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Shen Y, Jia J, Teng J, Yang C, Hu Q. Advancing personalised precision treatment for Still's disease based on molecular characteristics and disease progression. THE LANCET. RHEUMATOLOGY 2025; 7:e127-e140. [PMID: 39433056 DOI: 10.1016/s2665-9913(24)00225-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 07/21/2024] [Accepted: 07/22/2024] [Indexed: 10/23/2024]
Abstract
Still's disease, a systemic autoinflammatory disorder with a classic multigenetic background, is characterised by polyarthritis, high-spiking fever, salmon-like evanescent skin rash, and hyperferritinaemia. Although the exact cause of Still's disease remains unclear, it is believed to be influenced by genetic factors, infections, and immune dysregulation. Current studies indicate that neutrophils and macrophages play crucial roles in the pathogenesis of Still's disease, along with involvement of natural killer cells, T cells, and B cells. Advances in biologic agents have expanded treatment strategies beyond conventional approaches, with cytokine-targeted agents showing promise in the management of Still's disease. Some cytokine-targeting biologic agents can be developed based on clinical manifestations, complications, immune cells, and molecular networks. Emphasis of immunophenotyping for precise clinical subtyping and targeted molecular therapies based on these findings is crucial for optimising treatment outcomes. In this Review, we discuss the latest advancements in the understanding of Still's disease pathogenesis and corresponding therapeutic approaches.
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Affiliation(s)
- Yujie Shen
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinchao Jia
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jialin Teng
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chengde Yang
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiongyi Hu
- Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Bindoli S, De Matteis A, Mitrovic S, Fautrel B, Carmona L, De Benedetti F. Efficacy and safety of therapies for Still's disease and macrophage activation syndrome (MAS): a systematic review informing the EULAR/PReS guidelines for the management of Still's disease. Ann Rheum Dis 2024; 83:1731-1747. [PMID: 39317415 PMCID: PMC11671904 DOI: 10.1136/ard-2024-225854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 06/18/2024] [Indexed: 09/26/2024]
Abstract
OBJECTIVES To analyse the efficacy and safety of treatments for Still's disease and macrophage activation syndrome (MAS). METHODS Medline, Embase and Cochrane Library were searched for clinical trials (randomised, randomised controlled trial (RCT), controlled and clinical controlled trial (CCT)), observational studies (retrospective, longitudinal observational retrospective (LOR), prospective and longitudinal observational prospective (LOP)) and systematic reviews (SRs), in which the populations studied were patients with Still's disease and MAS. The intervention was any pharmacological treatment (approved or under evaluation) versus any comparator drug or placebo, and as outcomes, any relevant efficacy and safety event. The risk of bias (RoB) was assessed with the Cochrane RoB and AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews-2, version 2) for SRs. RESULTS 128 full texts were included: 25 RCTs, 1 CCT, 11 SRs published after 2013 and 91 LOP/LOR studies. In Still's disease, interleukin (IL)-1 inhibitors (IL-1i) and IL-6R inhibitors (IL-6i) were the most studied drugs. Two meta-analyses on RCTs showed an OR, to achieve an ARC50 response rate, of 6.02 (95% CI 2.24 to 21.36) and 8.08 (95% CI 1.89 to 34.57) for IL-1i and IL-6Ri, respectively. Retrospective studies showed that early initiation of IL-1i or IL-6i was associated with high rates of clinically inactive disease. In MAS, GCs were employed in all patients, often associated with ciclosporin and/or anakinra. Rates of complete response were reported, with a range from 53% to 100%. Emapalumab was the only drug tested in a CCT, with a complete response of 93%. CONCLUSION IL-1i and IL-6Ri show the highest level of efficacy in the treatment of Still's disease. For MAS, IL-1 and interferon-γ inhibition appear to be effective on a background of high-dose glucocorticoids.
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Affiliation(s)
- Sara Bindoli
- Rheumatology Unit, Department of Medicine (DIMED), University of Padova, Padova, Italy
| | - Arianna De Matteis
- Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, ERN-RITA center, Roma, Italy
| | - Stéphane Mitrovic
- Department of Rheumatology, Pitié-Salpêtriere Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne University, Paris, France
- CRI-IMIDIATE Clinical Research Network and ERN Rita, CEREMAIA Reference Center, Paris, France
| | - Bruno Fautrel
- Department of Rheumatology, Pitié-Salpêtriere Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne University, Paris, France
- CRI-IMIDIATE Clinical Research Network and ERN Rita, CEREMAIA Reference Center, Paris, France
- Pierre Louis Institute of Epidemiology and Public Health, INSERM UMR-S 1136, Paris, France
| | - Loreto Carmona
- Instituto de Salud Musculoesquelética (INMUSC), Madrid, Spain
| | - Fabrizio De Benedetti
- Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, ERN-RITA center, Roma, Italy
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Hinze CH, Foell D, Kessel C. Treatment of systemic juvenile idiopathic arthritis. Nat Rev Rheumatol 2023; 19:778-789. [PMID: 37923864 DOI: 10.1038/s41584-023-01042-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/28/2023] [Indexed: 11/06/2023]
Abstract
Systemic juvenile idiopathic arthritis (sJIA) is an inflammatory disease with hallmarks of severe systemic inflammation, which can be accompanied by arthritis. Contemporary scientific insights set this paediatric disorder on a continuum with its counterpart, adult-onset Still disease (AOSD). Patients with sJIA are prone to complications, including life-threatening hyperinflammation (macrophage activation syndrome (sJIA-MAS)) and sJIA-associated lung disease (sJIA-LD). Meanwhile, the treatment arsenal in sJIA has expanded markedly. State-of-the-art therapeutic approaches include biologic agents that target the IL-1 and IL-6 pathways. Beyond these, a range of novel agents are on the horizon, some of them already being used on a compassionate use basis, including JAK inhibitors and biologic agents that target IL-18, IFNγ, or IL-1β and IL-18 simultaneously. However, sJIA, sJIA-MAS and sJIA-LD still pose challenging conundrums to rheumatologists treating paediatric and adult patients worldwide. Although national and international consensus treatment plans exist for the treatment of 'classic' sJIA, the treatment approaches for early sJIA without arthritis, and for refractory or complicated sJIA, are not well defined. Therefore, in this Review we outline current approaches for the treatment of sJIA and provide an outlook on knowledge gaps.
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Affiliation(s)
- Claas H Hinze
- Department of Paediatric Rheumatology and Immunology, Münster University Hospital, Münster, Germany
| | - Dirk Foell
- Department of Paediatric Rheumatology and Immunology, Münster University Hospital, Münster, Germany.
| | - Christoph Kessel
- Department of Paediatric Rheumatology and Immunology, Münster University Hospital, Münster, Germany
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Ambler WG, Nanda K, Onel KB, Shenoi S. Refractory systemic onset juvenile idiopathic arthritis: current challenges and future perspectives. Ann Med 2022; 54:1839-1850. [PMID: 35786149 PMCID: PMC9258439 DOI: 10.1080/07853890.2022.2095431] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 06/18/2022] [Accepted: 06/23/2022] [Indexed: 12/14/2022] Open
Abstract
Systemic juvenile idiopathic arthritis (SJIA) is a rare disease with distinct features not seen in other categories of juvenile idiopathic arthritis. In recent years, advances in the understanding of disease immunopathogenesis have led to improved targeted therapies with significant improvement in patient outcomes. Despite these advances, there remain subsets of SJIA with refractory disease and severe disease-associated complications. This review highlights existing options for treatment of refractory SJIA and explores potential future therapeutics for refractory disease.Key Points:Despite targeted Interleukin IL-1 and IL-6 inhibitors a subset of SJIA remains refractory to therapy. About 1 in 7 SJIA patients will be refractory to targeted IL-1 or IL-6 therapy.There is no current agreed upon definition for refractory SJIA and we propose in this review that refractory SJIA is presence of active systemic or arthritic features despite treatment with anti-IL-1 or anti-IL-6 therapy or disease requiring glucocorticoids for control beyond 6 months.SJIA disease associated complications include presence of associated macrophage activation syndrome (MAS), interstitial lung disease (ILD) or amyloidosis and management of each differs.Refractory SJIA treatment options currently include additional conventional synthetic disease modifying anti-rheumatic drugs (csDMARDS), biologic (bDMARDS), combination biologic therapy, targeted synthetic (tsDMARDS) or other immunomodulatory therapies.
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Affiliation(s)
- William G. Ambler
- Division of Pediatric Rheumatology, Hospital for Special Surgery, New York, NY, USA
- Department of Pediatrics, Weill Cornell Medical College, New York, NY, USA
| | - Kabita Nanda
- Department of Pediatrics, Division of Rheumatology, University of Washington School of Medicine & Seattle Children’s Hospital, Seattle, WA, USA
| | - Karen Brandt Onel
- Division of Pediatric Rheumatology, Hospital for Special Surgery, New York, NY, USA
- Department of Pediatrics, Weill Cornell Medical College, New York, NY, USA
| | - Susan Shenoi
- Department of Pediatrics, Division of Rheumatology, University of Washington School of Medicine & Seattle Children’s Hospital, Seattle, WA, USA
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Rong JM, Shi ML, Niu JK, Luo J, Miao YL. Thalidomide combined with endoscopy in the treatment of Cronkhite-Canada syndrome: A case report. World J Clin Cases 2022; 10:10366-10374. [PMID: 36246833 PMCID: PMC9561581 DOI: 10.12998/wjcc.v10.i28.10366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/05/2022] [Accepted: 08/24/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Cronkhite-Canada syndrome (CCS) is a rare non-hereditary disease with a poor prognosis and a mortality rate of up to 55%. Currently, there is no standard treatment for CCS. The department of gastroenterology of our hospital admitted a patient with CCS whose symptoms improved significantly after treatment with thalidomide combined with endoscopy, and there was no obvious adverse reaction during the 2-year follow-up.
