Nadera Sweiss - Academia.edu (original) (raw)

Papers by Nadera Sweiss

Journal of Clinical Rheumatology Practical Reports on Rheumatic Musculoskeletal Diseases, Aug 1, 2009

Case Reports in Ophthalmological Medicine, 2013

Eyelid involvement in sarcoidosis is very rare. A search of the medical literature indicates one ... more Eyelid involvement in sarcoidosis is very rare. A search of the medical literature indicates one previous report of sarcoidosis with destructive eyelid lesions. We describe the case of a 50-year-old woman with severe systemic sarcoidosis, which included her eyelids. To our knowledge, the case presented herein represents the first to show the full-thickness histopathology of destructive eyelid lesions in sarcoidosis.

The Journal of Immunology, 2014

Operative Techniques in Otolaryngology-Head and Neck Surgery, 2008

Sarcoidosis is chronic multisystem disease of unknown etiology. It is characterized by non caseat... more Sarcoidosis is chronic multisystem disease of unknown etiology. It is characterized by non caseating granulomas in the involved organs. Lung involvement is the most common organ involvement. Other common manifestations include skin, joint and ocular lesions. ...

Therapeutics and Clinical Risk Management, 2010

The Laryngoscope, 2009

ABSTRACT

The Laryngoscope, 2009

Objectives/Hypothesis: In suspected cases of Sjogren syndome (SS), patients are often referred fo... more Objectives/Hypothesis: In suspected cases of Sjogren syndome (SS), patients are often referred for a labial minor salivary gland biopsy. However, studies have shown this test to be unreliable. Pathologic misinterpretation and immunosuppressive medications may affect the results of the biopsy. As a result, it is best to perform this procedure only when necessary. The purpose of the current study was to review clinical signs and symptoms of patients who underwent a lip biopsy to determine which patients benefited most from this procedure. Study Design: Retrospective review. Methods: A retrospective chart review of patients referred to otolaryngology for a lip biopsy for the diagnosis of SS. Results: Joint pain, salivary gland swelling, and abnormal serology (anti-Sjogren syndrome A/anti-Sjogren syndrome B) were more prevalent in the positive lip biopsy group (grade ¼ 3 or 4). Out of the 12 patients who had both sicca symptoms and positive serology, nine (75%) had a grade ¼ 4. Presence of sicca symptoms and positive serology were predictive of a positive biopsy (P ¼ .017). Excluding those patients who were on immunosuppression for more than 6 weeks prior to the biopsy, the correlation became stronger (P ¼ .011). Conclusions: In this study, clinical presentation of sicca symptoms and positive serology reliably predicted the results of a lip biopsy. The results of this study suggest that patients with clear criterion for SS may not require a lip biopsy, especially those patients on immunosuppression. When physicians suspect SS, a thorough clinical and laboratory examination is necessary to determine if a patient will benefit from a minor salivary gland biopsy.

Multiple Sclerosis Journal, 2008

Devic’s disease is often considered as a variant of multiple sclerosis (MS). However, evidence su... more Devic’s disease is often considered as a variant of multiple sclerosis (MS). However, evidence suggests that Devic’s disease may be distinct from MS. Devic’s disease can coexist with connective tissue diseases, particularly Sjögren’s disease, but this association is rare with MS. Diagnosis of Sjögren’s disease in patients with neurological symptoms is often difficult. During early stages of Sjögren’s disease, patients may not fulfill all criteria for Sjögren’s disease. A high percentage of patients with Sjögren’s disease have inflammatory infiltrates in minor salivary glands, and this may be a reliable indicator of early or subclinical disease. We show high prevalence (80%) of salivary gland inflammation in Devic’s disease and longitudinally extensive transverse myelitis (LETM). We diagnosed 16 patients with Devic’s disease, and 2 of these satisfied criteria for Sjögren’s disease as did 2 of 9 patients with LETM. Anti-SSA/B titers were infrequently elevated. Although most did not sa...

