Michael H Pillinger, M.D.

Polydactyly in a patient with a cardiovascular anomaly [Note]
Furer V.; Pillinger M.H.; Rosenthal P.B.
2012 ;18(1):54-55, Journal of clinical rheumatology. JCR
— id: 149819, year: 2012, vol: 18, page: 54, stat: Journal Article,

The next generation of gout therapeutics: ready for prime time?
Abeles, Aryeh M; Pillinger, Michael H
2011 Apr;13(2):100-102, Current rheumatology reports
— id: 136466, year: 2011, vol: 13, page: 100, stat: Journal Article,

The year in gout - 2010-2011
Crittenden, Daria B; Pillinger, Michael H
2011 ;69(3):257-263, Bulletin of the NYU Hospital for Joint Diseases
Over the past decade, the pace of investigation in the field of gout has accelerated tremendously. New advances have led to deeper insight into the processes of inflammation and innate immunity, and new treatments are now available, or likely to become available in the near future. Some of the more interesting new findings in the field of gout are presented in the context of gout biology and treatment overall. Gout epidemiology, current understanding of renal urate handling, recent investigations into the mechanism of inflammation in acute gout, dietary factors in gout development, the potential role of hyperuricemia in cardiovascular and renal disease, and treatments that are either newly available or in development are discussed
— id: 139927, year: 2011, vol: 69, page: 257, stat: Journal Article,

Bilateral pinna chondritis preceded by glucosamine chondroitin supplement initiation
Furer, V; Wieczorek, Rl; Pillinger, Mh
2011 May;40(3):241-243, Scandinavian journal of rheumatology
— id: 131952, year: 2011, vol: 40, page: 241, stat: Journal Article,

Response to letter to the editor by Filippou MD, et al. on the article by Howard RG, Pillinger MH, Gyftopoulos S et al. Reproducibility of musculoskeletal ultrasound for determining monosodium urate deposition: Concordance between readers. Arthritis Care Res. 2011 Oct;63(10):1456-62. doi: 10.1002/acr.20527
Howard RG; Pillinger MH; Gyftopoulos S; Thiele RG; Swearingen CJ; Samuels J
2011 Dec 20;:?-?, Arthritis care & research
— id: 149926, year: 2011, vol: , page: ?, stat: Journal Article,

Reproducibility of musculoskeletal ultrasound for determining monosodium urate deposition: Concordance between readers
Howard, Rennie G; Pillinger, Michael H; Gyftopoulos, Soterios; Thiele, Ralf G; Swearingen, Christopher J; Samuels, Jonathan
2011 Oct;63(10):1456-1462, Arthritis care & research
OBJECTIVE: Criteria for sonographic diagnosis of monosodium urate (MSU) crystal deposition have been developed, but the interreader reproducibility of this modality is not well established. We therefore assessed agreement using a systematic approach. METHODS: Fifty male subjects ages 55-85 years were recruited during primary care visits to an urban Veterans Affairs hospital, and were assessed by musculoskeletal ultrasound (US) of the knees and first metatarsophalangeal (MTP) joints to evaluate for the double contour sign and tophi as evidence of MSU crystal deposition. Images were read by 2 blinded rheumatologists trained in musculoskeletal US, and the degree of concordance was determined for individual subjects, total joints, femoral articular cartilage (FAC), and first MTP joints. Subjects were further categorized into 3 diagnostic groups: gout, asymptomatic hyperuricemia (no gout, serum uric acid [UA] >/=6.9 mg/dl), and controls (no gout, serum UA </=6.8 mg/dl), and reader concordance within these 3 groups was assessed. RESULTS: We observed almost perfect agreement between readers for 1) individual subjects (yes/no; n = 50, 100% agreement, kappa = 1.000), 2) total joints (n = 200, 99% agreement, kappa = 0.942), 3) FAC (n = 100, 99% agreement, kappa = 0.942), and 4) first MTP joints (n = 100, 99% agreement, kappa = 0.942). Furthermore, findings by side (right/left) and diagnostic group (gout, asymptomatic hyperuricemia, control) showed substantial to almost perfect concordance for all measures. MSU deposition was seen most commonly in gout patients, and deposition was also seen in some subjects with asymptomatic hyperuricemia, but in only 1 control. CONCLUSION: Musculoskeletal US is reliable for detecting MSU deposition in FAC and first MTP joints in gout and asymptomatic hyperuricemia
— id: 137880, year: 2011, vol: 63, page: 1456, stat: Journal Article,

The reply
Keenan R.T.; Pillinger M.H.
2011 ;124(10):e19-e19, American journal of medicine
— id: 138721, year: 2011, vol: 124, page: e19, stat: Journal Article,

Prevalence of contraindications and prescription of pharmacologic therapies for gout
Keenan, Robert T; O'Brien, William R; Lee, Kristen H; Crittenden, Daria B; Fisher, Mark C; Goldfarb, David S; Krasnokutsky, Svetlana; Oh, Cheongeun; Pillinger, Michael H
2011 Feb;124(2):155-163, American journal of medicine
BACKGROUND: Patients with gout have comorbidities, but the impact of these comorbidities on treatment has not been studied. METHODS: A total of 575 patients with gout were stratified according to certainty of diagnosis according to International Classification of Diseases, 9th Revision, Clinical Modification code alone (cohort I), American College of Radiology criteria (cohort II), and crystal diagnosis (cohort III). Comorbid conditions were defined according to International Classification of Diseases, 9th Revision, Clinical Modification codes, and stratified as either moderate or severe. Drug contraindications were defined as moderate or strong, based on Food and Drug Administration criteria and severity of disease. RESULTS: The most common comorbidity was hypertension (prevalence 0.89). The presence of comorbidities resulted in a high frequency of contraindications to approved gout medications. More than 90% of patients had at least 1 contraindication to nonsteroidal anti-inflammatory drugs. Many patients demonstrated multiple contraindications to 1 or more gout medications. Frequently, patients were prescribed medications to which they harbored contraindications. The prevalence of patients prescribed colchicine despite having at least 1 strong contraindication was 30% (cohort I), 37% (cohort II), and 39.6% (cohort III). CONCLUSION: Patients with gout typically harbor multiple comorbidities that result in contraindications to many of the medications available to treat gout. Frequently, despite contraindications to gout therapies, patients are frequently prescribed these medications
— id: 122694, year: 2011, vol: 124, page: 155, stat: Journal Article,

Drugs causing muscle disease
Mor, Adam; Wortmann, Robert L; Mitnick, Hal J; Pillinger, Michael H
2011 May;37(2):219-231, Rheumatic diseases clinics of North America
Many drugs can cause myopathies, and such myopathies may range widely from asymptomatic elevations in the serum creatine phosphokinase levels to severe myalgias, cramps, exercise intolerance, muscle weakness, and even rhabdomyolysis. In this article, some of the commonly used drugs that may induce myopathies, as well as the clinical phenotypes, diagnosis, and management of these syndromes are reviewed
— id: 129327, year: 2011, vol: 37, page: 219, stat: Journal Article,

Advances in the management of gout: critical appraisal of febuxostat in the control of hyperuricemia
Beara-Lasic, Lada; Pillinger, Michael H; Goldfarb, David S
2010 ;3:1-10, International journal of nephrology & renovascular disease
Gout recently passed rheumatoid arthritis to become the most common inflammatory arthritis in the United States (US). However, epidemiologic studies indicate that the quality of gout management is suboptimal owing to both patient and physician issues. Only three options for urate-lowering therapy are currently available in the US: allopurinol, probenecid, and recently, febuxostat. Probenecid is generally safe except for the occurrence of urolithiasis, but is only effective for the subset of patients with better kidney function. Allopurinol use is limited due to its side effects, potential toxicity of uncertain magnitude in patients with renal disease, and failure to achieve targeted serum urate levels. In part this failure may be due to the necessity for it to be titrated for optimal therapeutic effect. Febuxostat is a new medication that may offer several advantages and can be given as an alternative to allopurinol. We review the basic biology and clinical performance of febuxostat, and consider the potential utility of this agent in comparison to the older, better-established gout therapeutics
— id: 135260, year: 2010, vol: 3, page: 1, stat: Journal Article,

