorders were common in first-degree family members (71% and 78%, respectively). Most acute-onset patients had a relapsing/remitting course (84%), prominent sleep disturbances (84%), urinary issues (58%), sensory amplification (66%), gastrointestinal symptoms (42%), and generalized pain (68%). Inflammatory back pain (21%) and other arthritis conditions (28%) were also common. Suicidal and homicidal thoughts and gestures were common (44% and 17%, respectively) as were violent outbursts (61%). Group A streptococcus (GAS) was the most commonly identified infection at onset (21%) and during flares (74%). Rates of the abovementioned characteristics did not differ between the acute-onset group and the subacute/insidious-onset groups. Low levels of immunoglobulins were more common in the subacute/insidious-onset group (75%) compared with the acute-onset group (22%), but this was not statistically significant (p=0.06).
In our PANS clinic, 40% of patients had acute onset of symptoms. However, those with and without acute onset of symptoms had similar symptom presentation, rates of inflammatory conditions, somatic symptoms, and violent thoughts and behaviors. GAS infections were the most commonly identified infection at onset and at symptom flares. Because of the wide variety of medical and psychiatric symptoms, youth with PANS may require a multidisciplinary team for adequate care management.
Abstract On May 23 and 24, 2013, the First PANS Consensus Conference was convened at Stanford University, calling together a geographically diverse group of clinicians and researchers from complementary fields of pediatrics: General and developmental pediatrics, infectious diseases, immunology, rheumatology, neurology, and child psychiatry. Participants were academicians with clinical and research interests in pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS) in youth, and the larger category of pediatric acute-onset neuropsychiatric syndrome (PANS). The goals were to clarify the diagnostic boundaries of PANS, to develop systematic strategies for evaluation of suspected PANS cases, and to set forth the most urgently needed studies in this field. Presented here is a consensus statement proposing recommendations for the diagnostic evaluation of youth presenting with PANS.
We applied PET scanning with (11)C-[R]-PK11195 (PK) to evaluate neuroinflammatory changes in basal ganglia and thalamus in children with clinically diagnosed pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) and Tourette syndrome. Seventeen children with PANDAS (mean age: 11.4 ± 2.6 years; 13 males), 12 with Tourette syndrome (mean age: 11.0 ± 3.0 years; 10 males), and 15 normal adults (mean age: 28.7 ± 7.9 years; 8 males) underwent dynamic PK PET imaging and binding potential, a measure of ligand-TSPO receptor (expressed by activated microglia) binding, was calculated for basal ganglia and thalamus. Binding potential values, suggesting underlying activated microglia-mediated neuroinflammation, were found to be increased in bilateral caudate and bilateral lentiform nucleus in the PANDAS group and in bilateral caudate nuclei only in the Tourette syndrome group, compared to control group. These differences in the pattern and extent of neuroinflammation also signify a possible difference in pathophysiological etiology between PANDAS and Tourette syndrome patients.
Group A β-hemolytic streptococcal (GAS) infection is associated with a spectrum of neuropsychiatric disorders. The leading hypothesis regarding this association proposes that a GAS infection induces the production of auto-antibodies, which cross-react with neuronal determinants in the brain through the process of molecular mimicry. We have recently shown that exposure of rats to GAS antigen leads to the production of anti-neuronal antibodies concomitant with the development of behavioral alterations. The present study tested the causal role of the antibodies by assessing the behavior of naïve rats following passive transfer of purified antibodies from GAS-exposed rats. Immunoglobulin G (IgG) purified from the sera of GAS-exposed rats was infused directly into the striatum of naïve rats over a 21-day period. Their behavior in the induced-grooming, marble burying, food manipulation and beam walking assays was compared to that of naïve rats infused with IgG purified from adjuvant-exposed rats as well as of naïve rats. The pattern of in vivo antibody deposition in rat brain was evaluated using immunofluorescence and colocalization. Infusion of IgG from GAS-exposed rats to naïve rats led to behavioral and motor alterations partially mimicking those seen in GAS-exposed rats. IgG from GAS-exposed rats reacted with D1 and D2 dopamine receptors and 5HT-2A and 5HT-2C serotonin receptors in vitro. In vivo, IgG deposits in the striatum of infused rats colocalized with specific brain proteins such as dopamine receptors, the serotonin transporter and other neuronal proteins. Our results demonstrate the potential pathogenic role of autoantibodies produced following exposure to GAS in the induction of behavioral and motor alterations, and support a causal role for autoantibodies in GAS-related neuropsychiatric disorders.