CASE SUMMARY A 47-year-old Chinese man presented with diarrhea for more than 4 mo, accompanied by loss of taste, fatigue, and weight loss. Physical examination demonstrated that the patient’s skin and hands were hyperpigmented, the front edges of the nails of both hands were notably thickened and yellow, and the nails were partially atrophied. Gastrointestinal endoscopy identified a diffuse polypoid bulge, and the patient bore an albumin level of 27.3 g/L. The level of the calcium correction amount was (2.164 mM) which allowed for a comprehensive diagnosis of Cronkhite-Canada syndrome, combined with hypoalbuminemia and hypocalcemia. Thalidomide of 150 mg per day was administered to regulate immunity, and the symptoms were relieved after 1 wk. During the follow-up period, polyps were still found that had not been resolved by thalidomide treatment, and endoscopic therapy was performed. This resulted in further improvement of his condition and no particular discomfort during the 2 years of follow-up.
CONCLUSION The patient’s symptoms were significantly relieved by thalidomide 2 years after treatment, proposing it as a potential treatment for CCS.
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Affiliation(s)
- Jia-Mei Rong
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Meng-Lin Shi
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jun-Kun Niu
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Juan Luo
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Ying-Lei Miao
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
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Di Cola I, Cipriani P, Ruscitti P. Perspectives on the use of non-biological pharmacotherapy for adult-onset Still's disease. Expert Opin Pharmacother 2022; 23:1577-1587. [PMID: 36124816 DOI: 10.1080/14656566.2022.2126764] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION The treatment of the patients with adult-onset Still's disease (AOSD) remains largely empirical and it is based on the administration of immunosuppressive drugs. In this work, we described the use of non-biological pharmacotherapies for AOSD. AREA COVERED Although nonsteroidal anti-inflammatory drugs (NSAIDs) are employed during the diagnostic phase, glucocorticoids (GCs) are the first-line therapy, administered at the beginning of the disease. As second-line therapy, conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) are used when GCs do not fully control the disease and/or to reduce the dosage of concomitant GCs. Methotrexate (MTX) is the most commonly administered csDMARDs whereas calcineurin inhibitors (CNIs) are used in severe patients. The lack of achievement of clinical response may lead to the administration of biologic DMARDs, with or without csDMARDs. EXPERT OPINION The management of AOSD may benefit from the administration of non-biological pharmacotherapies, including GCs, MTX, and CNIs. These therapies showed efficacy in inducing a clinical response, in managing life-threatening complications, and may be well tolerated in combination with biologic DMARDs. However, further specific studies are needed to fully clarify the specific role of such drugs in clinical practice to improve the management of AOSD and to provide a more tailored treatment.
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Affiliation(s)
- Ilenia Di Cola
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Paola Cipriani
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Piero Ruscitti
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
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Onel KB, Horton DB, Lovell DJ, Shenoi S, Cuello CA, Angeles-Han ST, Becker ML, Cron RQ, Feldman BM, Ferguson PJ, Gewanter H, Guzman J, Kimura Y, Lee T, Murphy K, Nigrovic PA, Ombrello MJ, Rabinovich CE, Tesher M, Twilt M, Klein-Gitelman M, Barbar-Smiley F, Cooper AM, Edelheit B, Gillispie-Taylor M, Hays K, Mannion ML, Peterson R, Flanagan E, Saad N, Sullivan N, Szymanski AM, Trachtman R, Turgunbaev M, Veiga K, Turner AS, Reston JT. 2021 American College of Rheumatology Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Oligoarthritis, Temporomandibular Joint Arthritis, and Systemic Juvenile Idiopathic Arthritis. Arthritis Care Res (Hoboken) 2022; 74:521-537. [PMID: 35233986 PMCID: PMC10124899 DOI: 10.1002/acr.24853] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 09/29/2021] [Accepted: 11/23/2021] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To provide updated guidelines for pharmacologic management of juvenile idiopathic arthritis (JIA), focusing on treatment of oligoarthritis, temporomandibular joint (TMJ) arthritis, and systemic JIA with and without macrophage activation syndrome. Recommendations regarding tapering and discontinuing treatment in inactive systemic JIA are also provided. METHODS We developed clinically relevant Patient/Population, Intervention, Comparison, and Outcomes questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the quality of evidence (high, moderate, low, or very low). A Voting Panel including clinicians and patients/caregivers achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS Similar to those published in 2019, these JIA recommendations are based on clinical phenotypes of JIA, rather than a specific classification schema. This guideline provides recommendations for initial and subsequent treatment of JIA with oligoarthritis, TMJ arthritis, and systemic JIA as well as for tapering and discontinuing treatment in subjects with inactive systemic JIA. Other aspects of disease management, including factors that influence treatment choice and medication tapering, are discussed. Evidence for all recommendations was graded as low or very low in quality. For that reason, more than half of the recommendations are conditional. CONCLUSION This clinical practice guideline complements the 2019 American College of Rheumatology JIA and uveitis guidelines, which addressed polyarthritis, sacroiliitis, enthesitis, and uveitis. It serves as a tool to support clinicians, patients, and caregivers in decision-making. The recommendations take into consideration the severity of both articular and nonarticular manifestations as well as patient quality of life. Although evidence is generally low quality and many recommendations are conditional, the inclusion of caregivers and patients in the decision-making process strengthens the relevance and applicability of the guideline. It is important to remember that these are recommendations. Clinical decisions, as always, should be made by the treating clinician and patient/caregiver.
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Affiliation(s)
- Karen B Onel
- Hospital for Special Surgery, New York, New York
| | - Daniel B Horton
- Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Daniel J Lovell
- Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio
| | - Susan Shenoi
- Seattle Children's Hospital and Research Center and University of Washington, Seattle
| | | | - Sheila T Angeles-Han
- Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio
| | | | | | | | | | - Harry Gewanter
- Children's Hospital of Richmond at VCU, Richmond, Virginia
| | - Jaime Guzman
- BC Children's Hospital, Vancouver, British Columbia, Canada
| | - Yukiko Kimura
- Hackensack Meridian School of Medicine, Hackensack, New Jersey
| | | | | | - Peter A Nigrovic
- Boston Children's Hospital and Brigham and Women's Hospital, Boston, Massachusetts
| | | | | | | | - Marinka Twilt
- University of Calgary and Alberta Children's Hospital, Calgary, Alberta, Canada
| | - Marisa Klein-Gitelman
- Ann & Robert Lurie Children's Hospital of Chicago and Northwestern University, Chicago, Illinois
| | | | | | | | | | - Kimberly Hays
- Penn State Health Children's Hospital, Hershey, Pennsylvania
| | | | | | | | | | | | | | | | | | - Keila Veiga
- Maria Fareri Children's Hospital, Valhalla, New York
| | - Amy S Turner
- American College of Rheumatology, Atlanta, Georgia
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8
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Onel KB, Horton DB, Lovell DJ, Shenoi S, Cuello CA, Angeles-Han ST, Becker ML, Cron RQ, Feldman BM, Ferguson PJ, Gewanter H, Guzman J, Kimura Y, Lee T, Murphy K, Nigrovic PA, Ombrello MJ, Rabinovich CE, Tesher M, Twilt M, Klein-Gitelman M, Barbar-Smiley F, Cooper AM, Edelheit B, Gillispie-Taylor M, Hays K, Mannion ML, Peterson R, Flanagan E, Saad N, Sullivan N, Szymanski AM, Trachtman R, Turgunbaev M, Veiga K, Turner AS, Reston JT. 2021 American College of Rheumatology Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Oligoarthritis, Temporomandibular Joint Arthritis, and Systemic Juvenile Idiopathic Arthritis. Arthritis Rheumatol 2022; 74:553-569. [PMID: 35233993 PMCID: PMC10161784 DOI: 10.1002/art.42037] [Citation(s) in RCA: 119] [Impact Index Per Article: 39.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 09/29/2021] [Accepted: 11/23/2021] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To provide updated guidelines for pharmacologic management of juvenile idiopathic arthritis (JIA), focusing on treatment of oligoarthritis, temporomandibular joint (TMJ) arthritis, and systemic JIA with and without macrophage activation syndrome. Recommendations regarding tapering and discontinuing treatment in inactive systemic JIA are also provided. METHODS We developed clinically relevant Patient/Population, Intervention, Comparison, and Outcomes questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the quality of evidence (high, moderate, low, or very low). A Voting Panel including clinicians and patients/caregivers achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS Similar to those published in 2019, these JIA recommendations are based on clinical phenotypes of JIA, rather than a specific classification schema. This guideline provides recommendations for initial and subsequent treatment of JIA with oligoarthritis, TMJ arthritis, and systemic JIA as well as for tapering and discontinuing treatment in subjects with inactive systemic JIA. Other aspects of disease management, including factors that influence treatment choice and medication tapering, are discussed. Evidence for all recommendations was graded as low or very low in quality. For that reason, more than half of the recommendations are conditional. CONCLUSION This clinical practice guideline complements the 2019 American College of Rheumatology JIA and uveitis guidelines, which addressed polyarthritis, sacroiliitis, enthesitis, and uveitis. It serves as a tool to support clinicians, patients, and caregivers in decision-making. The recommendations take into consideration the severity of both articular and nonarticular manifestations as well as patient quality of life. Although evidence is generally low quality and many recommendations are conditional, the inclusion of caregivers and patients in the decision-making process strengthens the relevance and applicability of the guideline. It is important to remember that these are recommendations. Clinical decisions, as always, should be made by the treating clinician and patient/caregiver.