Knee and shoulder cadaver teaching improves internal Medicine residents' self-reported anatomy, exam and injection skills
Berman J.; Pillinger M.H.; Jensen B.; Hammann J.; Paget S.A.
2010 ;62:43-43, Arthritis & rheumatism
Purpose: Medicine residents need to gain confidence and ability in basic musculoskeletal skills such as the joint exam, anatomy knowledge and joint injections. However, opportunities to develop these skills are frequently limited. Possible impediments include inadequate hands-on experience and the ineffectiveness of lectures and simulation models. To address these limitations, we have developed a series of innovative modules that focus on instruction in knee and shoulder anatomy, examination and injection teaching in the cadaver lab. Methods: Rheumatology knee and shoulder teaching modules were designed for 3-4 second-year medicine residents each month, with over forty completing the program in the past year. Residents were surveyed (9-point Likert scale) before and after the rotation for their self-assessed ability to perform joint examination and aspiration. Modules were taught by an experienced rheumatologist and consisted of twice-monthly participation in interactive lectures with demonstrations of the relevant anatomy and injection classes employing cadaveric models. Examination skills relevant to the area discussed were also emphasized. Ample opportunity was given to practice injections using different approaches on the cadaver knee and shoulder joints. Results: Before and after completing the above curriculum, second-year residents surveyed rated their abilities (1=poor to 9=very good) in specific musculoskeletal tasks as follows: (Table presented) The average number of joints injected by each resident prior to the rotation was 0.88. By the end of the rotation this had risen only to 2.08. Conclusion: Even in the setting of only limited opportunity to perform actual joint procedures, a rheumatology curriculum that includes an integrated, intense, hands-on exposure to musculoskeletal anatomy and injection teaching in the cadaver lab can improve residents' perceptions of their abilities and confidence in the anatomy, examination and injection of the knee and shoulder. This teaching approach may be a valuable alternative for programs wishing to improve musculoskeletal procedure skills, particularly in settings where actual experience may be limited
— id: 130942, year: 2010, vol: 62, page: 43, stat: Journal Article,

The role of microRNA in rheumatoid arthritis and other autoimmune diseases
Furer, Victoria; Greenberg, Jeffrey D; Attur, Mukundan; Abramson, Steven B; Pillinger, Michael H
2010 Jul;136(1):1-15, Clinical immunology
MicroRNAs (miRNAs) represent a class of non-coding RNA molecules playing pivotal roles in cellular and developmental processes. miRNAs modulate the expression of multiple target genes at the post-transcriptional level and are predicted to affect up to one-third of all human protein-encoding genes. Recently, miRNA involvement in the adaptive and innate immune systems has been recognized. Rheumatoid arthritis serves an example of a chronic inflammatory disorder in which miRNAs modulate the inflammatory process in the joints, with the potential to serve as biomarkers for both the inflammatory process and the potential for therapeutic response. This review discusses the investigations that led to miRNA discovery, miRNA biogenesis and mode of action, and the diverse roles of miRNAs in modulating the immune and inflammatory responses. We conclude with a discussion of the implications of miRNA biology in rheumatoid arthritis and other autoimmune disorders
— id: 110075, year: 2010, vol: 136, page: 1, stat: Journal Article,

Concordance between ultrasound readers determining presence of monosodium urate crystal deposition in knee and toe joints
Howard R.N.G.; Pillinger M.H.; Gyftopoulos S.; Thiele R.G.; Swearingen C.; Samuels J.
2010 ;62:1616-1616, Arthritis & rheumatism
Background: Determination of monosodium urate (MSU) deposition in joints by musculoskeletal ultrasound (MSK-US) could have implications for uric acid (UA) management in patients with gout and possibly asymptomatic hyperuricemia (AH). Recently, criteria for sonographic diagnosis of MSU crystal deposition have been developed, but reproducibility of readings using these criteria has not been well established. Methods: We consecutively recruited male patients ages 55-85 during primary care visits to an urban VA hospital. We assessed all patients for gout by ACR criteria, and obtained serum UA levels. Patients were divided into 3 groups: gout, AH (no gout, UA >= 6.9 mg/dL), and controls (no gout, UA <= 6.8 mg/dL). 50 patients (14 with gout, 17 with AH, and 19 controls) returned for subsequent evaluation which included MSK-US of knees and 1st metatarsalphalangeal (MTP) joints to evaluate for the double contour sign (knees) and tophi (MTPs). All images were read blindly by two observers trained in rheumatology and MSK-US. Kappa statistics were used to estimate the amount of agreement between ultrasound measures scored by the two raters. We also calculated the total percent of observations in agreement. Results: Evidence of MSU crystal deposition was found in the same 10 patients by both observers (6 gout, 3 AH, 1 control), and in 3 additional patients by one of the observers (1 gout, 2 AH). These findings were further analyzed by site. MSU crystal deposition was identified in a total of 14 common joints by both observers, and in 4 additional joints by the first observer and 6 additional joints by the second observer. Percentage agreement and kappa statistics for our three primary ultrasound measures were as follows; total joints (n=200, 95% agreement, kappa 0.709), femoral articular cartilage (n=100, 95% agreement, kappa 0.679) and 1st MTPs (n=100, 95% agreement, kappa 0.734). Additional analyses by left and right side are shown in the table below. Ratings on only 10 out of 200 joints were in disagreement. (Table Presented) Conclusions: Both percentage agreement and agreement beyond chance between the raters (as estimated by kappa statistics) were very high for the three ultrasound measures. These findings support the use of MSK-US as a reliable modality for detecting MSU deposition. Since MSU deposition is an indication for urate lowering, this type of imaging could be performed noninvasively at the bedside or in the clinic to help direct therapy in gout patients, with possible implications for treatment in AH patients as well should these findings be reproducible in larger cohorts
— id: 130930, year: 2010, vol: 62, page: 1616, stat: Journal Article,

Consequences of chinese foot binding
Howard, Rennie; Pillinger, Michael H
2010 Dec;16(8):408-408, Journal of clinical rheumatology. JCR
— id: 114857, year: 2010, vol: 16, page: 408, stat: Journal Article,

Helicobacter pylori CagA Phosphorylation Status Determines the gp130-activated SHP2/ERK and JAK/STAT Signal Transduction Pathways in Gastric Epithelial Cells
Lee, IO; Kim, JH; Choi, YJ; Pillinger, MH; Kim, SY; Blaser, MJ; Lee, YC
2010 MAY 21 ;285(21):16042-16050, Journal of biological chemistry
The Helicobacter pylori protein CagA may undergo tyrosine phosphorylation following its entry into human gastric epithelial cells with downstream effects on signal transduction. Disruption of the gp130 receptor that modulates the balance of the SHP2/ERK and JAK/STAT pathways enhanced peptic ulceration and gastric cancer in gp130 knock-out mice. In this study, we evaluated the effect of translocated CagA in relation to its tyrosine phosphorylation status on the gp130-mediated signal switch between the SHP2/ERK and JAK/STAT3 pathways. We showed that in the presence of CagA, SHP2 was recruited to gp130. Phosphorylated CagA showed enhanced SHP2 binding activity and ERK1/2 phosphorylation, whereas unphosphorylated CagA showed preferential STAT3 activation. These findings indicate that the phosphorylation status of CagA affects the signal switch between the SHP2/ERK and JAK/STAT3 pathways through gp130, providing a novel mechanism to explain H. pylori signaling
— id: 109777, year: 2010, vol: 285, page: 16042, stat: Journal Article,

New treatments for gout
Mapa, Janet B; Pillinger, Michael H
2010 May;11(5):499-506, Current opinion in investigational drugs
Gout is a commonly occurring medical condition that can lead to significant morbidity. Therapies available for the treatment of both acute and chronic gouty arthritis have not changed significantly since the 1960s. Although these treatments are well established, they are often contraindicated in the presence of various different comorbidities, including diabetes, renal insufficiency, hypertension and gastrointestinal disease, all of which can occur frequently in patients with gout. Therefore, new treatments are needed. This review describes recent advances in therapeutics for gout, including drugs designed to reduce levels of urate and to inhibit acute or chronic inflammation. While some of these strategies are currently available, others are undergoing regulatory evaluation or are at earlier stages of development
— id: 109522, year: 2010, vol: 11, page: 499, stat: Journal Article,

The role of uric acid and other crystals in osteoarthritis
Nowatzky, Johannes; Howard, Rennie; Pillinger, Michael H; Krasnokutsky, Svetlana
2010 Apr;12(2):142-148, Current rheumatology reports
Clinicians have long assumed that an association exists between crystal arthropathies and the presence of osteoarthritis (OA). However, studies establishing an independent association between calcium pyrophosphate or uric acid crystal disease and OA are sparse. Even less is known about a possible pathogenic relationship. Whereas some studies suggest that the relationships between crystals and OA may not be incidental and that crystal deposition may contribute to the onset and/or acceleration of OA joint damage, other authors have challenged this assertion. In this review, we provide an overview of past and current research elucidating the role of crystal deposition, including monosodium urate, calcium pyrophosphate, and other crystals, in OA. Given the clinical frequency of gout and that agents exist to modulate serum UA levels, special attention is given to the role of monosodium urate crystals
— id: 109526, year: 2010, vol: 12, page: 142, stat: Journal Article,