The basal ganglia are deep nuclei in the brain that include the caudate, putamen, globus pallidus, and substantia nigra. Pathological processes involving the basal ganglia often result in disorders of movement and behavior. A number of different autoimmune disorders predominantly involve the basal ganglia and can result in movement and psychiatric disorders. The classic basal ganglia autoimmune disorder is Sydenham chorea, a poststreptococcal neuropsychiatric disorder. Resurgence in the interest in Sydenham chorea is the result of the descriptions of other poststreptococcal neuropsychiatric disorders including tics and obsessive-compulsive disorder, broadly termed pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection. Encephalitic processes affecting the basal ganglia are also described including the syndromes basal ganglia encephalitis, encephalitis lethargica, and bilateral striatal necrosis. Last, systemic autoimmune disorders such as systemic lupus erythematosus and antiphospholipid syndrome can result in chorea or parkinsonism. Using paradigms learned from other autoantibody associated disorders, the authors discuss the autoantibody hypothesis and the role of systemic inflammation in autoimmune basal ganglia disorders. Identification of these entities is important as the clinician has an increasing therapeutic repertoire to modulate or suppress the aberrant immune system.
It has been proposed that the mechanism of the antidepressant effect of celecoxib is linked to its anti-inflammatory action and particularly its inhibitory effect on pro-inflammatory cytokines (e.g. interleukin-6(IL-6)). We measured changes in serum IL-6 concentrations and depressive symptoms following administration of celecoxib in patients with major depressive disorder (MDD).
In a randomized double-blind placebo-controlled study, 40 patients with MDD and Hamilton Depression Rating Scale-17 items (Ham-D) score ≥18 were randomly assigned to either celecoxib (200mg twice daily) or placebo in addition to sertraline (200mg/day) for 6weeks. Outcome measures were serum IL-6 concentrations at baseline and week 6, and Ham-D scores at baseline and weeks 1, 2, 4, and 6.
The celecoxib group showed significantly greater reduction in serum IL-6 concentrations (mean difference (95%CI)=0.42(0.30 to 0.55) pg/ml, t(35)=6.727, P<0.001) as well as Ham-D scores (mean difference (95%CI)=3.35(1.08 to 5.61), t(38)=2.99, P=0.005) than the placebo group. The patients in the celecoxib group experienced more response (95%) and remission (35%) than the placebo group (50% and 5%, P=0.003 and 0.04 respectively). Baseline serum IL-6 levels were significantly correlated with baseline Ham-D scores (r=0.378, P=0.016). Significant correlation was observed between reduction of Ham-D scores and reduction of serum IL-6 levels at week 6 (r=0.673, P<0.001).
We did not measure other inflammatory biomarkers.
We showed that the antidepressant activity of celecoxib might be linked to its capability of reducing IL-6 concentrations. Moreover, supporting previous studies we showed that celecoxib is both safe and effective as an adjunctive antidepressant (Registration number: IRCT138903124090N1).
Obsessive-compulsive disorder is a common neuropsychiatric condition. Although a variety of pharmaceutical agents is available for its treatment, psychiatrists have found that many patients cannot tolerate the side effects, do not respond to treatment adequately, and may finally discontinue their treatment. However, augmentation strategies have been shown to have some benefits in the treatment of OCD. These include reducing both the overall cost of treatment and the side effects. The purpose of this study was to assess the efficacy of celecoxib as an adjuvant agent in the treatment of OCD in an 8-week, double-blind, placebo controlled trial. To this end, 25 patients were assigned to a study group and were given fluoxetine 20mg/day plus celecoxib 400mg/day (200mg BID). The control group included 25 patients who were given fluoxetine 20mg/day plus placebo. Both protocols significantly lowered scores on the Yale-Brown Obsessive-Compulsive Scale over the trial period. The combination of fluoxetine and celecoxib decreased the symptoms of obsessions and compulsions significantly more than fluoxetine plus placebo. The results of this study suggest that celecoxib can be an effective adjuvant agent in the management of patients with OCD; therefore, anti-inflammatory therapies should be further investigated.