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Affiliation(s)
- Karen B Onel
- Hospital for Special Surgery, New York, New York
| | - Daniel B Horton
- Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Daniel J Lovell
- Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio
| | - Susan Shenoi
- Seattle Children's Hospital and Research Center and University of Washington, Seattle
| | | | - Sheila T Angeles-Han
- Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio
| | | | | | | | | | - Harry Gewanter
- Children's Hospital of Richmond at VCU, Richmond, Virginia
| | - Jaime Guzman
- BC Children's Hospital, Vancouver, British Columbia, Canada
| | - Yukiko Kimura
- Hackensack Meridian School of Medicine, Hackensack, New Jersey
| | | | | | - Peter A Nigrovic
- Boston Children's Hospital and Brigham and Women's Hospital, Boston, Massachusetts
| | | | | | | | - Marinka Twilt
- University of Calgary and Alberta Children's Hospital, Calgary, Alberta, Canada
| | - Marisa Klein-Gitelman
- Ann & Robert Lurie Children's Hospital of Chicago and Northwestern University, Chicago, Illinois
| | | | | | | | | | - Kimberly Hays
- Penn State Health Children's Hospital, Hershey, Pennsylvania
| | | | | | | | | | | | | | | | | | - Keila Veiga
- Maria Fareri Children's Hospital, Valhalla, New York
| | - Amy S Turner
- American College of Rheumatology, Atlanta, Georgia
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Abstract
Juvenile idiopathic arthritis (JIA) is an umbrella term for arthritis of unknown origin, lasting for >6 weeks with onset before 16 years of age. JIA is the most common chronic inflammatory rheumatic condition of childhood. According to the International League Against Rheumatism (ILAR) classification, seven mutually exclusive categories of JIA exist based on disease manifestations during the first 6 months of disease. Although the ILAR classification has been useful to foster research, it has been criticized mainly as it does not distinguish those forms of chronic arthritis observed in adults and in children from those that may be unique to childhood. Hence, efforts to provide a new evidence-based classification are ongoing. Similar to arthritis observed in adults, pathogenesis involves autoimmune and autoinflammatory mechanisms. The field has witnessed a remarkable improvement in therapeutic possibilities of JIA owing to the availability of new potent drugs and the possibility to perform controlled trials with support from legislative interventions and large networks availability. The goal of drug therapy in JIA is to rapidly reduce disease activity to inactive disease or clinical remission, minimize drug side effects and achieve a quality of life comparable to that of healthy peers. As JIA can influence all aspects of a child's and their family's life, researchers increasingly recognize improvement of health-related quality of life as a key treatment goal.
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Unal U, Comertpay B, Demirtas TY, Gov E. Drug repurposing for rheumatoid arthritis: Identification of new drug candidates via bioinformatics and text mining analysis. Autoimmunity 2022; 55:147-156. [PMID: 35048767 DOI: 10.1080/08916934.2022.2027922] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease that results in the destruction of tissue by attacks on the patient by his or her own immune system. Current treatment strategies are not sufficient to overcome RA. In the present study, various transcriptomic data from synovial fluids, synovial fluid-derived macrophages, and blood samples from patients with RA were analysed using bioinformatics approaches to identify tissue-specific repurposing drug candidates for RA. Differentially expressed genes (DEGs) were identified by integrating datasets for each tissue and comparing diseased to healthy samples. Tissue-specific protein-protein interaction (PPI) networks were generated and topologically prominent proteins were selected. Transcription-regulating biomolecules for each tissue type were determined from protein-DNA interaction data. Common DEGs and reporter biomolecules were used to identify drug candidates for repurposing using the hypergeometric test. As a result of bioinformatic analyses, 19 drugs were identified as repurposing candidates for RA, and text mining analyses supported our findings. We hypothesize that the FDA-approved drugs momelotinib, ibrutinib, and sodium butyrate may be promising candidates for RA. In addition, CHEMBL306380, Compound 19a (CHEMBL3116050), ME-344, XL-019, TG100801, JNJ-26483327, and NV-128 were identified as novel repurposing candidates for the treatment of RA. Preclinical and further validation of these drugs may provide new treatment options for RA.
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Affiliation(s)
- Ulku Unal
- Department of Bioengineering, Adana Alparslan Türkeş Science and Technology University, Adana, Turkey
| | - Betul Comertpay
- Department of Bioengineering, Adana Alparslan Türkeş Science and Technology University, Adana, Turkey
| | - Talip Yasir Demirtas
- Department of Bioengineering, Adana Alparslan Türkeş Science and Technology University, Adana, Turkey
| | - Esra Gov
- Department of Bioengineering, Adana Alparslan Türkeş Science and Technology University, Adana, Turkey
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Atemnkeng Ntam V, Klein A, Horneff G. Safety and efficacy of anakinra as first-line or second-line therapy for systemic onset juvenile idiopathic arthritis - data from the German BIKER registry. Expert Opin Drug Saf 2020; 20:93-100. [PMID: 33148061 DOI: 10.1080/14740338.2021.1843631] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Background: The IL-1 receptor-antagonist anakinra is recommended for the treatment of systemic juvenile idiopathic arthritis (sJIA) and was recently approved for first-line treatment. Long-term data from clinical practise are scarce. Methods: SJIA patients from the German biologics in pediatric rheumatology (BIKER) registry starting anakinra were grouped into two cohorts: Patients in the first-line cohort received no prior sJIA treatment except NSAID and a maximum of 3 days of steroids. Second-line cohort patients were pre-treated with steroids; DMARDs or biologics. Patient characteristics, disease-activity parameters, efficacy, and safety-parameters were compared. Results: Until December 2018, 51 anakinra patients were documented, representing 117.96 patient-years. Mean disease duration was 3.5 (± 3.8) years. At baseline, all anakinra first-line users had active systemic disease compared to 82% in the second-line users. Significant JADAS-10 improvement at last follow-up was observed in both cohorts (p = 0.02, p = 0.0014). Substantial numbers of patients in both groups reached JADAS-MDA/JADAS-remission/inactive disease (66.7%50%50% in first-liners and 60%45%70% in second-liners). Rates of serious adverse events were comparable and consistent with the overall AE profile of anakinra in patients. Conclusion: This analysis adds to the established safety profile of anakinra and demonstrates that anakinra is effective as first-line or second-line treatment.
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Affiliation(s)
- V Atemnkeng Ntam
- Asklepios Clinic Sankt Augustin, Centre of Pediatric Rheumatology , Sankt Augustin, Germany
| | - A Klein
- Asklepios Clinic Sankt Augustin, Centre of Pediatric Rheumatology , Sankt Augustin, Germany.,Department of Pediatrics, University Clinic, University of Cologne , Germany
| | - G Horneff
- Asklepios Clinic Sankt Augustin, Centre of Pediatric Rheumatology , Sankt Augustin, Germany.,Department of Pediatrics, University Clinic, University of Cologne , Germany
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12
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Vastert SJ, Jamilloux Y, Quartier P, Ohlman S, Osterling Koskinen L, Kullenberg T, Franck-Larsson K, Fautrel B, de Benedetti F. Anakinra in children and adults with Still's disease. Rheumatology (Oxford) 2020; 58:vi9-vi22. [PMID: 31769856 PMCID: PMC6878842 DOI: 10.1093/rheumatology/kez350] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 06/17/2019] [Indexed: 12/29/2022] Open
Abstract
Systemic juvenile idiopathic arthritis and adult-onset Still’s disease are rare autoinflammatory disorders with common features, supporting the recognition of these being one disease—Still’s disease—with different ages of onset. Anakinra was recently approved by the European Medicines Agency for Still’s disease. In this review we discuss the reasoning for considering Still’s disease as one disease and present anakinra efficacy and safety based on the available literature. The analysis of 27 studies showed that response to anakinra in Still’s disease was remarkable, with clinically inactive disease or the equivalent reported for 23–100% of patients. Glucocorticoid reduction and/or stoppage was reported universally across the studies. In studies on paediatric patients where anakinra was used early or as first-line treatment, clinically inactive disease and successful anakinra tapering/stopping occurred in >50% of patients. Overall, current data support targeted therapy with anakinra in Still’s disease since it improves clinical outcome, especially if initiated early in the disease course.