Journal of the American College of Cardiology, 2010

The Journal of Immunology, 2013

JCR: Journal of Clinical Rheumatology, 2009

Journal of Cardiovascular Magnetic Resonance, 2009

Expert Opinion on Biological Therapy, 2009

Recent advances in our understanding of B-cell dysregulation and its important link to autoimmuni... more Recent advances in our understanding of B-cell dysregulation and its important link to autoimmunity have brought about a radical change in the management of autoimmune diseases. Over the past few years, encouraging data from several clinical trials of rituximab, a chimeric anti-CD20 antibody, have led to its approval for use in rheumatoid arthritis (RA). These data, regarding clinical efficacy, safety, improved patient-reported outcomes and cost-effectiveness with the use of rituximab in patients with RA, have led to the exploration of other agents targeting B-cell functions. Ocrelizumab, a novel humanized anti-CD20 antibody, has shown clinical efficacy and safety in a recently reported trial in patients with RA. Future clinical trials will help evaluate further the role of ocrelizumab in RA and its potential use in other autoimmune diseases. This review describes current understanding of B-cell therapy, the role of rituximab in the treatment of RA and the evolving role of ocrelizumab as a B-cell-targeted therapy.

European Journal of Radiology, 2008

Nephrogenic systemic fibrosis (NSF) is a systemic fibrosing disorder that principally affects the... more Nephrogenic systemic fibrosis (NSF) is a systemic fibrosing disorder that principally affects the skin, but can involve virtually any tissue in the human body and result in significant disability and even death. Since 2006 numerous retrospective case reports and case series have reported a very strong association of this disease with exposure to gadolinium-based contrast agents (Gd-CA) for MR imaging in the setting of severe or end-stage renal disease. The purpose of this report is to summarize the medical literature reporting of biopsy-proven NSF cases in which the authors specifically investigated patient exposure to Gd-CA. A Pub Med MEDLINE search was performed using the key words-nephrogenic systemic fibrosis and nephrogenic fibrosing dermopathy. All case reports and case series of NSF were reviewed to determine if patients had a preceding exposure to Gd-CA and which specific Gd-CA was involved. If the original reports did not clarify the specific Gd-CA, I reviewed follow-up letters to the editors or contacted the authors to clarify which specific Gd-CA were linked to the NSF cases. If several reports originated from the same institution, clarification was also obtained to avoid redundant reporting. As of February 1, 2008 there have been 190 biopsy-proven cases of NSF published in the peer-reviewed literature with the following associations: 157 gadodiamide (Omniscan, GE Healthcare), 8 gadopentetate (Magnevist, Bayer Healthcare), 3 gadoversetamide (OptiMARK, Covidien), and 18 unspecified Gd-CA, and 4 confounded cases with more than one Gd-CA. Five cases of NSF were unassociated with Gd-CA.

European Journal of Heart Failure, 2011

Late gadolinium enhanced cardiovascular magnetic resonance (LGE-CMR) is a valuable test to detect... more Late gadolinium enhanced cardiovascular magnetic resonance (LGE-CMR) is a valuable test to detect myocardial damage in patients with sarcoidosis; however, the clinical significance of LGE in sarcoidosis patients with preserved left ventricular ejection fraction (LVEF) is not defined. We aim to characterize the prevalence of LGE, its associated cardiac findings, and its clinical implications in sarcoidosis patients with preserved LVEF. One hundred and fifty-two patients with biopsy proven extra-cardiac sarcoidosis, no known cardiac sarcoidosis, and LVEF ≥ 50% referred for LGE-CMR were included in this observational study. The presence of LGE in the left ventricular myocardium was considered diagnostic for cardiac sarcoidosis. The cohort was divided into two groups based on the presence or absence of LGE. Twenty-nine patients (19%) had LGE involving 11 ± 9% of the left ventricle. The modified Japanese Ministry of Health and Welfare (JMHW) criteria for diagnosing cardiac sarcoidosis only had a sensitivity of 52% and specificity of 83% for identifying myocardial LGE in these patients. Compared with those patients without LGE, those with LGE had a higher heart rate (84 ± 19 vs. 76 ± 18 b.p.m., P= 0.002), greater prevalence of an abnormal electrocardiogram (76 vs. 31%, P< 0.001), diastolic dysfunction (67 vs. 33%, P= 0.05), reduced right ventricular ejection fraction (49 ± 8 vs. 55 ± 6%, P= 0.012), and evidence of non-sustained ventricular tachycardia (33 vs. 6%). In patients with sarcoidosis and preserved systolic function, myocardial damage is commonly present and may increase the risk of ventricular tachy-arrhythmias. The JMHW Criteria were neither sensitive nor specific for predicting the presence of myocardial LGE.