Anti-inflammatory efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) has been related to their properties as inhibitors of cyclooxygenase (COX)-mediated prostaglandin (PG) synthesis. However, recent studies have suggested that variations of the in vivo anti-inflammatory actions among different NSAIDs could not be solely explained by COX inhibition. Here, we have analyzed the effects on T cell activation of novel 4,5-dihydro-3 trifluoromethyl pyrazole anti-inflammatory drugs with different potencies as COX-2 inhibitors, namely E-6087, E-6232, E-6231, E-6036 and E-6259 as well as the chemically related COX-2 inhibitor Celecoxib. These drugs inhibited mitogen-mediated T cell proliferation as well as Interleukin (IL)-2, tumor necrosis factor (TNF)-α and Interferon (IFN)-γ synthesis by activated T cells, independently of their ability to inhibit COX-2 enzymatic activity. Immunosuppressive effects of these drugs seem to be due to their interference on transcription factor activation as induced transcription from Nuclear Factor (NF)-κB and Nuclear Factor of Activated T cells (NFAT)-dependent enhancers was inhibited in a dose-dependent manner, being the latter effect the most sensitive to the action of those compounds. Both NFAT dephosphorylation, required for its nuclear translocation, as well as transcriptional activity of a GAL4-NFAT chimera were diminished in the presence of these compounds. These findings provide new insights into the molecular mechanisms involved in the immunomodulatory and anti-inflammatory actions of NSAIDs, which may have important implications in anti-inflammatory therapy, through inhibition of NFAT.
The contribution of Th1 and Th17 cells in chronic inflammatory conditions leading to autoimmunity remains highly controversial. In inflamed tissues, production of prostaglandins by COX-2 has been proposed to favor Th17 responses indirectly by increasing IL-23 and blocking IL-12 release from APC. We report here that prostaglandin E2 (PGE2) can directly modulate cytokine production by human memory CD4(+) T cells. TCR triggering in the presence of PGE2 increased IL-17 and reduced IFN-gamma production by freshly isolated memory T cells or T-cell clones. PGE2 triggered the EP2 and EP4 receptors expressed on T cells leading to a rapid increase of retinoic-acid-related orphan receptor-gammat (ROR-gammat) and decrease of T-cell-specific T-box transcription factor 21 (T-bet) mRNA. Moreover, PGE2 promoted the selective enrichment of IL-17-producing cells by differentially modulating the proliferation of memory T-cell subsets in vitro. Taken together our results indicate that T-cell effector function is a direct target for PGE2 modulation and suggest a novel mechanism by which inhibitors of prostaglandin synthesis, such as COX-2 inhibitors, exert their anti-inflammatory effect.
Anti-inflammatory drugs have been suggested as a possible treatment for Alzheimer's disease (AD). The association of immune proteins and immune-competent microglial cells with senile plaques (SP) in both AD and normal aging suggests that these drugs may be able to modify the course of AD, either by interfering with SP formation or by suppressing the inflammation associated with SP. We compared postmortem brain tissue from elderly, nondemented, arthritic patients with a history of chronic nonsteroidal anti-inflammatory drug (NSAID) use (n = 32, aged 77 +/- 7 years) and nondemented control subjects with no history of arthritis or other condition that might promote the regular use of NSAIDs (n = 34, aged 77 +/- 6 years). In both the NSAID-treated group and control subjects, 59% of patients had some SP. There was no difference between the two groups in the mean number of plaques or in the number of specific SP subtypes (diffuse or neuritic). The degree of neurofibrillary pathology was also similar. Activated microglia were identified using CR3/43, an anti-MHC class II antibody. Both patient age and the presence of SP correlated positively with the number of CR3/43+ microglia (p < 0.02), whereas NSAID use was associated with less microglial activation (p < 0.01). Control patients with SP had almost three times the number of activated microglia as NSAID-treated patients with SP (11 versus 4 cells/mm2, p < 0.02). These results suggest that if NSAID use is effective in treating AD, the mechanism is more likely to be through the suppression of microglial activity than by inhibiting the formation of SP or neurofibrillary tangles.
The goal of this pilot study was to investigate the prevalence of obsessive-compulsive disorder (OCD) in a group of patients with systemic lupus erythematosus (SLE).
Fifty adult patients enrolled in out-patient SLE studies at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (February 1995-October 1996) completed a self-report questionnaire adapted from the Yale-Brown Obsessive Compulsive Scale and an in-person psychiatric clinical interview with a psychiatrist or psychiatric clinical nurse specialist. DSM-IV lifetime diagnosis of OCD was determined by clinical interview.
Sixteen subjects (32%) met DSM-IV lifetime diagnostic criteria for OCD and an additional 5 (10%) met criteria for subclinical OCD. Mean +/- SD number of symptoms reported on the self-report questionnaire was significantly higher among subjects diagnosed with OCD on clinical interview (40.7 +/- 23.2) compared with those without OCD (8.9 +/- 11.7; t = 5.8, df = 27, p <.001).