Such sweet sorrow: fructose and the incidence of gout
Pillinger, Michael H; Abeles, Aryeh M
2010 Apr;12(2):77-79, Current rheumatology reports
— id: 109525, year: 2010, vol: 12, page: 77, stat: Journal Article,

Gout and its comorbidities
Pillinger, Michael H; Goldfarb, David S; Keenan, Robert T
2010 ;68(3):199-203, Bulletin of the NYU Hospital for Joint Diseases
Gout is a chronic disease in which excessively high levels of serum urate (hyperuricemia) result in tissue depositions of sodium urate crystals and intermittent inflammatory attacks. Patients who have gout frequently experience a range of comorbidities, which complicates management and affects long-term prognosis. We review some of the more important of these comorbidities and consider the extent to which gout or hyperuricemia may be either a consequence or a cause of these related conditions. In addition, we briefly consider several neurological conditions in which the presence of gout or a high serum urate level may be associated with less disease, rather than more
— id: 114056, year: 2010, vol: 68, page: 199, stat: Journal Article,

Erosive spinal tophus in a patient with gout and back pain
Samuels, Jonathan; Keenan, Robert T; Yu, Rena; Pillinger, Michael H; Bescke, Tibor
2010 ;68(2):147-148, Bulletin of the NYU Hospital for Joint Diseases
— id: 111386, year: 2010, vol: 68, page: 147, stat: Journal Article,

Characteristic oral and intestinal microbiota in rheumatoid arthritis (RA): A trigger for autoimmunity?
Scher J.U.; Ubeda C.; Pillinger M.H.; Bretz W.; Buischi Y.; Rosenthal P.B.; Reddy S.M.
2010 ;62:1390-1390, Arthritis & rheumatism
Purpose: The etiology of RA remains unknown, but genetic and environmental factors have been implicated. An infectious trigger has been sought but conventional microbiologic techniques have been uninformative. The human intestine contains a dense, diverse and poorly characterized (>=80% uncultured) bacterial population whose collective genome (microbiome) is >=100 times larger than its human host. We (DRL) have recently shown in mice that gut-residing bacteria drive autoimmune arthritis via Th17 cell activation (Immunity 2010). Multiple lines of investigation also suggest a link between RA and oral microbes. Methods: As part of an NIH ARRA grant, the NYU Microbiome Center for Rheumatology and Autoimmunity was established to study gut and oral microbiota in RA and related conditions. A cross-sectional study and prospective proof-of-concept antibiotic intervention trial are ongoing. Fecal samples are collected, periodontal status assessed and oral samples obtained by subgingival biofilm collection. To date, oral/intestinal microbiomes have been analyzed in 8 RA patients, 3 psoriatic arthritis (PsA) patients and 9 healthy controls. Periodontal status was characterized in 30 RA, 4 PsA and 8 controls. DNA was purified and variable 16s rRNA gene regions amplified. PCR products were pyrosequenced (454 Life Sciences), and DNA sequences compared to the RDP and BLAST catalogs. rDNA-based phylogenetic trees were created, and the UNIFRAC metric used to compare bacterial communities across individuals. Sera from all subjects were evaluated for anti-citrullinated peptide antibodies (ACPA). Results: Prevotellaceae family was significantly overrepresented in fecal microbiota from ACPA+ RA patients (range 13%-85%; mean=38%) vs ACPA-individuals (mean=4.3%); p=0.003. One ACPA+ healthy individual and 1 ACPA+ PsA patient shared similar microbiomes with ACPA+ RA. Subgingival microbiomes in patients with new-onset drug-naive RA exhibited overabundance of the Spirochetaceae/Prevotellaceae/Porphyromonaceae families (mean=53%) compared to chronic-active RA and healthy controls (mean=18.5%). Periodontal assessment revealed 78% of examined sites bled upon probing in RA patients (mean age 39; 73% female), significantly more than controls (38% PsA, 12% healthy; p<0.001 vs RA); 66% of RA patients also presented with moderate periodontitis compared to PsA (25%) and controls (12%). Conclusions: This is the first study using high-throughput technologies to assess oral and intestinal microbiota in RA. Our data corroborate prior reports demonstrating an underappreciated high prevalence of periodontal disease at a young age in patients with RA. Moreover, our preliminary data suggest that ACPA generation may be associated with larger populations of Prevotellaceae in both oral and intestinal microbiomes. In response to such altered microbial flora, certain predisposed individuals may develop auto-inflammatory disease, through mechanisms that may include the generation of cyclic citrullinated peptides or Th17 cell activation in the intestinal mucosa. Thus, the oral and intestinal microbiota merit further investigation as potential triggers for autoimmunity and clinical RA
— id: 130927, year: 2010, vol: 62, page: 1390, stat: Journal Article,

The New York City Rheumatology Objective Structured Clinical Examination: five-year data demonstrates its validity, usefulness as a unique rating tool, objectivity, and sensitivity to change
Berman, Jessica R; Lazaro, Deana; Fields, Theodore; Bass, Anne R; Weinstein, Elena; Putterman, Chaim; Dwyer, Edward; Krasnokutsky, Svetlana; Paget, Stephen A; Pillinger, Michael H
2009 Dec 15;61(12):1686-1693, Arthritis & rheumatism
OBJECTIVE: Traditional means of testing rheumatology fellows do not adequately assess some skills that are required to practice medicine well, such as humanistic qualities, communication skills, or professionalism. Institution of the New York City Rheumatology Objective Structured Clinical Examination (ROSCE) and our sequential 5 years of experience have provided us with a unique opportunity to assess its usefulness and objectivity as a rheumatology assessment tool. METHODS: Prior to taking the examination, all of the fellows were rated by their program directors. Fellows from the participating institutions then underwent a multistation patient-interactive examination observed and rated by patient actors and faculty raters. Assessments were recorded by all of the participants using separate but overlapping sets of instruments testing the Accreditation Council of Graduate Medical Education (ACGME) core competencies of patient care, interpersonal and communication skills, professionalism, and overall medical knowledge. RESULTS: Although the program directors tended to rate their fellows more highly than the ROSCE raters, typically there was agreement between the program directors and the ROSCE faculty in distinguishing between the highest- and lowest- performing fellows. The ROSCE faculty and patient actor assessments of individual trainees were notable for a high degree of concordance, both quantitatively and qualitatively. CONCLUSION: The ROSCE provides a unique opportunity to obtain a patient-centered assessment of fellows' ACGME-mandated competencies that traditional knowledge-based examinations, such as the rheumatology in-service examination, cannot measure. The ability of the ROSCE to provide a well-rounded and objective assessment suggests that it should be considered an important component of the rheumatology training director's toolbox
— id: 120725, year: 2009, vol: 61, page: 1686, stat: Journal Article,

Gout management in primary care vs. rheumatology: Evidence for suboptimal treatment
Keenan R.T.; Lehman R.A.; O'Brien W.R.; Crittenden D.B.; Lee K.H.; Pillinger M.H.
2009 ;60:1110-1110, Arthritis & rheumatism
Purpose: Primary care physicians (PCPs) manage most gout patients, but several studies suggest that the quality of PCP gout management may differ from that of rheumatologists. To prevent acute gouty attacks, a serum uric acid (UA) of <= 6 is the consensus UA lowering target. We compared the achievement of UA <= 6 in patients managed by PCPs vs. rheumatologists. Methods: Gout patients were identified, from among all NY Harbor VAMC patients ages 18-100 (n-33,000) as having any 1 of 7 ICD codes for gout. Gout patients were defined as managed by their PCP if they had not seen a rheumatologist during the study period (7/07-6/09), or treated by a rheumatologist if they had seen a rheumatologist >=3 times during the interval. Patients with 1-2 rheumatology visits were excluded. Mean serum UA for the two groups were compared using R statistical software (version 2.8.1). Results: Prevalence of gout in the overall population was 2.5% (34% African-American, 49% White, 8% Hispanic, 2.5% South East Asian, 1% Pacific Islander, 0.5% Native American and 5% unknown). All subjects were male; average age was 72 years. Among 575 patients meeting ICD-9 diagnosis for gout, 474 had been treated for gout only in primary care, whereas 85 had been managed by a rheumatologist. 5.3% in the PCP cohort vs. 14.1% in the rheumatology cohort had a crystal confirmation of their disease. Patients receiving allopurinol achieved UA <=6 in the rheumatology- but not the PCP-treated group. Among 191 patients prescribed allopurinol in the PCP cohort, 25.7% had no UA measurement during the study period; in contrast, 100% of the 57 rheumatology patients receiving allopurinol had >=1 UA measurement. Average allopurinol dose in the PCP and rheumatology cohorts were 196 mg and 182 mg, respectively. Among patients with gout and hypertension, 16.7% were prescribed hydrochlorothiazide (HCTZ) in the PCP cohort vs. 11.8% in the rheumatology cohort. (Table presented) Conclusion: Our analyses suggest that gout patients cared for by PCPs may be undertreated. Compared with rheumatologists, PCPs are more likely to under dose, and/or inadequately monitor the results of, UA-lowering therapy. PCPs may also be more likely than rheumatologists to eschew crystal diagnosis, and to fail to account for the UA-raising properties of anti-hypertensive diuretics. To ensure proper clinical care, rheumatologists may need to assume a greater role in treating gout patients, and/or better educate PCPs in appropriate gout management
— id: 130330, year: 2009, vol: 60, page: 1110, stat: Journal Article,