Arthritis & Rheumatism, 2007

... Tochi M. Okwuosa,; Edward W. Lee,; Monika Starosta,; Saima Chohan ,† ,; Suncica Volkov,; Mich... more ... Tochi M. Okwuosa,; Edward W. Lee,; Monika Starosta,; Saima Chohan ,† ,; Suncica Volkov,; Michael Flicker,; James Curran ,‡ ,; Kourous A. Rezaei,; Nadera J. Sweiss ,§. ... 4 Kadar J, Petrovicz E. Adult-onset Still's disease. Best Pract Res Clin Rheumatol 2004; 18: 663–76. ...

Arthritis & Rheumatism, 2008

Ocrelizumab, a humanized anti-CD20 monoclonal antibody, was studied in a first-in-human trial in ... more Ocrelizumab, a humanized anti-CD20 monoclonal antibody, was studied in a first-in-human trial in rheumatoid arthritis (RA) patients receiving concomitant methotrexate (MTX). The ACTION trial was a combined phase I/II study of placebo plus MTX versus ocrelizumab plus MTX in 237 RA patients (intent-to-treat population). During phase I, 45 patients were treated with 1 of 5 escalating doses of study drug (infusions on days 1 and 15, 10-1,000 mg per each infusion). An additional 192 patients were randomized during phase II. Eligible patients had active disease, an inadequate response to treatment with at least MTX, rheumatoid factor positivity, and elevated levels of acute-phase reactants. The total study duration was 72 weeks. B cell pharmacodynamics over time was investigated. Baseline demographics were similar among the treatment groups. Based on the entire 72-week data set, the incidence of serious adverse events in the ocrelizumab-treated patients was 17.9%, as compared with 14.6% in placebo-treated patients. The incidence of serious infections was 2.0% in all ocrelizumab-treated patients and 4.9% in placebo-treated patients. Infusion-associated adverse events were mostly grade 1 or grade 2 and were more frequent around the time of the first infusion. No serious infusion-associated adverse events were reported in the ocrelizumab group. Evidence of clinical activity was observed at all doses evaluated. Peripheral B cell depletion after infusion was rapid at all doses, with earlier repletion of B cells at doses of 10 mg and 50 mg. Human anti-human antibodies were detected in 19% and 10%, respectively, of those receiving 10 mg and 50 mg of ocrelizumab, compared with 0-5% of those receiving 200, 500, and 1,000 mg. Ocrelizumab therapy in combination with MTX was well tolerated. Doses of 200 mg (2 infusions) and higher showed better clinical responses, better reduction of C-reactive protein levels, and very low immunogenicity.

Clinical pulmonary medicine, 2016

Patients with sarcoidosis undergo spontaneous remission or may be effectively controlled with glu... more Patients with sarcoidosis undergo spontaneous remission or may be effectively controlled with glucocorticoids alone in many cases. Progressive and refractory pulmonary sarcoidoisis constitute more than 10% of patients seen at specialized centers. Pulmonary fibrosis and associated complications, such as infections and pulmonary hypertension are leading causes of mortality. No universal definition of refractoriness exists, we therefore propose classifying patients as having refractory disease when the following criteria are fulfilled: (1) progressive disease despite at least 10 mg of prednisolone or equivalent for at least three months and need for additional disease-modifying anti-sarcoid drugs due to lack of efficacy, drug toxicity or intolerability and (2) treatment started for significant impairment of life due to progressive pulmonary symptoms. Both criteria should be fulfilled. Treatment options in addition to or instead of glucocorticoids for these patients include second- (met...