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Affiliation(s)
- Sebastiaan J Vastert
- Department of Pediatric Rheumatology and Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Yvan Jamilloux
- Department of Internal Medicine Hospices Civils de Lyon, Croix-Rousse Hospital, Lyon, France
| | - Pierre Quartier
- Pediatric Immunology-Hematology and Rheumatology Unit, RAISE Rare Disease Reference Centre, IMAGINE Institute, Necker Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.,Université Paris-Descartes, Paris, France
| | | | | | | | | | - Bruno Fautrel
- Department of Rheumatology, AP-HP Pitié-Salpêtrière Hospital, Paris, France
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13
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Juvenile Idiopathic Arthritis: A Focus on Pharmacologic Management. J Pediatr Health Care 2018; 32:515-528. [PMID: 30177013 DOI: 10.1016/j.pedhc.2018.02.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2017] [Accepted: 02/27/2018] [Indexed: 12/29/2022]
Abstract
Juvenile idiopathic arthritis is a chronic condition that affects many pediatric patients. It is a prevalent disease and has become the most common rheumatologic disease of childhood. The condition encompasses multiple different forms of chronic arthritides classified based on the location and number of joints affected as well as the presence or lack of a number of different inflammatory markers. The exact etiology is unknown but is thought to be multifactorial with genetic, humoral, and environmental factors playing a key role. Many pharmacologic agents are available for use in the treatment of juvenile idiopathic arthritis, with management involving the use of symptom-reducing agents and disease-modifying antirheumatic drugs. Treatment is not without adverse events, with many of the agents require monitoring regimens and patient education. Without treatment, the progression and chronicity of the disease can result in significant morbidity, with the potential for devastating consequences on the child's quality of life.
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14
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Khan MI, Momeny M, Ostadhadi S, Jahanabadi S, Ejtemaei-Mehr S, Sameem B, Zarrinrad G, Dehpour AR. Thalidomide attenuates development of morphine dependence in mice by inhibiting PI3K/Akt and nitric oxide signaling pathways. Prog Neuropsychopharmacol Biol Psychiatry 2018; 82:39-48. [PMID: 29223784 DOI: 10.1016/j.pnpbp.2017.12.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Revised: 12/01/2017] [Accepted: 12/05/2017] [Indexed: 12/17/2022]
Abstract
Morphine dependence and the subsequent withdrawal syndrome restrict its clinical use in management of chronic pain. The precise mechanism for the development of dependence is still elusive. Thalidomide is a glutamic acid derivative, recently has been reconsidered for its clinical use due to elucidation of different clinical effects. Phosphoinositide 3-kinase (PI3K) is an intracellular transducer enzyme which activates Akt which in turns increases the level of nitric oxide. It is well established that elevated levels of nitric oxide has a pivotal role in the development of morphine dependence. In the present study, we aimed to explore the effect of thalidomide on the development of morphine dependence targeting PI3K/Akt (PKB) and nitric oxide (NO) pathways. Male NMRI mice and human glioblastoma T98G cell line were used to study the effect of thalidomide on morphine dependence. In both models the consequent effect of thalidomide on PI3K/Akt and/or NO signaling in morphine dependence was determined. Thalidomide alone or in combination with PI3K inhibitor, Akt inhibitor or nitric oxide synthase (NOS) inhibitors significantly reduced naloxone induced withdrawal signs in morphine dependent mice. Also, the levels of nitrite in hippocampus of morphine dependent mice were significantly reduced by thalidomide in compared to vehicle treated morphine dependent mice. In T98G human glioblastoma cells, thalidomide alone or in combination with PI3K and Akt inhibitors significantly reduced iNOS expression in comparison to the morphine treated cells. Also, morphine-induced p-Akt was suppressed when T98G cells were pretreated with thalidomide. Our results suggest that morphine induces Akt, which has a crucial role in the induction of NOS activity, leading to morphine dependence. Moreover, these data indicate that thalidomide attenuates the development of morphine dependence in vivo and in vitro by inhibition of PI3K/Akt and nitric oxide signaling pathways.
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Affiliation(s)
- Muhammad Imran Khan
- Department of Pharmacology, School of Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacy, Kohat University of Science and Technology, 26000 Kohat, KPK, Pakistan
| | - Majid Momeny
- Hematology/Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Sattar Ostadhadi
- Department of Pharmacology, School of Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Samane Jahanabadi
- Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran (g)
| | - Shahram Ejtemaei-Mehr
- Department of Pharmacology, School of Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Bilqees Sameem
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ghazaleh Zarrinrad
- Hematology/Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Reza Dehpour
- Department of Pharmacology, School of Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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15
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Khan MI, Ostadhadi S, Mumtaz F, Momeny M, Moghaddaskho F, Hassanipour M, Ejtemaei-Mehr S, Dehpour AR. Thalidomide attenuates the development and expression of antinociceptive tolerance to μ-opioid agonist morphine through l-arginine-iNOS and nitric oxide pathway. Biomed Pharmacother 2017; 85:493-502. [PMID: 27899254 DOI: 10.1016/j.biopha.2016.11.056] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2016] [Revised: 10/28/2016] [Accepted: 11/14/2016] [Indexed: 12/30/2022] Open
Abstract
Morphine is a μ-opioid analgesic drug which is used in the treatment and management of chronic pain. However, due to development of antinociceptive tolerance its clinical use is limited. Thalidomide is an old glutamic acid derivative which recently reemerged because of its potential to counteract a number of disorders including neurodegenerative disorders. The potential underlying mechanisms and effects of thalidomide on morphine-induced antinociceptive tolerance is still elusive. Hence, the present study was designed to explore the effect of thalidomide on the development and expression of morphine antinociceptive tolerance targeting l-arginine-nitric oxide (NO) pathway in mice and T98G human glioblastoma cell line. When thalidomide was administered in a dose of 17.5mg/kg before each dose of morphine chronically for 5days it prevented the development of antinociceptive tolerance. Also, a single dose of thalidomide 20mg/kg attenuated the expression phase of antinociceptive tolerance. The protective effect of thalidomide was augmented in development phase when co-administration with NOS inhibitors like L-NAME (non- selective NOS inhibitor; 2mg/kg) or aminoguanidine (selective inducible NOS inhibitor; 50mg/kg). Also, the reversal effect of thalidomide in expression phase was potentiated when concomitantly administrated with L-NAME (5mg/kg) or aminoguanidine (100mg/kg). Co-administration of ODQ (a guanylyl cyclase inhibitor) 10mg/kg in developmental phase or 20mg/kg in expression phase also progressively increased the pain threshold. In addition, thalidomide (20μM) also significantly inhibited the overexpression of iNOS gene induced by morphine (2.5μM) in T98G cell line. Hence, our findings suggest that thalidomide has protective effect both in the development and expression phases of morphine antinociceptive tolerance. It is also evident that this effect of thalidomide is induced by the inhibition of NOS enzyme predominantly iNOS.
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Affiliation(s)
- Muhammad Imran Khan
- Department of Pharmacology, School of Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sattar Ostadhadi
- Department of Pharmacology, School of Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Faiza Mumtaz
- Department of Pharmacology, School of Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Majid Momeny
- Department of Pharmacology, School of Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; UQ Center for Clinical Research, Department of Molecular Pathology, University of Queensland, Australia
| | - Farima Moghaddaskho
- Department of Pharmacology, School of Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahsa Hassanipour
- Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahram Ejtemaei-Mehr
- Department of Pharmacology, School of Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Reza Dehpour
- Department of Pharmacology, School of Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
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16
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Abstract
Severe, recalcitrant dermatologic conditions often require systemic treatment. Although efficacious, these medications have been associated with wide-ranging adverse reactions. Some are reversible, predictable, and either dose-dependent or treatment length-dependent, while others are unpredictable, irreversible, and potentially fatal. This review examines the neuropsychiatric adverse effects associated with US FDA-approved medications for treatment of the following dermatologic pathologies that typically require systemic therapy: autoimmune dermatoses, acne, psoriasis, and melanoma. A search of the literature was performed, with adverse effects ranging from mild headaches and neuropathy to severe encephalopathies. The medications associated with the most serious reactions were those used to treat psoriasis, especially the older non-biologic medications such as cyclosporine A and methotrexate. Given the importance of these systemic dermatologic therapies in treating severe, recalcitrant conditions, and the wide variety of potentially serious neuropsychiatric adverse effects of these medications, neurologists, psychiatrists, dermatologists, oncologists, and primary care providers must be aware of the potential for these neuropsychiatric adverse reactions to allow for appropriate counseling, management, and medication withdrawal.
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Hügle B, Horneff G. The role of synthetic drugs in the biologic era: therapeutic strategies for treating juvenile idiopathic arthritis. Expert Opin Pharmacother 2016; 17:703-14. [PMID: 26678914 DOI: 10.1517/14656566.2016.1133592] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Juvenile idiopathic arthritis is the most frequent chronic rheumatic disease in childhood. Synthetic disease modifying drugs (DMARDs) have been used in its treatment since the 1980s and have led to substantial improvement of quality of life and disease outcome. Recent pharmacological research has focused on newer medications, especially biologic agents. AREAS COVERED Synthetic DMARDS, especially methotrexate, rightfully remain the first-line treatment of most categories of juvenile arthritis, as attested by several international guidelines. A substantial body of evidence supports these medications, and recent research tries to clarify their optimal use in the clinical setting, both as monotherapy and in combination with biologics. In addition, new forms of synthetic DMARDs are in the research pipeline, or are already used for rheumatoid arthritis. EXPERT OPINION Methotrexate remains the preferred first-line medication for polyarticular arthritis, with leflunomide as a viable alternative in case of intolerance or toxicity, despite lack of approval in Europe and the US. Sulfasalazine and hydroxychloroquine are used only rarely in clinical practice, considered in combination with methotrexate if biologics are not available. New synthetic DMARDS are in the research pipeline for JIA, in the form of small molecules.