RS(3)PE Presenting in a Unilateral Pattern: Case Report and Review of the Literature
Keenan, Robert T; Hamalian, Gareen M; Pillinger, Michael H
2009 Jun;38(6):428-433, Seminars in arthritis & rheumatism
OBJECTIVES: To review the clinical features and pathophysiologic implications of remitting seronegative symmetrical synovitis with pitting edema (RS(3)PE) presenting in a unilateral manner. METHODS: We identified and characterized an index case of RS(3)PE presenting in a unilateral pattern. We subsequently performed a systematic literature search to identify other reports of patients with unilateral RS(3)PE. RESULTS: The index case was a 76-year-old male with a prior history of right hemiparesis owing to a cerebrovascular accident 25 years prior, who developed a classic picture of RS(3)PE involving hand (metacarpophalageal and wrist joint) arthritis and dorsal pitting edema, accompanied by an elevated erythrocyte sedimentation rate, but only in the nonhemiparetic hand. The condition responded rapidly to low-dose prednisone. Our literature search identified 5 other cases of unilateral RS(3)PE, including 2 presented only in the Italian or German literature. Of the 5 cases, 2 were in patients with preexisting neurologic disease, in which the neurologically affected side was spared. One additional case initially presented as unilateral disease but rapidly progressed to bilaterality. Two cases presented in a fully unilateral manner despite no reported neurologic abnormalities on the unaffected sides. CONCLUSIONS: While RS(3)PE is almost always a symmetric disease of the upper extremities, it may rarely present in a unilateral fashion. The apparent ability of neuropathic changes to protect against the expression of RS(3)PE in an extremity suggests a role for neural and possibly other local factors in the genesis/modulation of the onset or maintenance of RS(3)PE
— id: 97026, year: 2009, vol: 38, page: 428, stat: Journal Article,

Febuxostat: a new agent for lowering serum urate
Keenan, Robert T; Pillinger, Michael H
2009 Apr;45(4):247-260, Drugs of today (Barcelona, Spain : 1998)
The prevalence of gout has been increasing in epidemic proportions over the last several decades. Hyperuricemia has been shown to be associated with metabolic syndrome and to be an independent risk factor for cardiovascular disease. Associations between hyperuricemia, obesity and aging have provided an impetus in recent years to develop alternative methods of treating hyperuricemia and gout. Febuxostat is a new non-purine xanthine oxidase inhibitor indicated for chronic gout. Febuxostat has been shown to quickly and effectively lower serum urate levels in patients with chronic gout. This manuscript will review febuxostat, its pharmacokinetics and pharmacodynamics, efficacy and adverse events and use in patients with comorbid conditions. The review will also summarize the phase III trials leading up to the drug's approval by both the European Commission in 2008 and the U.S. FDA in 2009. Possible implications the medication may have in the future on gout and hyperuricemia will also be discussed
— id: 99329, year: 2009, vol: 45, page: 247, stat: Journal Article,

Hyperuricemia, gout, and cardiovascular disease--an important "muddle"
Keenan, Robert T; Pillinger, Michael H
2009 ;67(3):285-290, Bulletin of the NYU Hospital for Joint Diseases
Multiple epidemiologic studies confrm an association between hyperuricemia and cardiovascular disease (CVD), but it remains uncertain whether hyperuricemia is an independent or dependent risk factor for CVD. The question is particularly complex since patients with gout frequently have multiple comorbid conditions and adjusting for these conditions tends to reduce the strength of hyperuricemia as a risk factor. In this article, we review the data supporting a possible independent role for hyperuricemia in CVD. A close reading of the literature suggests that hyperuricemia may be both an independent and dependent risk factor, and is more likely to act as an independent risk factor in blacks, women, and patients with high risk for CVD. We also review the literature that suggests that hyperuricemia may directly contribute to the development of a number of comorbid conditions that in turn contribute to CVD risk (e.g., hypertension, glucose intolerance, renal insuffciency, and adiposity), suggesting that adjusting studies for these risk factors may be biologically inappropriate. Finally, we review the limited literature addressing the question of whether gout per se, above and beyond the presence of hyperuricemia, may convey an additional independent CVD risk. Given the ready ability of physicians to pharmacologically manage serum urate levels, a better understanding of the interaction between hyperuricemia, gout and vascular disease may be critical for the reduction of morbidity and mortality in high-risk CVD patients
— id: 104899, year: 2009, vol: 67, page: 285, stat: Journal Article,

Arthritis as a risk factor for incident coronary heart disease in elderly Japanese-American males - the Honolulu Heart Program
Kishimoto, Mitsumasa; Greenberg, Jeffrey; Lee, Ryan; Masaki, Kamal H; Chen, Randi; Rodriguez, Beatriz L; Blanchette, Patricia; Pillinger, Michael; David Curb, J
2009 ;67(2):230-235, Bulletin of the NYU Hospital for Joint Diseases
BACKGROUND: Arthritis is the most common chronic disease in the elderly. Studies show that rheumatoid arthritis is a risk factor for cardiovascular morbidity and mortality, and osteoarthritis is associated with an unfavorable cardiovascular risk factor profile. METHODS: At the Honolulu Heart Program's fourth examination in 1991 to 1993, arthritis status was assessed among a cohort of 3741 Japanese-American males, ages 71 to 93 years. Arthritis was determined by self-report of physician diagnosis, and subjects were divided into two groups: current arthritis and no current arthritis. Eight years of follow-up data are available for incident coronary heart disease (CHD) in 2777 subjects free of CHD at baseline. Age-adjusted rates of incident CHD and means of cardiovascular risk factors were compared in each group. Cox proportional hazards models were used to calculate relative risks, adjusting for common cardiovascular risk factors, alcohol, and use of aspirin or NSAIDs, or both. RESULTS: There were 279 cases of incident CHD in the cohort over 8 years; in those with arthritis, 11.7% developed incident CHD, compared to 9.8% in those without arthritis (p = 0.24). Age-adjusted rates of incident CHD in those with and without arthritis were 20.5 and 18.0 per 1000 person-years, respectively (p = 0.25). Arthritis was not significantly associated with CHD risk factors. Arthritis was not a significant independent predictor of incident CHD (relative risk, 1.06; 95% CI, 0.74 to 1.51). CONCLUSIONS: Arthritis, and most probably osteoarthritis, may not be associated with most CHD risk factors or 8-year incident CHD in elderly Japanese-American males
— id: 101125, year: 2009, vol: 67, page: 230, stat: Journal Article,

SOMOSAT: Utility of a web-based self-assessment tool in undergraduate medical education
Leaf, David E; Leo, Joseph; Leaf, David E; Leo, Joseph; Smith, Phillip R; Yee, Herman; Stern, Arnold; Rosenthal, Pamela B; Cahill-Gallant, Eileen B; Pillinger, Michael H
2009 May;31(5):e211-e219, Medical teacher
BACKGROUND: Relatively few studies have rigorously assessed the effectiveness of computer-based self-assessment in medical education. AIM: To assess whether an online self-assessment tool can be an effective adjunct to a traditional curriculum for second-year medical students. METHODS: The NYU School of Medicine Online Self-Assessment Tool (SOMOSAT) consists of >450 multiple-choice questions spanning disciplines of internal medicine, administered as separate modules focused on individual organ systems. Questions are coded on multiple dimensions, permitting second-year medical students to receive low-stakes, highly specific feedback regarding their knowledge and performance. Students can also review their answers to guide future study. We employed data collected during SOMOSAT operation to assess its utility and effectiveness. RESULTS: Overall, SOMOSAT accurately predicted student performance on future exams. SOMOSAT participants generally performed better than non-participants on subsequent graded course examinations (p < 0.05). Students using SOMOSAT subsequently experienced greater improvement in areas in which they initially performed poorly, compared with those in which they initially performed well. Students reported that SOMOSAT was most helpful in filling knowledge gaps, and providing opportunities to practice exam-style questions. CONCLUSION: The ability of SOMOSAT to enhance learning and exam performance suggests that web-based self-assessment tools can be effective adjuncts to traditional educational methods
— id: 103162, year: 2009, vol: 31, page: e211, stat: Journal Article,