Arthritis & Rheumatology, 2015

TLR7 levels are elevated in rheumatoid arthritis (RA), however its impact in RA is unknown, due t... more TLR7 levels are elevated in rheumatoid arthritis (RA), however its impact in RA is unknown, due to its unidentified endogenous ligand. The aim was to identify a TLR7 endogenous ligand and to determine its role in RA pathogenesis. Presence of an endogenous TLR7 ligand, miR-Let7b, was examined using real-time PCR. Employing RA knockdown cells, TLR7 knockout mice or antagonist, the specificity of miR-Let7b as a potential ligand to TLR7 was tested. Next, the mechanism by which ligation of miR-Let7b to TLR7 promotes disease was investigated in RA myeloid cells by real-time PCR, ELISA and FACS. Last, we established the impact of the ectopic miR-Let7b expression on arthritic joint inflammation. We uncovered that a TLR7 endogenous ligand resides mainly in RA synovial fluid macrophages. We highlight that the GU rich domain in miR-Let7b is essential for TLR7 ligation as the GU positive control, miR-147, is capable of stimulating TLR7+ myeloid cells whereas the non-GU negative control, miR-124, is incapable of this function. We demonstrate that miR-Let7b or exosomes containing miR-Let7b can transform the RA and/or mouse naïve (M0) or anti-inflammatory (M2) macrophages into inflammatory M1 macrophages via TLR7 ligation. Consistently, we show that joint expression of miR-Let7b provokes arthritis through a mechanism that is dependent on TLR7 ligation and remodeling of naïve myeloid cells into M1 macrophages since joint swelling and M1 macrophages are absent in TLR7 deficient mice. These results underline the importance of miR-Let7b ligation to joint TLR7 in the effector phase of RA. This article is protected by copyright. All rights reserved.

Journal of Clinical Rheumatology Practical Reports on Rheumatic Musculoskeletal Diseases, Aug 1, 2009

Case Reports in Ophthalmological Medicine, 2013

Eyelid involvement in sarcoidosis is very rare. A search of the medical literature indicates one ... more Eyelid involvement in sarcoidosis is very rare. A search of the medical literature indicates one previous report of sarcoidosis with destructive eyelid lesions. We describe the case of a 50-year-old woman with severe systemic sarcoidosis, which included her eyelids. To our knowledge, the case presented herein represents the first to show the full-thickness histopathology of destructive eyelid lesions in sarcoidosis.

The Journal of Immunology, 2014

Operative Techniques in Otolaryngology-Head and Neck Surgery, 2008

Sarcoidosis is chronic multisystem disease of unknown etiology. It is characterized by non caseat... more Sarcoidosis is chronic multisystem disease of unknown etiology. It is characterized by non caseating granulomas in the involved organs. Lung involvement is the most common organ involvement. Other common manifestations include skin, joint and ocular lesions. ...