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Affiliation(s)
- Boris Hügle
- a German Center for Pediatric Rheumatology , Garmisch-Partenkirchen , Germany
| | - Gerd Horneff
- b Department of Pediatrics , Asklepios Clinic Sankt Augustin , Sankt Augustin , Germany
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18
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Woerner A, von Scheven-Gête A, Cimaz R, Hofer M. Complications of systemic juvenile idiopathic arthritis: risk factors and management recommendations. Expert Rev Clin Immunol 2015; 11:575-88. [PMID: 25843554 DOI: 10.1586/1744666x.2015.1032257] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Systemic juvenile idiopathic arthritis (SJIA) is an inflammatory condition characterized by fever, lymphadenopathy, arthritis, rash and serositis. Systemic inflammation has been associated with dysregulation of the innate immune system, suggesting that SJIA is an autoinflammatory disorder. IL-1 and IL-6 play a major role in the pathogenesis of SJIA, and treatment with IL-1 and IL-6 inhibitors has shown to be highly effective. However, complications of SJIA, including macrophage activation syndrome, limitations in functional outcome by arthritis and long-term damage from chronic inflammation, continue to be a major issue in SJIA patients' care. Translational research leading to a profound understanding of the cytokine crosstalk in SJIA and the identification of risk factors for SJIA complications will help to improve long-term outcome.
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Affiliation(s)
- Andreas Woerner
- Pediatric Rheumatology, University of Basel, University Children's Hospital, Basel, Switzerland
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19
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Yang CS, Kim C, Antaya RJ. Review of thalidomide use in the pediatric population. J Am Acad Dermatol 2015; 72:703-11. [DOI: 10.1016/j.jaad.2015.01.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2014] [Revised: 12/22/2014] [Accepted: 01/05/2015] [Indexed: 02/08/2023]
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20
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Oberle EJ, Harris JG, Verbsky JW. Polyarticular juvenile idiopathic arthritis - epidemiology and management approaches. Clin Epidemiol 2014; 6:379-93. [PMID: 25368531 PMCID: PMC4216020 DOI: 10.2147/clep.s53168] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Juvenile idiopathic arthritis (JIA) is a group of disorders characterized by arthritis persisting for at least 6 weeks with onset before the age of 16 years. Within this cluster of conditions, the polyarticular form (involving more than four joints within the first 6 months) is further divided based on the presence of rheumatoid factor. Children with polyarticular JIA pose unique diagnostic and therapeutic challenges compared to children with involvement of fewer joints. Polyarticular JIA patients tend to have a more refractory course and therefore are at increased risk for joint damage, resulting in poorer functional outcomes and decreased quality of life. Although the ability to treat this disorder continues to improve, especially with the advent of biologic agents, there is still much about the epidemiology and pathogenesis of polyarticular JIA that is unknown. The epidemiology of polyarticular JIA varies worldwide with a vast difference in reported cases between different global regions as well as within individual countries. Several genetic risk loci have been identified conferring increased susceptibility to JIA, many within the human leukocyte antigen region. Beyond the genome, environmental factors also seem to contribute to the etiology of polyarticular JIA. This review article will focus on the epidemiology and current treatments of polyarticular JIA and briefly discuss genetic and environmental influences on the pathogenesis of JIA as well as new and emerging therapies.
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Affiliation(s)
- Edward J Oberle
- Department of Pediatrics, Division of Rheumatology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Julia G Harris
- Department of Pediatrics, Division of Rheumatology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - James W Verbsky
- Department of Pediatrics, Division of Rheumatology, Medical College of Wisconsin, Milwaukee, WI, USA
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21
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Advances in the pathogenesis and treatment of systemic juvenile idiopathic arthritis. Pediatr Res 2014; 75:176-83. [PMID: 24213625 DOI: 10.1038/pr.2013.187] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Accepted: 07/11/2013] [Indexed: 11/08/2022]
Abstract
Systemic juvenile idiopathic arthritis (s-JIA) is clinically distinct from other types of JIA. It is typified by extraarticular features such as quotidian fevers, rash, splenomegaly, lymphadenopathy, laboratory abnormalities (including leukocytosis, thrombocytosis, anemia, hyperferritinemia, and elevated inflammatory markers), and a close association with the macrophage activation syndrome. Recent investigations have highlighted dysregulation of the innate immune system as the critical pathogenic driver of s-JIA. Key innate immune mediators of s-JIA are the macrophage-derived cytokines interleukin-1 (IL-1) and IL-6. Increased understanding of the roles of IL-1 and IL-6 in the pathogenesis of s-JIA has led to major changes in therapeutic options. Until recently, the most commonly used medications included corticosteroids, methotrexate, and tumor necrosis factor (TNF) inhibitors, which are incompletely effective in most cases. Newer biologic agents targeting IL-1 and IL-6 have proven very effective in treating s-JIA and in minimizing corticosteroid exposure. Here we review recent advances in the understanding of the pathogenesis of s-JIA and the recent clinical trials that have revolutionized the care of children with s-JIA.
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Abstract
Juvenile idiopathic arthritis (JIA) is one of the most common chronic diseases of childhood. Although the pathophysiology behind this disease is poorly understood, there are effective treatments for JIA based on the subtype of disease. Treatment options include non-steroidal anti-inflammatory drugs, intra-articular glucocorticoid injections, and traditional disease modifying anti-rheumatic drugs such as methotrexate. In the past decade, the use of biologic therapy in JIA, including tumor necrosis factor inhibitors, interleukin-1 inhibitors, and interleukin-6 inhibitors, has dramatically increased with promising outcomes.
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23
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Asher C, Furnish T. Lenalidomide and thalidomide in the treatment of chronic pain. Expert Opin Drug Saf 2013; 12:367-74. [DOI: 10.1517/14740338.2013.775242] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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Bai N, Cui XY, Wang J, Sun CG, Mei HK, Liang BB, Cai Y, Song XJ, Gu JK, Wang R. Determination of thalidomide concentration in human plasma by liquid chromatography-tandem mass spectrometry. Exp Ther Med 2012; 5:626-630. [PMID: 23404219 PMCID: PMC3570145 DOI: 10.3892/etm.2012.847] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2012] [Accepted: 11/12/2012] [Indexed: 12/02/2022] Open
Abstract
A rapid, sensitive and specific analytical method based on high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed for the determination of thalidomide concentration in human plasma. The analyte and internal standard were extracted by liquid-liquid extraction with ether-dichloromethane (3:2, v/v) and separated on a TC-C18 column using methanol-10 mM ammonium acetate-formic acid (60:40:0.04, v/v/v) as the mobile phase at a flow rate of 0.9 ml/min. The detection was performed using an API 4000 triple quadrupole mass spectrometer in the positive electrospray ionization (ESI) mode and completed within 3.0 min. The multiple reaction monitoring (MRM) transitions were m/z 259.1→84.0 for the analyte and m/z 195.9→138.9 for temozolomide. The calibration curve exhibited a linear dynamic range of 2–1500 ng/ml (r>0.9991). The intra-and inter-day precisions (as relative standard deviation; RSD) were 6.8–13.5% and 4.3–5.0% respectively and the accuracy (as relative error; RE) was 2.0–3.5%. The recoveries and matrix effects were satisfactory in all the biological matrices examined. This method was successfully used in a pharmacokinetic study of thalidomide in healthy male volunteers receiving an oral administration of a 200-mg dose.
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Affiliation(s)
- Nan Bai
- The Center of Medicine Clinical Research, Chinese PLA General Hospital, Beijing 100853
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25
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26
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Abstract
Systemic juvenile idiopathic arthritis (sJIA) sets well apart from all the other forms of JIA. Several observations show that sJIA is etiopathogenically different from all the other forms of JIA and has a prominent autoinflammatory component. A major role in the pathogenesis is played by two proinflammatory cytokines, interleukin-6 and interleukin-1. The specific inhibition of these two cytokines is going to change not only the therapeutic approach to the disease but also, presumably, its long term prognosis.
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27
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Gurion R, Lehman TJA, Moorthy LN. Systemic arthritis in children: a review of clinical presentation and treatment. Int J Inflam 2011; 2012:271569. [PMID: 22235382 PMCID: PMC3253447 DOI: 10.1155/2012/271569] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2011] [Accepted: 09/06/2011] [Indexed: 12/14/2022] Open
Abstract
Systemic juvenile idiopathic arthritis (sJIA) constitutes a small part of juvenile idiopathic arthritis (JIA), yet has a disproportionally higher rate of mortality. Despite being grouped under JIA, it is considered to be a multifactorial autoinflammatory disease. The objective of this paper is to review the epidemiology, pathogenesis, genetics, clinical manifestations, complications, therapy, prognosis, and outcome of sJIA. The presentation and clinical manifestations of sJIA have not changed much in the past several decades, but the collective understanding of the pathogenesis and the development of new targeted therapies (particularly the biologic agents) have transformed and improved the disease outcome for children with sJIA.