Drug-induced myopathies
Mor, Adam; Mitnick, Hal J; Pillinger, Michael H; Wortmann, Robert L
2009 ;67(4):358-369, Bulletin of the NYU Hospital for Joint Diseases
The most common drugs currently in use that may cause myopathies were reviewed using the Medline database (U.S. National Library of Medicine, Bethesda, Maryland). Our review included results from epidemiologic and database surveys, clinical trials, and case reports. The clinical spectrum is wide, and presentations range from asymptomatic elevations in serum creatine phosphokinase levels to severe life-threatening rhabdomyolysis. Management of suspected drug-induced myopathy should include immediate discontinuation of the offending agent, as well as supportive care when needed. Earlier diagnosis and drug discontinuation raises the likelihood of resolution and recovery
— id: 105975, year: 2009, vol: 67, page: 358, stat: Journal Article,

The Anti-Inflammatory Effects of Prostaglandins
Scher, Jose U; Pillinger, Michael H
2009 Aug;57(6):703-708, Journal of investigative medicine
Long regarded as proinflammatory molecules, prostaglandins (PGs) also have anti-inflammatory effects. Both prostaglandin D2 (PGD2) and its dehydration end product 15-deoxy-Delta-prostaglandin J2 (15d-PGJ2) seem to play important roles in regulating inflammation, via both receptor-dependent (DP1 and DP2 receptors) and receptor-independent mechanisms. Intracellular effects of PGD2 and 15d-PGJ2 that may suppress inflammation include inhibition of nuclear factor-kappaB (NF-kappaB) by multiple mechanisms (IkappaB kinase inhibition and blockade of NF-kappaB nuclear binding) and activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Prostaglandin F2alpha (PGF2alpha) may also have important anti-inflammatory effects, although current data are limited. In animal models, expression of both PGD and PGF synthases declines during acute inflammation, only to rise again during the resolution phase, suggesting their possible role in resolving inflammation. Prostaglandin E2 (PGE2), the classic model of a proinflammatory lipid mediator, also has anti-inflammatory effects that are both potent and context dependent. Thus, accumulating data suggest that PGs not only participate in initiation, but may also actively contribute to the resolution of inflammation. Indeed, classic inhibitors of PG synthesis such as nonselective and cyclooxygenase-2 (COX-2) selective inhibitors (nonsteroidal anti-inflammatory drugs) may actually prolong inflammation when administered during the resolution phase. These effects may regulate not only tissue inflammation but also vascular disease, possibly shedding light on the controversy surrounding nonsteroidal anti-inflammatory drug use and its relation to myocardial infarction. In this review, we summarize the current understanding of PGs as dichotomous molecules in the inflammatory process
— id: 97024, year: 2009, vol: 57, page: 703, stat: Journal Article,

Update on fibromyalgia therapy
Abeles, Micha; Solitar, Bruce M; Pillinger, Michael H; Abeles, Aryeh M
2008 Jul;121(7):555-561, American journal of medicine
Primary fibromyalgia, a poorly-understood chronic pain syndrome, is characterized by widespread musculoskeletal pain, nonrestorative sleep, fatigue, psychological distress, and specific regions of localized tenderness, all in the absence of otherwise apparent organic disease. While the etiology of fibromyalgia is unclear, accumulating data suggest that disordered central pain processing likely plays a role in the pathogenesis of symptoms. Although various pharmacological treatments have been studied and espoused for treating fibromyalgia, no single drug or group of drugs has proved to be particularly useful in treating fibromyalgia patients as a whole, and only one drug to date has earned U.S. Food and Drug Administration approval for treating the syndrome in the United States. This review critically and systematically evaluates clinical investigations of medicinal and nonmedicinal treatments for fibromyalgia dating from 1970 to 2007
— id: 94805, year: 2008, vol: 121, page: 555, stat: Journal Article,

Prostaglandin E2 exerts catabolic effects in osteoarthritis cartilage: evidence for signaling via the EP4 receptor
Attur, Mukundan; Al-Mussawir, Hayf E; Patel, Jyoti; Kitay, Alison; Dave, Mandar; Palmer, Glyn; Pillinger, Michael H; Abramson, Steven B
2008 Oct 1;181(7):5082-5088, Journal of immunology
Elevated levels of PGE(2) have been reported in synovial fluid and cartilage from patients with osteoarthritis (OA). However, the functions of PGE(2) in cartilage metabolism have not previously been studied in detail. To do so, we cultured cartilage explants, obtained from patients undergoing knee replacement surgery for advanced OA, with PGE(2) (0.1-10 muM). PGE(2) inhibited proteoglycan synthesis in a dose-dependent manner (maximum 25% inhibition (p < 0.01)). PGE(2) also induced collagen degradation, in a manner inhibitable by the matrix metalloproteinase (MMP) inhibitor ilomastat. PGE(2) inhibited spontaneous MMP-1, but augmented MMP-13 secretion by OA cartilage explant cultures. PCR analysis of OA chondrocytes treated with PGE(2) with or without IL-1 revealed that IL-1-induced MMP-13 expression was augmented by PGE(2) and significantly inhibited by the cycolooygenase 2 selective inhibitor celecoxib. Conversely, MMP-1 expression was inhibited by PGE(2), while celecoxib enhanced both spontaneous and IL-1-induced expression. IL-1 induction of aggrecanase 5 (ADAMTS-5), but not ADAMTS-4, was also enhanced by PGE(2) (10 muM) and reversed by celecoxib (2 muM). Quantitative PCR screening of nondiseased and end-stage human knee OA articular cartilage specimens revealed that the PGE(2) receptor EP4 was up-regulated in OA cartilage. Moreover, blocking the EP4 receptor (EP4 antagonist, AH23848) mimicked celecoxib by inhibiting MMP-13, ADAMST-5 expression, and proteoglycan degradation. These results suggest that PGE(2) inhibits proteoglycan synthesis and stimulates matrix degradation in OA chondrocytes via the EP4 receptor. Targeting EP4, rather than cyclooxygenase 2, could represent a future strategy for OA disease modification
— id: 91441, year: 2008, vol: 181, page: 5082, stat: Journal Article,

The fifth annual New York Rheumatology Objective Structured Clinical Examination (ROSCE): The trainee self-assessment of professionalism vs. exam raters
Berman, J; Krasnokutsky, S; Bass, A; Fields, T; Lazaro, D; Weinstein, E; Dwyer, E; Paget, S; Pillinger, MH
2008 SEP ;58(9):S196-S196, Arthritis & rheumatism
— id: 88545, year: 2008, vol: 58, page: S196, stat: Journal Article,

Gout Management in a Primary Care Setting: Evidence for Possible Suboptimal Treatment
Keenan, RT; O'Brien, WR; Crittenden, DB; Goldfarb, DS; Pillinger, MH
2008 DEC ;58(12):3983-3983, Arthritis & rheumatism
— id: 91333, year: 2008, vol: 58, page: 3983, stat: Journal Article,

Drug-Induced Arthritic and Connective Tissue Disorders
Mor, Adam; Pillinger, Michael H; Wortmann, Robert L; Mitnick, Hal J
2008 Dec;38(3):249-264, Seminars in arthritis & rheumatism
OBJECTIVES: All pharmacologic agents have the potential for both benefit and toxicity. Among the more interesting and important adverse consequences of drug therapy are a range of joint and connective tissue complaints that may mimic or reproduce primary rheumatologic diseases. In this article, we review the literature on commonly used drugs reported to induce arthritis and/or connective tissue-based diseases. We assess the strength of the reported associations, discuss diagnostic features and treatment implications, and consider possible mechanisms for drug-induced genesis of rheumatic conditions. METHODS: We reviewed the Medline database from 1987 to 2006 to identify drug-induced arthritic and connective-tissue disease syndromes, utilizing 48 search terms. A qualitative review was performed after the articles were abstracted and the relevant information was organized. RESULTS: Three hundred fifty-seven articles of possible relevance were identified. Two hundred eleven publications were included in the final analysis (case series and reports, clinical trials, and reviews). Many drugs were identified as mimicking existing rheumatic conditions, including both well-established small molecules (eg, sulfasalazine) and recently introduced biologic agents (eg, antitumor necrosis factor agents). The most commonly reported drug-induced rheumatic conditions were lupus-like syndromes. Arthritis and vasculitis were also often reported. CONCLUSIONS: Drug-induced rheumatic syndromes are manifold and offer the clinician an opportunity to define an illness that may remit with discontinuation of the offending agent. Early diagnosis and withdrawal of the drug may prevent unnecessary morbidity and disability
— id: 80339, year: 2008, vol: 38, page: 249, stat: Journal Article,