Therapeutics and Clinical Risk Management, 2010

The Laryngoscope, 2009

ABSTRACT

The Laryngoscope, 2009

Objectives/Hypothesis: In suspected cases of Sjogren syndome (SS), patients are often referred fo... more Objectives/Hypothesis: In suspected cases of Sjogren syndome (SS), patients are often referred for a labial minor salivary gland biopsy. However, studies have shown this test to be unreliable. Pathologic misinterpretation and immunosuppressive medications may affect the results of the biopsy. As a result, it is best to perform this procedure only when necessary. The purpose of the current study was to review clinical signs and symptoms of patients who underwent a lip biopsy to determine which patients benefited most from this procedure. Study Design: Retrospective review. Methods: A retrospective chart review of patients referred to otolaryngology for a lip biopsy for the diagnosis of SS. Results: Joint pain, salivary gland swelling, and abnormal serology (anti-Sjogren syndrome A/anti-Sjogren syndrome B) were more prevalent in the positive lip biopsy group (grade ¼ 3 or 4). Out of the 12 patients who had both sicca symptoms and positive serology, nine (75%) had a grade ¼ 4. Presence of sicca symptoms and positive serology were predictive of a positive biopsy (P ¼ .017). Excluding those patients who were on immunosuppression for more than 6 weeks prior to the biopsy, the correlation became stronger (P ¼ .011). Conclusions: In this study, clinical presentation of sicca symptoms and positive serology reliably predicted the results of a lip biopsy. The results of this study suggest that patients with clear criterion for SS may not require a lip biopsy, especially those patients on immunosuppression. When physicians suspect SS, a thorough clinical and laboratory examination is necessary to determine if a patient will benefit from a minor salivary gland biopsy.

Multiple Sclerosis Journal, 2008

Devic’s disease is often considered as a variant of multiple sclerosis (MS). However, evidence su... more Devic’s disease is often considered as a variant of multiple sclerosis (MS). However, evidence suggests that Devic’s disease may be distinct from MS. Devic’s disease can coexist with connective tissue diseases, particularly Sjögren’s disease, but this association is rare with MS. Diagnosis of Sjögren’s disease in patients with neurological symptoms is often difficult. During early stages of Sjögren’s disease, patients may not fulfill all criteria for Sjögren’s disease. A high percentage of patients with Sjögren’s disease have inflammatory infiltrates in minor salivary glands, and this may be a reliable indicator of early or subclinical disease. We show high prevalence (80%) of salivary gland inflammation in Devic’s disease and longitudinally extensive transverse myelitis (LETM). We diagnosed 16 patients with Devic’s disease, and 2 of these satisfied criteria for Sjögren’s disease as did 2 of 9 patients with LETM. Anti-SSA/B titers were infrequently elevated. Although most did not sa...

Journal of the American College of Cardiology, 2010

The Journal of Immunology, 2013

JCR: Journal of Clinical Rheumatology, 2009

Journal of Cardiovascular Magnetic Resonance, 2009

Expert Opinion on Biological Therapy, 2009

Recent advances in our understanding of B-cell dysregulation and its important link to autoimmuni... more Recent advances in our understanding of B-cell dysregulation and its important link to autoimmunity have brought about a radical change in the management of autoimmune diseases. Over the past few years, encouraging data from several clinical trials of rituximab, a chimeric anti-CD20 antibody, have led to its approval for use in rheumatoid arthritis (RA). These data, regarding clinical efficacy, safety, improved patient-reported outcomes and cost-effectiveness with the use of rituximab in patients with RA, have led to the exploration of other agents targeting B-cell functions. Ocrelizumab, a novel humanized anti-CD20 antibody, has shown clinical efficacy and safety in a recently reported trial in patients with RA. Future clinical trials will help evaluate further the role of ocrelizumab in RA and its potential use in other autoimmune diseases. This review describes current understanding of B-cell therapy, the role of rituximab in the treatment of RA and the evolving role of ocrelizumab as a B-cell-targeted therapy.

European Journal of Radiology, 2008

Nephrogenic systemic fibrosis (NSF) is a systemic fibrosing disorder that principally affects the... more Nephrogenic systemic fibrosis (NSF) is a systemic fibrosing disorder that principally affects the skin, but can involve virtually any tissue in the human body and result in significant disability and even death. Since 2006 numerous retrospective case reports and case series have reported a very strong association of this disease with exposure to gadolinium-based contrast agents (Gd-CA) for MR imaging in the setting of severe or end-stage renal disease. The purpose of this report is to summarize the medical literature reporting of biopsy-proven NSF cases in which the authors specifically investigated patient exposure to Gd-CA. A Pub Med MEDLINE search was performed using the key words-nephrogenic systemic fibrosis and nephrogenic fibrosing dermopathy. All case reports and case series of NSF were reviewed to determine if patients had a preceding exposure to Gd-CA and which specific Gd-CA was involved. If the original reports did not clarify the specific Gd-CA, I reviewed follow-up letters to the editors or contacted the authors to clarify which specific Gd-CA were linked to the NSF cases. If several reports originated from the same institution, clarification was also obtained to avoid redundant reporting. As of February 1, 2008 there have been 190 biopsy-proven cases of NSF published in the peer-reviewed literature with the following associations: 157 gadodiamide (Omniscan, GE Healthcare), 8 gadopentetate (Magnevist, Bayer Healthcare), 3 gadoversetamide (OptiMARK, Covidien), and 18 unspecified Gd-CA, and 4 confounded cases with more than one Gd-CA. Five cases of NSF were unassociated with Gd-CA.