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Affiliation(s)
- R. Gurion
- Division of Pediatric Rheumatology, Rainbow Babies & Children's Hospital, University Hospitals Case Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA
| | - T. J. A. Lehman
- Division of Pediatric Rheumatology, Hospital for Special Surgery and Clinical Pediatrics Weill Medical Center, Cornell University, 535 E 70 St, New York, NY 10021, USA
| | - L. N. Moorthy
- Division of Pediatric Rheumatology, Department of Pediatrics, University of Medicine and Dentistry of NJ-Robert Wood Johnson Medical School, 89 French Street, New Brunswick, NJ 08901, USA
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Rehman W, Arfons LM, Lazarus HM. The rise, fall and subsequent triumph of thalidomide: lessons learned in drug development. Ther Adv Hematol 2011; 2:291-308. [PMID: 23556097 PMCID: PMC3573415 DOI: 10.1177/2040620711413165] [Citation(s) in RCA: 100] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Perhaps no other drug in modern medicine rivals the dramatic revitalization of thalidomide. Originally marketed as a sedative, thalidomide gained immense popularity worldwide among pregnant women because of its effective anti-emetic properties in morning sickness. Mounting evidence of human teratogenicity marked a dramatic fall from grace and led to widespread social, legal and economic ramifications. Despite its tragic past thalidomide emerged several decades later as a novel and highly effective agent in the treatment of various inflammatory and malignant diseases. In 2006 thalidomide completed its remarkable renaissance becoming the first new agent in over a decade to gain approval for the treatment of plasma cell myeloma. The catastrophic collapse yet subsequent revival of thalidomide provides important lessons in drug development. Never entirely abandoned by the medical community, thalidomide resurfaced as an important drug once the mechanisms of action were further studied and better understood. Ongoing research and development of related drugs such as lenalidomide now represent a class of irreplaceable drugs in hematological malignancies. Further, the tragedies associated with this agent stimulated the legislation which revamped the FDA regulatory process, expanded patient informed consent procedures and mandated more transparency from drug manufacturers. Finally, we review recent clinical trials summarizing selected medical indications for thalidomide with an emphasis on hematologic malignancies. Herein, we provide a historic perspective regarding the up-and-down development of thalidomide. Using PubMed databases we conducted searches using thalidomide and associated keywords highlighting pharmacology, mechanisms of action, and clinical uses.
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Affiliation(s)
- Waqas Rehman
- Department of Medicine, Division of Hematology-Oncology, Case Comprehensive Cancer Center, University Hospitals Case Medical Center, Cleveland, OH, USA
| | - Lisa M. Arfons
- Department of Medicine, Division of Hematology/Oncology, Louis Stokes Cleveland VAMC, Cleveland, OH, USA
| | - Hillard M. Lazarus
- Department of Medicine, University Hospitals Case Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA
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Palencia G, Rubio C, Custodio-Ramirez V, Paz C, Sotelo J. Strong anticonvulsant effect of thalidomide on amygdaloid kindling. Epilepsy Res 2011; 95:263-9. [PMID: 21592729 DOI: 10.1016/j.eplepsyres.2011.04.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2011] [Revised: 04/07/2011] [Accepted: 04/17/2011] [Indexed: 11/28/2022]
Abstract
Thalidomide was synthesized more than 50 years ago as hypnotic sedative with unique pharmacologic properties. Recently, we have described a notorious anticonvulsant effect of thalidomide on pentylenetetrazole-induced seizures. Here, we report the results of thalidomide administration on amygdaloid kindling. A total of 100 male Wistar rats were implanted with brain electrodes in the basolateral amygdaloid nucleus and the sensory motor cortex. After surgery the animals received a daily electric stimulus through the amygdaline electrode (500 μA intensity, 60 Hz frequency, 1 ms duration) until seizures appeared. The following treatment groups were made: (a) controls; (b) rats treated daily with thalidomide (10 mg/kg) or with topiramate (80 mg/kg); (c) rats treated with different doses of thalidomide. Significant reduction in the after-discharge and retard of behavioral stages were observed in rats treated with thalidomide or with topiramate as compared with controls (p<0.01): Also, a similar anticonvulsant outcome of thalidomide therapy was obtained with doses of either 2.5, 5, 10 or 50 mg/kg; at 100 mg/kg all epileptic activity was suppressed. Anticonvulsant efficacy of thalidomide was superior in most parameters than that obtained with topiramate. In amygdaloid kindling, which simulates human epilepsy characterized by focal seizures secondarily generalized, low doses of thalidomide display strong anticonvulsant properties.
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Affiliation(s)
- Guadalupe Palencia
- Neuroimmunology Unit, National Institute of Neurology and Neurosurgery of Mexico, Insurgentes Sur 3877, Mexico City 14269, Mexico
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Rao RS, Medhi B, Khanduja KL, Pandhi P. Correlation of seizures and biochemical parameters of oxidative stress in experimentally induced inflammatory rat models. Fundam Clin Pharmacol 2011; 24:325-31. [PMID: 20584211 DOI: 10.1111/j.1472-8206.2009.00773.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
The role of oxidative stress in the pathogenesis of various conditions including epilepsy, inflammatory bowel disease and rheumatoid arthritis is evolving. The aim of this study was to find out the correlation between various inflammatory models with seizures and antioxidant parameters. Fifty-four male rats were divided into three groups of colitis, adjuvant arthritis and cotton wool granuloma (CWG). Each group had three subgroups of control, model and treatment. Thalidomide was used as treatment in colitis and arthritis group, whereas etoricoxib was used in CWG group. In colitis and arthritis groups, thalidomide was administered for 3 and 17 days, respectively, whereas etoricoxib was administered for 7 days in CWG group. At the end of treatment protocols, a subconvulsive dose of pentylenetetrazole (PTZ) (40 mg/kg i.p.) was injected intraperitoneally to note seizure onset and score. After confirming the presence of inflammation by morphological and histological studies, plasma and brain biochemical parameters of oxidative stress were estimated. The models of colitis, arthritis and CWG were effectively produced as evidenced by morphological scores (P < 0.001). Thalidomide reduced the morphological score (P < 0.002) and seizure grade (P < 0.001), whereas increased seizure onset (P < 0.001) in the arthritis group. There was an increase in malondialdehyde levels in the brain of thalidomide-treated groups (P < 0.002) and a significant decrease in superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels. There was neither improvement in seizure nor any significant changes in lipid peroxidation and antioxidant enzyme levels in etoricoxib-treated group. Thalidomide was effective in reducing the extent of arthritis as well as reducing the seizure scoring and increasing seizure onset in the adjuvant arthritis group. As it increased lipid peroxidation and reduced SOD and GPx, further evaluation is necessary with respect to oxidative stress.
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Affiliation(s)
- Ramya S Rao
- Department of Pharmacology, Postgraduate Institute of Medical Education & Research (PIGMER), Chandigarh-160012, India
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Lo SZY, Steer JH, Joyce DA. Tumor necrosis factor-alpha promotes survival in methotrexate-exposed macrophages by an NF-kappaB-dependent pathway. Arthritis Res Ther 2011; 13:R24. [PMID: 21324111 PMCID: PMC3241368 DOI: 10.1186/ar3248] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2010] [Revised: 02/01/2011] [Accepted: 02/15/2011] [Indexed: 02/07/2023] Open
Abstract
Introduction Methotrexate (MTX) induces macrophage apoptosis in vitro, but there is not much evidence for increased synovial macrophage apoptosis in MTX-treated patients. Macrophage apoptosis is reported, however, during clinical response to anti-tumor necrosis factor-alpha (TNF-α) treatments. This implies that TNF-α promotes macrophage survival and suggests that TNF-α may protect against MTX-induced apoptosis. We, therefore, investigated this proposal and the macrophage signaling pathways underlying it. Methods Caspase-3 activity, annexin-V binding/7-aminoactinomycin D (7-AAD) exclusion and cell-cycle analysis were used to measure steps in apoptosis of primary murine macrophages and cells of the RAW264.7 macrophage cell line that had been exposed to clinically-relevant concentrations of MTX and TNF-α. Results MTX induces apoptosis in primary murine macrophages at concentrations as low as 100 nM in vitro. TNF-α, which has a context-dependent ability to increase or to suppress apoptosis, efficiently suppresses MTX-induced macrophage apoptosis. This depends on NF-κB signaling, initiated through TNF Receptor Type 1 ligation. Macrophage colony stimulating factor, the primary macrophage survival and differentiation factor, does not activate NF-κB or protect macrophages from MTX-induced apoptosis. A weak NF-κB activator, Receptor Activator of NF-κB Ligand (RANKL) is likewise ineffective. Blocking NF-κB in TNF-α-exposed macrophages allowed pro-apoptotic actions of TNF-α to dominate, even in the absence of MTX. MTX itself does not promote apoptosis through interference with NF-κB signaling. Conclusions These findings provide another mechanism by which TNF-α sustains macrophage numbers in inflamed tissue and identify a further point of clinical complementarity between MTX and anti-TNF-α treatments for rheumatoid arthritis.
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Affiliation(s)
- Susan Z Y Lo
- Pharmacology Unit, School of Medicine and Pharmacology, University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, Australia.