Prevalence of Co-morbidities and Relative Contraindications to Standard Therapies in a Cohort of Gout Patients
O'Brien, WR; Keenan, RT; Crittenden, DB; Goldfarb, DS; Pillinger, MH
2008 DEC ;58(12):4012-4013, Arthritis & rheumatism
— id: 91334, year: 2008, vol: 58, page: 4012, stat: Journal Article,

Update on the management of hyperuricemia and gout
Pillinger, Michael H; Keenan, Robert T
2008 ;66(3):231-239, Bulletin of the NYU Hospital for Joint Diseases
Gout is the most common inflammatory arthritis in the United States, with more than three million sufferers. Management of gout has changed relatively little in the past 50 years, despite the fact that many gout patients have contraindications to one or more currently available gout therapies. However, recent insights into gout pathophysiology suggest that time is ripe for a change. This article reviews recent updates in the management of gout, including new insights into dietary management that may permit better control of hyuperuricemia. Also reviewed are the biological and clinical data behind newly-developed drugs for gout that are likely to receive serious consideration for FDA approval, and clinical use, in the foreseeable future
— id: 97025, year: 2008, vol: 66, page: 231, stat: Journal Article,

Annexin-1 mediates TNF-alpha-stimulated matrix metalloproteinase secretion from rheumatoid arthritis synovial fibroblasts
Tagoe, Clement E; Marjanovic, Nada; Park, Jean Y; Chan, Edwin S; Abeles, Aryeh M; Attur, Mukundan; Abramson, Steven B; Pillinger, Michael H
2008 Aug 15;181(4):2813-2820, Journal of immunology
Annexins are intracellular molecules implicated in the down-regulation of inflammation. Recently, annexin-1 has also been identified as a secreted molecule, suggesting it may have more complex effects on inflammation than previously appreciated. We studied the role of annexin-1 in mediating MMP-1 secretion from rheumatoid arthritis (RA) synovial fibroblasts (SF) stimulated with TNF-alpha. TNF-alpha induced a biphasic secretion of annexin-1 from RA SF. Early (< or = 60 min), cycloheximide-independent secretion from preformed intracellular pools was followed by late (24 h) cycloheximide-inhibitable secretion requiring new protein synthesis. Exogenous annexin-1 N-terminal peptide Ac2-26 stimulated MMP-1 secretion in a dose- (EC(50) approximately 25 microM) and time- (8-24 h) dependent manner; full-length annexin-1 had a similar effect. Down-regulation of annexin-1 using small interfering RNA resulted in decreased secretion of both annexin-1 and MMP-1, confirming that annexin-1 mediates TNF-alpha-stimulated MMP-1 secretion. Erk, Jnk, and NF-kappaB have been implicated in MMP-1 secretion. Erk, Jnk, and NF-kappaB inhibitors had no effect on annexin-1 secretion stimulated by TNF-alpha but inhibited MMP-1 secretion in response to Ac2-26, indicating that these molecules signal downstream of annexin-1. Annexin-1 stimulation of MMP-1 secretion was inhibited by both a formyl peptide receptor antagonist and pertussis toxin, suggesting that secreted annexin-1 acts via formyl peptide family receptors, most likely FPLR-1. In contrast to its commonly appreciated anti-inflammatory roles, our data indicate that annexin-1 is secreted by RA SF in response to TNF-alpha and acts in an autacoid manner to engage FPRL-1, activate Erk, Jnk, and NF-kappaB, and stimulate MMP-1 secretion
— id: 87806, year: 2008, vol: 181, page: 2813, stat: Journal Article,

Protein isoprenylation regulates secretion of matrix metalloproteinase 1 from rheumatoid synovial fibroblasts: effects of statins and farnesyl and geranylgeranyl transferase inhibitors
Abeles, Aryeh M; Marjanovic, Nada; Park, Jean; Attur, Mukundan; Chan, Edwin S; Al-Mussawir, Hayf E; Dave, Mandar; Fisher, Mark C; Stuchin, Steven A; Abramson, Steven B; Pillinger, Michael H
2007 Sep;56(9):2840-2853, Arthritis & rheumatism
OBJECTIVE: To determine whether protein prenylation (farnesyl/geranylgeranylation) regulates matrix metalloproteinase (MMP) secretion from rheumatoid arthritis (RA) synovial fibroblasts (RASFs), and whether MMP-1 secretion can be regulated by statins or prenyltransferase inhibitors via effects mediated by ERK, JNK, and NF-kappaB. METHODS: RASFs obtained from patients during elective knee replacement surgery were assessed by immunoblotting and/or enzyme-linked immunosorbent assay for secretion of MMP-1 and MMP-13 in the presence of tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), statins, the farnesyl transferase (FT) inhibitor FTI-276 and geranylgeranyl transferase inhibitor GGTI-298, and prenyl substrates (farnesyl pyrophosphate [FPP] and geranylgeranyl pyrophosphate [GGPP]). Activities of JNK and ERK were determined by phosphoimmunoblotting, and NF-kappaB activation was determined by nuclear translocation of the p65 component. RESULTS: FTI-276, but not statins, inhibited RASF secretion of MMP-1, but not MMP-13, following induction with TNFalpha (P = 0.0007) or IL-1beta (P = 0.006). Loading RASFs with FPP to promote farnesylation enhanced MMP-1 secretion. FTI-276 inhibited activation of JNK (P < 0.05) and NF-kappaB (P = 0.02), but not ERK. In contrast, GGTI-298 enhanced, while GGPP inhibited, MMP-1 secretion. FTI-276 and GGTI-298 together had no effect on MMP-1 secretion. Stimulation of RASFs with TNFalpha or IL-1beta led to increased expression and activity of FT. CONCLUSION: Protein farnesylation is required for expression and secretion of MMP-1 from RASFs, via effects on JNK and NF-kappaB. The ability of cytokines to stimulate the expression and activity of FT suggests that FT may be increased in the rheumatoid joint. In contrast, geranylgeranylation down-regulates MMP-1 expression. Statins simultaneously inhibit farnesylation and geranylgeranylation, and in consequence do not inhibit MMP-1 secretion. The ability of FTI-276 to inhibit MMP-1 secretion suggests a potential therapeutic strategy in RA
— id: 93879, year: 2007, vol: 56, page: 2840, stat: Journal Article,

Update on gout: pathophysiology and potential treatments
Abeles, Aryeh M; Park, Jean Y; Pillinger, Michael H; Cronstein, Bruce N
2007 Dec;11(6):440-446, Current pain & headache reports
After several decades of senescence, the twin fields of hyperuricemia and gout have again regained attention in both the scientific and clinical spheres, and this review highlights several recent advancements. Specifically, we review newly discovered mechanisms of uric acid-induced inflammation, uric acid's putative role as a 'danger signal' in innate immunity, the possible link between hyperuricemia and cardiovascular disease, and evolutionary evidence suggesting that hyperuricemia conferred a survival advantage in primates (when the gene for uricase was lost) several million years ago. Finally, we provide an overview of the current approach to gout, as well as what treatments are on the horizon
— id: 96261, year: 2007, vol: 11, page: 440, stat: Journal Article,

Narrative review: the pathophysiology of fibromyalgia
Abeles, Aryeh M; Pillinger, Michael H; Solitar, Bruce M; Abeles, Micha
2007 May 15;146(10):726-734, Annals of internal medicine
Primary fibromyalgia is a common yet poorly understood syndrome characterized by diffuse chronic pain accompanied by other somatic symptoms, including poor sleep, fatigue, and stiffness, in the absence of disease. Fibromyalgia does not have a distinct cause or pathology. Nevertheless, in the past decade, the study of chronic pain has yielded new insights into the pathophysiology of fibromyalgia and related chronic pain disorders. Accruing evidence shows that patients with fibromyalgia experience pain differently from the general population because of dysfunctional pain processing in the central nervous system. Aberrant pain processing, which can result in chronic pain and associated symptoms, may be the result of several interplaying mechanisms, including central sensitization, blunting of inhibitory pain pathways, alterations in neurotransmitters, and psychiatric comorbid conditions. This review provides an overview of the mechanisms currently thought to be partly responsible for the chronic diffuse pain typical of fibromyalgia.
— id: 72876, year: 2007, vol: 146, page: 726, stat: Journal Article,

A subclass of peripheral blood T cells demonstrates increased CD86 expression in patients with rheumatoid arthritis (RA
Ben-Artzi, A; Tse, DB; Attur, M; Greenberg, JD; Nasir, A; Pillinger, MH; Abramson, SB
2007 DEC ;56(12):4305-4306, Arthritis & rheumatism
— id: 87214, year: 2007, vol: 56, page: 4305, stat: Journal Article,