European Journal of Heart Failure, 2011

Late gadolinium enhanced cardiovascular magnetic resonance (LGE-CMR) is a valuable test to detect... more Late gadolinium enhanced cardiovascular magnetic resonance (LGE-CMR) is a valuable test to detect myocardial damage in patients with sarcoidosis; however, the clinical significance of LGE in sarcoidosis patients with preserved left ventricular ejection fraction (LVEF) is not defined. We aim to characterize the prevalence of LGE, its associated cardiac findings, and its clinical implications in sarcoidosis patients with preserved LVEF. One hundred and fifty-two patients with biopsy proven extra-cardiac sarcoidosis, no known cardiac sarcoidosis, and LVEF ≥ 50% referred for LGE-CMR were included in this observational study. The presence of LGE in the left ventricular myocardium was considered diagnostic for cardiac sarcoidosis. The cohort was divided into two groups based on the presence or absence of LGE. Twenty-nine patients (19%) had LGE involving 11 ± 9% of the left ventricle. The modified Japanese Ministry of Health and Welfare (JMHW) criteria for diagnosing cardiac sarcoidosis only had a sensitivity of 52% and specificity of 83% for identifying myocardial LGE in these patients. Compared with those patients without LGE, those with LGE had a higher heart rate (84 ± 19 vs. 76 ± 18 b.p.m., P= 0.002), greater prevalence of an abnormal electrocardiogram (76 vs. 31%, P< 0.001), diastolic dysfunction (67 vs. 33%, P= 0.05), reduced right ventricular ejection fraction (49 ± 8 vs. 55 ± 6%, P= 0.012), and evidence of non-sustained ventricular tachycardia (33 vs. 6%). In patients with sarcoidosis and preserved systolic function, myocardial damage is commonly present and may increase the risk of ventricular tachy-arrhythmias. The JMHW Criteria were neither sensitive nor specific for predicting the presence of myocardial LGE.

Arthritis & Rheumatism, 2007

... Tochi M. Okwuosa,; Edward W. Lee,; Monika Starosta,; Saima Chohan ,† ,; Suncica Volkov,; Mich... more ... Tochi M. Okwuosa,; Edward W. Lee,; Monika Starosta,; Saima Chohan ,† ,; Suncica Volkov,; Michael Flicker,; James Curran ,‡ ,; Kourous A. Rezaei,; Nadera J. Sweiss ,§. ... 4 Kadar J, Petrovicz E. Adult-onset Still's disease. Best Pract Res Clin Rheumatol 2004; 18: 663–76. ...