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Hashkes PJ, Laxer RM. Management of juvenile idiopathic arthritis. Rheumatology (Oxford) 2011. [DOI: 10.1016/b978-0-323-06551-1.00100-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022] Open
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Quartier P. Current treatments for juvenile idiopathic arthritis. Joint Bone Spine 2010; 77:511-6. [DOI: 10.1016/j.jbspin.2010.09.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/18/2010] [Indexed: 10/18/2022]
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Bader-Meunier B, Wouters C, Job-Deslandre C, Cimaz R, Hofer M, Pillet P, Quartier P. Recommandations pour la prise en charge de la forme systémique l’arthrite juvénile idiopathique (maladie de Still). Arch Pediatr 2010. [DOI: 10.1016/j.arcped.2010.04.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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[New treatments for idiopathic juvenile arthritis]. Arch Pediatr 2009; 16:1607-11. [PMID: 19896351 DOI: 10.1016/j.arcped.2009.07.020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2009] [Revised: 06/19/2009] [Accepted: 07/27/2009] [Indexed: 11/30/2022]
Abstract
Immunosuppressants, including methotrexate and more recently anti-TNF alpha, anti-IL1 and anti-IL6 receptor, have modified the prognosis of juvenile idiopathic arthritis. Growth hormone was shown to limit growth retardation due to general corticotherapy.
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Yasui K, Yashiro M, Nagaoka Y, Manki A, Wada T, Tsuge M, Kondo Y, Morishima T. Thalidomide prevents formation of multinucleated giant cells (Langhans-type cells) from cultured monocytes: possible pharmaceutical applications for granulomatous disorders. Int J Immunopathol Pharmacol 2009; 22:707-14. [PMID: 19822087 DOI: 10.1177/039463200902200316] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Thalidomide is an effective drug for chronic inflammatory diseases, but the mechanism underlying its immunomodulatory action remains uncertain. Thalidomide has been reported to clinically improve chronic inflammatory granulomatous disorders. In such disorders, the granulomas consist of epithelioid cells, scattered lymphocytes and multinucleated giant cells (MNGC; Langhans-type cells). The present experimental approach permitted the reproduction of MNGC formation from peripheral blood monocytes and examination of thalidomides effect on it. MNGC can be effectively generated from monocytes cultured in the presence of interleukin-4 (IL-4) and macrophage colony-stimulating factor(M-CSF) for 14 days. Thalidomide can inhibit the formation of MNGC in a dose-dependent manner. MNGC formation was partly inhibited by the presence of neutralizing TNF-alpha antibody in the responses induced by IL-4 and M-CSF. Autocrinal TNF-alpha production and modulation of cadhelin expression to regulate cell adhesion might be involved in this inhibitory action of thalidomide. Our results support thalidomides clinical efficacy in the treatment of chronic granulomatous disorders (granulomatosis).
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Affiliation(s)
- K Yasui
- Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
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Vastert SJ, Kuis W, Grom AA. Systemic JIA: new developments in the understanding of the pathophysiology and therapy. Best Pract Res Clin Rheumatol 2009; 23:655-64. [PMID: 19853830 PMCID: PMC2774820 DOI: 10.1016/j.berh.2009.08.003] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Systemic juvenile idiopathic arthritis (sJIA) is a rare, systemic inflammatory disease classified as a subtype of JIA. Besides arthritis, it is characterised by systemic features such as spiking fever, skin rash, hepatosplenomegaly or serositis. It is becoming clear now that abnormalities in the innate immunity (cytokines such as interleukin (IL)-1, IL-6 and IL-18, and neutrophils and monocytes/macrophages rather than lymphocytes) play a major role in the pathogenesis of sJIA, distinguishing it from other JIA subtypes. Another distinctive feature of sJIA is its strong association with macrophage activation syndrome (MAS). Based on this, consensus is emerging that sJIA should be viewed as an autoinflammatory syndrome rather than a classic auto-immune disease. As a consequence of the progression in understanding the underlying mechanisms of sJIA, major changes in the management are evolving. So far, treatment has been based on glucocorticosteroids in combination with disease-modifying drugs such as methotrexate. Recently, remarkable improvement has been observed with IL-1 and IL-6 targeted therapies. These therapies might also change the long-term outcome of this disease. However, controlled trials set up in international collaboration are needed to determine the optimal treatment strategies for all sJIA patients.
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Affiliation(s)
- Sebastiaan J Vastert
- Department of Pediatric Immunology Wilhelmina Children s Hospital, University Medical Center Utrecht, Lundlaan 6, 3584 EA, Utrecht, the Netherlands.
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Rao RS, Medhi B, Khanduja KL, Pandhi P. Correlation of seizures and biochemical parameters of oxidative stress in experimentally induced inflammatory rat models. Fundam Clin Pharmacol 2009. [DOI: 10.1111/j.1472-8206.2009.0773.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Hayward K, Wallace CA. Recent developments in anti-rheumatic drugs in pediatrics: treatment of juvenile idiopathic arthritis. Arthritis Res Ther 2009; 11:216. [PMID: 19291269 PMCID: PMC2688259 DOI: 10.1186/ar2619] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Juvenile idiopathic arthritis (JIA) is the most common autoimmune-autoinflammatory disease in childhood and affects approximately 1 in 1,000 children. Despite advances in diagnosis and treatment options, JIA remains a chronic condition for most affected children. Recent evidence suggests that disease control at onset may determine the tempo of subsequent disease course and long-term outcomes, and raises the concept of a therapeutic window of opportunity in patients with JIA. This underscores the importance of early aggressive treatment in patients with JIA. With the advent of novel biologic therapeutics, the repertoire of agents available for treatment of children with JIA has greatly increased. The present article will summarize recent developments in the medical treatment of children with JIA and will offer insights into emerging therapies.
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Affiliation(s)
- Kristen Hayward
- Division of Rheumatology, University of Washington School of Medicine, Seattle Children's Hospital, 4800 Sandpoint Way, NE MS R-5420, Seattle, WA 98105, USA.
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Abstract
Juvenile idiopathic arthritis is the most common rheumatic disorder of childhood, and is defined as arthritis beginning prior to the age of 16 years, lasting more than 6 weeks, with an unknown cause. Seven subtypes of juvenile idiopathic arthritis have recently been categorized and named. These subtypes differ broadly in the number of affected joints and the presence of systemic illness. Although many children with juvenile idiopathic arthritis may achieve remission prior to entering adulthood, many others will continue to have debilitating disease into adulthood. Pharmacotherapy plays a major role in the treatment of juvenile idiopathic arthritis. Nonsteroidal anti-inflammatory drugs and corticosteroids can be beneficial for many children and are used as initial therapy. Methotrexate may offer benefits to children unresponsive to these initial agents. Studies evaluating the use of several biologic agents and immunosuppressants have recently been published, and the role of these drugs for children with juvenile idiopathic arthritis is being assessed. Major clinical trials and pediatric implications are reviewed.
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Affiliation(s)
- Edward A. Bell
- Drake University College of Pharmacy and Health Sciences, Des Moines, Iowa,
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Kalliolias GD, Liossis SNC. The future of the IL-1 receptor antagonist anakinra: from rheumatoid arthritis to adult-onset Still's disease and systemic-onset juvenile idiopathic arthritis. Expert Opin Investig Drugs 2008; 17:349-59. [PMID: 18321234 DOI: 10.1517/13543784.17.3.349] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND IL-1 receptor antagonist (IL-1Ra) is a naturally occurring IL-1RI-binding molecule that blocks the biologic effects of the proinflammatory cytokine IL-1. A recombinant form of human IL-1Ra, anakinra (Kineret), has been approved for use in rheumatology initially to manage rheumatoid arthritis (RA) patients that are refractory to more conventional forms of treatment. OBJECTIVE This review summarizes the experience with anakinra in the treatment of patients with rheumatic diseases emphasizing its beneficial effects in novel applications. METHODS English-language trials of anakinra were searched using MEDLINE and abstracts from rheumatology scientific meetings. RESULTS/CONCLUSIONS In the treatment of patients with RA anakinra is effective but inferior to TNF-alpha blocking agents. Over the last few years it has become increasingly evident that anakinra is highly effective and safe in patients with systemic-onset juvenile idiopathic arthritis, adult-onset Still's disease, hereditary autoinflammatory syndromes, Schnitzler's syndrome and recently in gouty attacks.
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Affiliation(s)
- George D Kalliolias
- Hospital for Special Surgery, Arthritis and Tissue Degeneration Program, Department of Medicine, New York, NY 10021, USA
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Lequerré T, Quartier P, Rosellini D, Alaoui F, De Bandt M, Mejjad O, Kone-Paut I, Michel M, Dernis E, Khellaf M, Limal N, Job-Deslandre C, Fautrel B, Le Loët X, Sibilia J. Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Ann Rheum Dis 2008; 67:302-8. [PMID: 17947302 DOI: 10.1136/ard.2007.076034] [Citation(s) in RCA: 289] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
BACKGROUND Anakinra treatment has been reported to be effective in some patients with systemic-onset juvenile idiopathic arthritis (SoJIA) or adult-onset Still disease (AoSD). OBJECTIVES To assess the efficacy and the safety of anakinra treatment in SoJIA and AoSD. METHODS SoJIA and AoSD patients were treated with anakinra (1-2 mg/kg/day in children, 100 mg/day in adults); we analysed its effect on fever, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, numbers of swollen and tender joints, the assessment of disease activity (by physician and parent/patient) and pain (by parent/patient), and American College of Rheumatology (ACR) pediatric core set criteria for JIA activity. RESULTS A total of 35 patients were included, 20 with SoJIA and 15 with AoSD. Their mean age (range) at the onset of treatment was 12.4 (3-23) and 38.1 (22-62) years, respectively; disease duration was 7.0 (1-16) and 7.8 (2-27) years, respectively. Active arthritis was present in all cases but one. Of the 20 SoJIA patients, 5 achieved ACR 50% improvement in symptoms (ACR50) response criteria at 6 months. Steroid dose had been decreased by 15% to 78% in 10 cases. A total of 11 of the 15 AoSD patients achieved at least a 50% improvement for all disease markers (mean follow-up: 17.5 (11-27) months). Steroids had been stopped in two cases and the dose was decreased by 45% to 95% in 12 patients. Two patients stopped anakinra due to severe skin reaction, and two patients due to infection: one visceral leishmaniasis and one varicella. CONCLUSION Anakinra was effective in most AoSD patients, but less than half SoJIA patients achieved a marked and sustained improvement.