Effect of cyclooxygenase inhibition on cholesterol efflux proteins and atheromatous foam cell transformation in THP-1 human macrophages: a possible mechanism for increased cardiovascular risk
Chan, Edwin S L; Zhang, Hongwei; Fernandez, Patricia; Edelman, Sari D; Pillinger, Michael H; Ragolia, Louis; Palaia, Thomas; Carsons, Steven; Reiss, Allison B
2007 ;9(1):R4-R4, Arthritis research & therapy
Both selective cyclooxygenase (COX)-2 inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs) have been beneficial pharmacological agents for many patients suffering from arthritis pain and inflammation. However, selective COX-2 inhibitors and traditional NSAIDs are both associated with heightened risk of myocardial infarction. Possible pro-atherogenic mechanisms of these inhibitors have been suggested, including an imbalance in prostanoid production leaving the pro-aggregatory prostaglandins unopposed, but the precise mechanisms involved have not been elucidated. We explored the possibility that downregulation of proteins involved in reverse cholesterol transport away from atheromatous plaques contributes to increased atherogenesis associated with COX inhibition. The reverse cholesterol transport proteins cholesterol 27-hydroxylase and ATP-binding cassette transporter A1 (ABCA1) export cholesterol from macrophages. When mechanisms to process lipid load are inadequate, uncontrolled cholesterol deposition in macrophages transforms them into foam cells, a key element of atheromatous plaques. We showed that in cultured THP-1 human monocytes/macrophages, inhibition of COX-1, COX-2, or both reduced expression of 27-hydroxylase and ABCA1 message (real-time reverse transcription-polymerase chain reaction) and protein (immunoblot). The selective COX-2 inhibitor N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide (NS398) significantly reduced 27-hydroxylase and ABCA1 message (to 62.4% +/- 2.2% and 71.1% +/- 3.9% of control, respectively). Incubation with prostaglandin (PG) E2 or PGD2 reversed reductions in both of these cholesterol transport proteins induced by NS398. Cholesterol-loaded THP-1 macrophages showed significantly increased foam cell transformation in the presence of NS398 versus control (42.7% +/- 6.6% versus 20.1% +/- 3.4%, p = 0.04) as determined by oil red O staining. Pharmacological inhibition of COX in monocytes is involved in downregulation of two proteins that mediate cholesterol efflux: cholesterol 27-hydroxylase and ABCA1. Because these proteins are anti-atherogenic, their downregulation may contribute to increased incidence of cardiac events in patients treated with COX inhibitors. Reversal of inhibitory effects on 27-hydroxylase and ABCA1 expression by PGD2 and PGE2 suggests involvement of their respective signaling pathways. NS398-treated THP-1 macrophages show greater vulnerability to form foam cells. Increased cardiovascular risk with COX inhibition may be ascribed at least in part to altered cholesterol metabolism
— id: 71926, year: 2007, vol: 9, page: R4, stat: Journal Article,

The role of Ras signaling in lupus T lymphocytes: biology and pathogenesis
Mor, Adam; Philips, Mark R; Pillinger, Michael H
2007 Dec;125(3):215-223, Clinical immunology
Ras is a GTP-binding protein that plays multiple important roles in cell activation, including proliferative and inflammatory responses. Ras regulation is complex and depends upon post-translational processing, organelle-specific localization and the activation/deactivation of Ras by a number of regulatory molecules. Ras activation in T lymphocytes demonstrates unique features, including its dependence on the T cell receptor and the ability of Ras to signal from both the plasma membrane and the Golgi. Abnormalities of Ras expression, activation and signaling pathways in T lymphocytes appear to play important roles in the development of autoimmunity in general, and systemic lupus erythematosus in particular. In this manuscript, we review the basic biology of Ras in T lymphocytes, and the ways in which T lymphocyte Ras abnormalities may contribute to the development of a lupus phenotype
— id: 75658, year: 2007, vol: 125, page: 215, stat: Journal Article,

Familial Mediterranean fever successfully treated with etanercept
Mor, Adam; Pillinger, Michael H; Kishimoto, Mitsumasa; Abeles, Aryeh M; Livneh, Avi
2007 Feb;13(1):38-40, Journal of clinical rheumatology. JCR
Colchicine is the only drug known to effectively prevent familial Mediterranean fever (FMF) attacks, as well as FMF-associated amyloidosis. Unfortunately, colchicine is neither always effective nor always well tolerated, leaving some patients and their physicians with inadequate weaponry to fight this hazardous disease. We present a patient with recurrent episodes of abdominal, scrotal, and joint attacks, who was diagnosed with FMF and advised to take colchicine. Diarrhea prevented optimal treatment with this drug and led to a trial of etanercept, with resolution of FMF manifestations. This case adds to a growing body of evidence suggesting that tumor necrosis factor (TNF) blockade may result in resolution and prevention of further FMF attacks
— id: 71346, year: 2007, vol: 13, page: 38, stat: Journal Article,

Interleukin-6 in the pathogenesis of rheumatoid arthritis
Park, Jean Y; Pillinger, Michael H
2007 ;65 Suppl 1:S4-10, Bulletin of the NYU Hospital for Joint Diseases
Cytokines such as TNF-alpha and IL-1beta play key roles in driving the inflammation and synovial cell proliferation that characterize rheumatoid arthritis (RA) joint destruction. It is, therefore, not surprising that therapies for RA have targeted these cytokines. While blockade of TNF-alpha or IL-1beta has been efficacious for many patients with RA, adequacy and maintenance of response are not universal, and increased risk of adverse events such as infection and malignancy remains a concern. Therefore, new targets in the treatment of RA continue to be examined. As interleukin-6 (IL-6) has been implicated in the pathogenesis of RA, blockade of its activity is of both scientific and clinical interest. The basic biology of IL-6, the in vitro animal data supporting its role in RA, and the human trials to date that test the possible efficacy of IL-6-directed therapy for RA are reviewed
— id: 74669, year: 2007, vol: 65 Suppl 1, page: S4, stat: Journal Article,

The language used by Helicobacter pylori to regulate human cells
Pillinger, Michael H; Blaser, Martin J
2007 Jul 1;196(1):6-9, Journal of infectious diseases
— id: 73298, year: 2007, vol: 196, page: 6, stat: Journal Article,

Hyperuricemia and gout: new insights into pathogenesis and treatment
Pillinger, Michael H; Rosenthal, Pamela; Abeles, Aryeh M
2007 ;65(3):215-221, Bulletin of the NYU Hospital for Joint Diseases
Over the past decade, significant advances have been made regarding the pathogenesis, clinical implications, and treatment of hyperuricemia. While physicians have understood for at least a century that uric acid causes gout, we are now beginning to address the question of why hyperuricemia exists and the mechanisms by which uric acid acts to stimulate inflammation. This review focuses on (1) previously unknown biological roles of uric acid; (2) why the loss of the uricase gene and resultant hyperuricemia may have provided an evolutionary advantage to primates and, in particular, to humans; (3) the molecular effects of uric acid on inflammatory cells; and (4) novel antihyperuricemic agents currently under study
— id: 75663, year: 2007, vol: 65, page: 215, stat: Journal Article,

Use of NSAIDs: Past, present, and future
Scher JU; Pillinger MH
2007 ;19(2):77-80, Drug Benefit Trends
Traditional NSAIDs and some cyclooxygenase (COX)-2 inhibitors used to treat persons with osteoarthritis (OA) have adverse effects. However, traditional NSAIDs remain first-line therapy for some patients. The toxicities (eg, renal and GI effects) mostly are the result of COX inhibition. The ideal NSAID would inhibit COX-2 while sparing COX-1. The mechanisms for increased COX-2 cardiovascular toxicity remain less than fully understood. Several conservative strategies may help physicians use these agents effectively and safely. OA therapies under investigation (eg, inhibition of prostaglandin E synthases and disease-modifying osteoarthritis drugs) may render NSAIDs and COX-2 inhibitors obsolete
— id: 72426, year: 2007, vol: 19, page: 77, stat: Journal Article,

Nitric oxide synthases and osteoarthritis
Scher, Jose U; Pillinger, Michael H; Abramson, Steven B
2007 Apr;9(1):9-15, Current rheumatology reports
The production of nitric oxide (NO) by chondrocytes is increased in human osteoarthritis. The excessive production of NO inhibits matrix synthesis and promotes its degradation. Furthermore, by reacting with oxidants such as superoxide anion, NO promotes cellular injury and renders the chondrocyte susceptible to cytokine-induced apoptosis. Thus, NO produced by activated chondrocytes in diseased cartilage may modulate disease progression in osteoarthritis and should therefore be considered a potential target for therapeutic intervention.
— id: 72992, year: 2007, vol: 9, page: 9, stat: Journal Article,