Arthritis & Rheumatism, 2008

Ocrelizumab, a humanized anti-CD20 monoclonal antibody, was studied in a first-in-human trial in ... more Ocrelizumab, a humanized anti-CD20 monoclonal antibody, was studied in a first-in-human trial in rheumatoid arthritis (RA) patients receiving concomitant methotrexate (MTX). The ACTION trial was a combined phase I/II study of placebo plus MTX versus ocrelizumab plus MTX in 237 RA patients (intent-to-treat population). During phase I, 45 patients were treated with 1 of 5 escalating doses of study drug (infusions on days 1 and 15, 10-1,000 mg per each infusion). An additional 192 patients were randomized during phase II. Eligible patients had active disease, an inadequate response to treatment with at least MTX, rheumatoid factor positivity, and elevated levels of acute-phase reactants. The total study duration was 72 weeks. B cell pharmacodynamics over time was investigated. Baseline demographics were similar among the treatment groups. Based on the entire 72-week data set, the incidence of serious adverse events in the ocrelizumab-treated patients was 17.9%, as compared with 14.6% in placebo-treated patients. The incidence of serious infections was 2.0% in all ocrelizumab-treated patients and 4.9% in placebo-treated patients. Infusion-associated adverse events were mostly grade 1 or grade 2 and were more frequent around the time of the first infusion. No serious infusion-associated adverse events were reported in the ocrelizumab group. Evidence of clinical activity was observed at all doses evaluated. Peripheral B cell depletion after infusion was rapid at all doses, with earlier repletion of B cells at doses of 10 mg and 50 mg. Human anti-human antibodies were detected in 19% and 10%, respectively, of those receiving 10 mg and 50 mg of ocrelizumab, compared with 0-5% of those receiving 200, 500, and 1,000 mg. Ocrelizumab therapy in combination with MTX was well tolerated. Doses of 200 mg (2 infusions) and higher showed better clinical responses, better reduction of C-reactive protein levels, and very low immunogenicity.

Clinical pulmonary medicine, 2016

Patients with sarcoidosis undergo spontaneous remission or may be effectively controlled with glu... more Patients with sarcoidosis undergo spontaneous remission or may be effectively controlled with glucocorticoids alone in many cases. Progressive and refractory pulmonary sarcoidoisis constitute more than 10% of patients seen at specialized centers. Pulmonary fibrosis and associated complications, such as infections and pulmonary hypertension are leading causes of mortality. No universal definition of refractoriness exists, we therefore propose classifying patients as having refractory disease when the following criteria are fulfilled: (1) progressive disease despite at least 10 mg of prednisolone or equivalent for at least three months and need for additional disease-modifying anti-sarcoid drugs due to lack of efficacy, drug toxicity or intolerability and (2) treatment started for significant impairment of life due to progressive pulmonary symptoms. Both criteria should be fulfilled. Treatment options in addition to or instead of glucocorticoids for these patients include second- (met...

Arthritis & Rheumatology, 2015

TLR7 levels are elevated in rheumatoid arthritis (RA), however its impact in RA is unknown, due t... more TLR7 levels are elevated in rheumatoid arthritis (RA), however its impact in RA is unknown, due to its unidentified endogenous ligand. The aim was to identify a TLR7 endogenous ligand and to determine its role in RA pathogenesis. Presence of an endogenous TLR7 ligand, miR-Let7b, was examined using real-time PCR. Employing RA knockdown cells, TLR7 knockout mice or antagonist, the specificity of miR-Let7b as a potential ligand to TLR7 was tested. Next, the mechanism by which ligation of miR-Let7b to TLR7 promotes disease was investigated in RA myeloid cells by real-time PCR, ELISA and FACS. Last, we established the impact of the ectopic miR-Let7b expression on arthritic joint inflammation. We uncovered that a TLR7 endogenous ligand resides mainly in RA synovial fluid macrophages. We highlight that the GU rich domain in miR-Let7b is essential for TLR7 ligation as the GU positive control, miR-147, is capable of stimulating TLR7+ myeloid cells whereas the non-GU negative control, miR-124, is incapable of this function. We demonstrate that miR-Let7b or exosomes containing miR-Let7b can transform the RA and/or mouse naïve (M0) or anti-inflammatory (M2) macrophages into inflammatory M1 macrophages via TLR7 ligation. Consistently, we show that joint expression of miR-Let7b provokes arthritis through a mechanism that is dependent on TLR7 ligation and remodeling of naïve myeloid cells into M1 macrophages since joint swelling and M1 macrophages are absent in TLR7 deficient mice. These results underline the importance of miR-Let7b ligation to joint TLR7 in the effector phase of RA. This article is protected by copyright. All rights reserved.