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Affiliation(s)
- T Lequerré
- Rheumatology Department, Rouen University Hospital & Inserm 905, 76031 Rouen, France.
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Yasui K, Uchida N, Akazawa Y, Nakamura S, Minami I, Amano Y, Yamazaki T. Thalidomide for treatment of intestinal involvement of juvenile-onset Behçet disease. Inflamm Bowel Dis 2008; 14:396-400. [PMID: 17973303 DOI: 10.1002/ibd.20317] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Thalidomide has been identified and its anti-inflammatory and immunomodulatory properties clarified. This report expands our report of 2 entero-Behçet disease children who developed significant steroid toxicity and improved dramatically with thalidomide. METHODS We studied the effects of thalidomide in 7 juvenile-onset patients with severe, recurrent intestinal involvement of Behçet disease. Thalidomide was given at an initial dose of 2 mg/kg per day, and the dose was increased to 3 mg/kg per day if necessary (3 of 7 patients) or decreased to 1-0.5 mg/kg per day according to the responses to the drug. RESULTS All 7 patients showed dramatic improvement in clinical symptoms with thalidomide therapy, and they successfully discontinued steroid therapy. Patients receiving thalidomide were monitored for prolonged neurotoxicity, and the treatment and a few side effects were well tolerated by all patients. CONCLUSIONS Our results indicate that thalidomide can be an efficacious medication in appropriately selected patients with some inflammatory bowel diseases with many chances of success.
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Affiliation(s)
- Kozo Yasui
- Department of Pediatrics, Nagano Red Cross Hospital, Nagano, Japan.
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Ravelli A, Martini A. Juvenile idiopathic arthritis. Clin Immunol 2008. [DOI: 10.1016/b978-0-323-04404-2.10053-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Lainer-Carr D, Brahn E. Angiogenesis inhibition as a therapeutic approach for inflammatory synovitis. ACTA ACUST UNITED AC 2007; 3:434-42. [PMID: 17664950 DOI: 10.1038/ncprheum0559] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2006] [Accepted: 05/29/2007] [Indexed: 12/27/2022]
Abstract
Angiogenesis inhibition, long studied in the treatment of malignancies, has begun to emerge as a potential therapeutic approach in managing inflammatory arthritis, particularly rheumatoid arthritis. The growth of new vessels is required for the development of the rheumatoid pannus, which then leads to extensive synovial inflammation and joint destruction. Vascular endothelial growth factor is the best studied mediator of angiogenesis, and several therapies have been developed that specifically target this molecule. Several other angiogenesis mediators, such as the angiopoietin-TIE system, hypoxia inducible factor and integrin alpha(V)beta(3), as well as naturally occurring inhibitors of angiogenesis, are also being investigated as potential therapeutic targets. Additionally, there are a number of drugs, including paclitaxel, 2-methoxyestradiol and fumagillin analogs, that might have a role in inhibiting angiogenesis and, thus, in treating proliferative synovitis.
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Affiliation(s)
- Dahlia Lainer-Carr
- Rheumatology Fellowship Program, UCLA School of Medicine, University of California-Los Angeles, 1000 Veteran Avenue, Los Angeles, CA 90095, USA
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García-Carrasco M, Fuentes-Alexandro S, Escárcega RO, Rojas-Rodriguez J, Escobar LE. Efficacy of thalidomide in systemic onset juvenile rheumatoid arthritis. Joint Bone Spine 2007; 74:500-3. [PMID: 17706449 DOI: 10.1016/j.jbspin.2006.12.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2006] [Accepted: 12/21/2006] [Indexed: 12/01/2022]
Abstract
UNLABELLED Thalidomide is an immunomodulating agent which reverses many of the cytokine disturbances seen in systemic onset juvenile idiopathic arthritis (SoJIA) with inadequate response to other treatments. We report 3 cases of recalcitrant SoJIA which improved dramatically after treatment with thalidomide. PATIENTS Three children aged 9, 8, and 6 years diagnosed with SoJIA treated with conventional therapy including NSAIDs, corticosteroids, methotrexate and etanercept failed to respond fully and their condition worsened. Thalidomide was begun based on two previous reports showing its efficacy in recalcitrant SoJIA. RESULTS Thalidomide produced successful remission of the disease in all 3 patients according to the preliminary criteria for inactive disease and clinical remission of JIA. CONCLUSION Thalidomide may be a viable, alternative corticoid-sparing therapy in patients with recalcitrant, multidrug-resistant SoJIA.
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Affiliation(s)
- Mario García-Carrasco
- Systemic Autoimmune Diseases Research Unit, HGZ #36, CMN Manuel Avila Camacho, Instituto Mexicano del Seguro Social, Puebla, Mexico.
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Palencia G, Calderon A, Sotelo J. Thalidomide inhibits pentylenetetrazole-induced seizures. J Neurol Sci 2007; 258:128-31. [PMID: 17449064 DOI: 10.1016/j.jns.2007.03.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2006] [Revised: 02/15/2007] [Accepted: 03/15/2007] [Indexed: 10/23/2022]
Abstract
Thalidomide was originally synthesized and tested as a sedative, hypnotic and antiemetic; however, after its teratogenicity was noted its use for treatment of neurological and psychiatric disorders was abandoned. We studied the potential anticonvulsant effect of thalidomide: Different doses of thalidomide were tested against seizures induced by 50 mg/kg or 70 mg/kg of pentylenetetrazole (PTZ); the anticonvulsant effect of thalidomide was also compared with that of valproic acid. Seizures and latency time were individually recorded. Thalidomide in low doses (5-10 mg/kg) prevented seizures in all animals treated with 50 mg/kg PTZ; also, in a dose-dependent manner thalidomide inhibited seizures in rats exposed to a high dose of PTZ (70 mg/kg); thalidomide exhibited an anticonvulsant activity similar to that of valproic acid. Thalidomide is an effective anticonvulsant, and further studies on this potential antiepileptic substance seem warranted.
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Affiliation(s)
- Guadalupe Palencia
- Neuroimmunology Unit, National Institute of Neurology and Neurosurgery, Insurgentes Sur 3877, 14269 Mexico City, Mexico
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Jarvis JN, Jiang K, Petty HR, Centola M. Neutrophils: the forgotten cell in JIA disease pathogenesis. Pediatr Rheumatol Online J 2007; 5:13. [PMID: 17567896 PMCID: PMC1904449 DOI: 10.1186/1546-0096-5-13] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2007] [Accepted: 06/13/2007] [Indexed: 01/08/2023] Open
Abstract
Juvenile idiopathic arthritis (JIA) has long been assumed to be an autoimmune disease, triggered by aberrant recognition of "self" antigens by T-cells. However, systems biology approaches to this family of diseases have suggested complex interactions between innate and adaptive immunity that underlie JIA. In particular, new data suggest an important role for neutrophils in JIA pathogenesis. In this short review, we will discuss the new data that support a role for neutrophils in JIA, discuss regulatory functions that link neutrophils to adaptive immune responses, and discuss future areas of investigation. Above all else, we invite the reader to re-consider the use of the term "autoimmunity" as applied to the family of illnesses we collectively call JIA.
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Affiliation(s)
- James N Jarvis
- Department of Pediatrics, University of Oklahoma College of Medicine, Oklahoma City, OK 73014, USA
| | - Kaiyu Jiang
- Department of Pediatrics, University of Oklahoma College of Medicine, Oklahoma City, OK 73014, USA
| | - Howard R Petty
- Deparment of Ophthamology, University of Michigan School of Medicine, Kellogg Eye Institute, Ann Arbor, MI 48105, USA
| | - Michael Centola
- Arthritis & Immunology Program, Oklahoma Medical research Foundation, Oklahoma City, OK 73104, USA
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Goli V. Does thalidomide have an analgesic effect? Current status and future directions. Curr Pain Headache Rep 2007; 11:109-14. [PMID: 17367589 DOI: 10.1007/s11916-007-0007-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Dramatic relief of pain and life-altering changes in quality of life in some patients treated with immunomodulators such as thalidomide compel us to look more closely at unconventional mechanisms that may be involved in propagation of persistent pain. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-10 are the cytokines with the most evidence in pain modulation. TNF-alpha and IL-1beta seem to initiate neuropathic pain, IL-6 maintains such pain, and IL-10 inhibits this persistent pain. Thalidomide was found to be effective in animal models by inhibiting TNF-alpha production. Several case reports and case series in humans have demonstrated mixed results, with some patients having dramatic responses, especially in chronic intractable conditions such as complex regional pain syndrome. Thalidomide may be an alternative for some patients with intractable pain. However, use of thalidomide is limited by its neurotoxic and teratogenic effects. Newer analogues may significantly improve the risk/benefit of using such immunomodulators.
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Affiliation(s)
- Veeraindar Goli
- Duke University Medical Center, 932 Morreene Road, Durham, NC 27705, USA.
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