Obsessive-compulsive disorder was 10 to 15 times more common in this cohort of patients with SLE compared with those in community-based studies of OCD. The use of an OCD self-report rating scale proved helpful in the identification of OCD symptoms among patients with SLE. Results suggest that further studies of OCD in patients with SLE are needed and may provide new insight into the pathophysiology of both disorders.
The protective effects of non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease have been demonstrated in multiple epidemiological studies. It has been hypothesized that this is due to their effects on amyloid beta-peptide (Abeta) metabolism, which is independent of the NSAID stereoisoform, rather than inhibition of cyclooxygenase (COX), which is a property of S-enantiomers. We compared the neuroprotective activity of S- and R-enantiomers of flurbiprofen and ibuprofen in a standard assay where secretions from activated human THP-1 or microglial cells are toxic to neuroblastoma SH-SY5Y cells. We found S- but not R-enantiomers to be protective at low concentrations, which is consistent with a COX-dependent mechanism.
In an international, multicenter, double-blind, randomized clinical trial we evaluated the short-term (3 months) and long-term (12 months) efficacy and safety of 2 different doses of meloxicam oral suspension compared with the efficacy and safety of naproxen oral suspension in children with oligoarticular-course (oligo-course) or polyarticular-course (poly-course) juvenile idiopathic arthritis (JIA).
Children ages 2-16 years who had active oligo-course or poly-course JIA and who required therapy with a nonsteroidal antiinflammatory drug were eligible for this trial. Patients were randomly allocated to receive therapy with meloxicam oral suspension, 0.125 mg/kg body weight in a single daily dose; meloxicam oral suspension, 0.25 mg/kg body weight in a single daily dose; or naproxen, 10 mg/kg body weight in 2 daily doses. The trial drugs were administered in a double-blind, double-dummy design for up to 12 months. Response rates were determined according to the American College of Rheumatology pediatric 30% improvement criteria (ACR pediatric 30). Safety parameters were assessed by evaluating the frequency of adverse events in the 3 groups.
Of 232 patients enrolled, 225 received treatment, 6 were not eligible for randomization, and 1 randomized patient was not treated. One hundred eighty-two patients (81%) completed the 12-month treatment period. Response rates according to the ACR pediatric 30 criteria improved from month 3 to month 12, as follows: from 63% to 77% in the meloxicam 0.125 mg/kg group, from 58% to 76% in the meloxicam 0.25 mg/kg group, and from 64% to 74% in the naproxen group. No statistically significant differences in response rates were observed between the groups. There were no differences in the frequency of adverse events or abnormal laboratory values between the 3 groups.
The short- and long-term safety and efficacy of meloxicam oral suspension appear to be comparable with the safety and efficacy of naproxen oral suspension in the treatment of oligo-course and poly-course JIA. The once-daily administration of meloxicam oral suspension might represent an improvement in the treatment of JIA.
Recent advances in immunological research regarding the differentiation between the type-1 and type-2 immune response are discussed. Increased levels of Interleukin-6 (IL-6) and the activation of the IL-6 system in schizophrenia might be the result of the activation of type-2 monocytes/macrophages, too. On the contrary, several parameters of the specific cellular immune system are blunted, e. g. the decreased type-1 related immune parameters in schizophrenic patients. This study was performed as a double-blind, placebo-controlled, randomized evaluation of risperidone and celecoxib versus risperidone and placebo. Fifty schizophrenic patients were included in the study: 25 patients received risperidone and placebo, and 25 patients received risperidone and celecoxib for 5 weeks after the wash-out period. The treatment effect was calculated by ANCOVA. In parallel, serum levels of sTNF-R1 and sIL- 2R, and the percentages of CD3(+)-, CD4(+)-, and CD19(+) lymphocytes were estimated. As expected, both groups of schizophrenic patients showed significant improvement. However, the celecoxib add-on therapy group showed a significant group effect in the PANSS total score. The cytokines and lymphocytes reflected the type-1/type-2 balancing effects of COX-2 inhibitors. Additional treatment with celecoxib has significant positive effects on the therapeutic action of risperidone with regard to the total schizophrenia psychopathology. Moreover, the fact that treatment with an immunomodulatory drug shows beneficial effects on the symptomatology of schizophrenia indicates that immune dysfunction in schizophrenia is not just an epiphenomenon, but related to the pathomechanism of the disorder.
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