Statins as antiinflammatory and immunomodulatory agents: a future in rheumatologic therapy?
Abeles, Aryeh M; Pillinger, Michael H
2006 Feb;54(2):393-407, Arthritis & rheumatism
— id: 68295, year: 2006, vol: 54, page: 393, stat: Journal Article,

The role of the synovial fibroblast in rheumatoid arthritis: cartilage destruction and the regulation of matrix metalloproteinases
Abeles, Aryeh M; Pillinger, Michael H
2006 ;64(1-2):20-24, Bulletin of the NYU Hospital for Joint Diseases
Rheumatoid arthritis (RA) is a complex multisystem disease, the hallmark of which is pannus, the abnormal proliferative synovial tissue that serves as both propagator of the immune response and as the engine of tissue damage. Conceptually, pannus may be divided into two compartments (Fig. 1). The first, comprised by T cells, B cells, macrophages, and dendritic cells, is an immune compartment that exists in what was formerly the subintimal layer of normal synovium. These immune cells partake in antigen presentation, immunoglobulin production (including rheumatoid factor and anti-cyclic citrullinated protein [CCP] antibodies) and cytokine generation; the T cell is thought by many investigators to be the driving force coordinating these various activities
— id: 71411, year: 2006, vol: 64, page: 20, stat: Journal Article,

NURR1 expression is increased in osteoarthritic cartilage and regulates cytokine and metalloproteinase gene transcription: A downstream action of cyclooxygenase 2-derived PGE2
Attur, M; Al-Mussawir, HE; Pillinger, MH; Mix, K; Tetradis, S; Abramson, SB
2006 SEP ;54(9):S616-S616, Arthritis & rheumatism
— id: 70128, year: 2006, vol: 54, page: S616, stat: Journal Article,

Prostaglandin E2 induces mitochondrial dysfunction in osteoarthritic chondrocytes and exerts catabolic effects aa the EP4 receptor
Attur, M; Dave, M; Patel, J; Al-Mussawir, HE; Pillinger, MH; Abramson, SB
2006 SEP ;54(9):S93-S93, Arthritis & rheumatism
— id: 70104, year: 2006, vol: 54, page: S93, stat: Journal Article,

Efficacy of arthrocentesis teaching tools including cadavers and synthetic joint models
Ben-Artzi, A; Berman, J; Fisher, MC; Pillinger, M
2006 DEC ;54(12):4104-4105, Arthritis & rheumatism
— id: 70765, year: 2006, vol: 54, page: 4104, stat: Journal Article,

The third annual new York rheumatology objective structured clinical examination (ROSCE): Expansion and validation of fellow assessment by patient and attending raters
Berman, JR; Fields, T; Pillinger, MH; Lazaro, D; Putterman, C; Bass, A; Davidson, A; Paget, S
2006 SEP ;54(9):S782-S782, Arthritis & rheumatism
— id: 70135, year: 2006, vol: 54, page: S782, stat: Journal Article,

Fulminating hydralazine-induced lupus pneumonitis
Birnbaum, Belinda; Sidhu, Gurdip S; Smith, Robert L; Pillinger, Michael H; Tagoe, Clement E
2006 Jun 15;55(3):501-506, Arthritis & rheumatism
— id: 64672, year: 2006, vol: 55, page: 501, stat: Journal Article,

Adenosine A2A receptors in diffuse dermal fibrosis: pathogenic role in human dermal fibroblasts and in a murine model of scleroderma
Chan, E S L; Fernandez, P; Merchant, A A; Montesinos, M C; Trzaska, S; Desai, A; Tung, C F; Khoa, D N; Pillinger, M H; Reiss, A B; Tomic-Canic, M; Chen, J F; Schwarzschild, M A; Cronstein, B N
2006 Aug;54(8):2632-2642, Arthritis & rheumatism
OBJECTIVE: Adenosine regulates inflammation and tissue repair, and adenosine A2A receptors promote wound healing by stimulating collagen matrix production. We therefore examined whether adenosine A2A receptors contribute to the pathogenesis of dermal fibrosis. METHODS: Collagen production by primary human dermal fibroblasts was analyzed by real-time polymerase chain reaction, 14C-proline incorporation, and Sircol assay. Intracellular signaling for dermal collagen production was investigated using inhibitors of MEK-1 and by demonstration of ERK phosphorylation. In vivo effects were studied in a bleomycin-induced dermal fibrosis model using adenosine A2A receptor-deficient wild-type littermate mice, C57BL/6 mice, and mice treated with adenosine A2A receptor antagonist. Morphometric features and levels of hydroxyproline were determined as measures of dermal fibrosis. RESULTS: Adenosine A2A receptor occupancy promoted collagen production by primary human dermal fibroblasts, which was blocked by adenosine A2A, but not A1 or A2B, receptor antagonism. Adenosine A2A receptor ligation stimulated ERK phosphorylation, and A2A receptor-mediated collagen production by dermal fibroblasts was blocked by MEK-1 inhibitors. Adenosine A2A receptor-deficient and A2A receptor antagonist-treated mice were protected from developing bleomycin-induced dermal fibrosis. CONCLUSION: These results demonstrate that adenosine A2A receptors play an active role in the pathogenesis of dermal fibrosis and suggest a novel therapeutic target in the treatment and prevention of dermal fibrosis in diseases such as scleroderma
— id: 68662, year: 2006, vol: 54, page: 2632, stat: Journal Article,

Adenosine A(2A) receptors play a role in the pathogenesis of hepatic cirrhosis
Chan, Edwin S L; Montesinos, Maria Carmen; Fernandez, Patricia; Desai, Avani; Delano, David L; Yee, Herman; Reiss, Allison B; Pillinger, Michael H; Chen, Jiang-Fan; Schwarzschild, Michael A; Friedman, Scott L; Cronstein, Bruce N
2006 Aug;148(8):1144-1155, British journal of pharmacology
Adenosine is a potent endogenous regulator of inflammation and tissue repair. Adenosine, which is released from injured and hypoxic tissue or in response to toxins and medications, may induce pulmonary fibrosis in mice, presumably via interaction with a specific adenosine receptor. We therefore determined whether adenosine and its receptors contribute to the pathogenesis of hepatic fibrosis.As in other tissues and cell types, adenosine is released in vitro in response to the fibrogenic stimuli ethanol (40 mg dl(-1)) and methotrexate (100 nM).Adenosine A(2A) receptors are expressed on rat and human hepatic stellate cell lines and adenosine A(2A) receptor occupancy promotes collagen production by these cells. Liver sections from mice treated with the hepatotoxins carbon tetrachloride (CCl(4)) (0.05 ml in oil, 50 : 50 v : v, subcutaneously) and thioacetamide (100 mg kg(-1) in PBS, intraperitoneally) released more adenosine than those from untreated mice when cultured ex vivo.Adenosine A(2A) receptor-deficient, but not wild-type or A(3) receptor-deficient, mice are protected from development of hepatic fibrosis following CCl(4) or thioacetamide exposure.Similarly, caffeine (50 mg kg(-1) day(-1), po), a nonselective adenosine receptor antagonist, and ZM241385 (25 mg kg(-1) bid), a more selective antagonist of the adenosine A(2A) receptor, diminished hepatic fibrosis in wild-type mice exposed to either CCl(4) or thioacetamide.These results demonstrate that hepatic adenosine A(2A) receptors play an active role in the pathogenesis of hepatic fibrosis, and suggest a novel therapeutic target in the treatment and prevention of hepatic cirrhosis.British Journal of Pharmacology advance online publication, 19 June 2006; doi:10.1038/sj.bjp.0706812
— id: 66126, year: 2006, vol: 148, page: 1144, stat: Journal Article,

Adenosine A(2A) receptors and dermal fibrosis: a pathogenic role for adenosine in diffuse dermal fibrosis
Chan, ESL; Fernandez, P; Merchant, AA; Desai, A; Montesinos, MC; Tung, CF; Khoa, DN; Pillinger, MH; Reiss, AB; Tomic-Canic, M; Chen, JF; Schwarzschild, MA; Cronstein, BN
2006 SEP ;11(1):144-144, Journal of investigative dermatology symposium proceedings
— id: 76164, year: 2006, vol: 11, page: 144, stat: Journal Article,

Syphilis Mimicking Reiter's Syndrome in an HIV-Positive Patient
Kishimoto, Mitsumasa; Lee, Maryann J; Mor, Adam; Abeles, Aryeh M; Solomon, Gary; Pillinger, Michael H
2006 Aug;332(2):90-92, American journal of the medical sciences
A 38-year-old man with HIV infection presented with panuveitis, urethritis, and a papulosquamous eruption on his palms and soles. Careful physical and laboratory examination led to the diagnosis of syphilitic keratoderma, uveitis, and balanitis. The patient was successfully treated with penicillin and prednisone therapy. Because the initial presentation was difficult to distinguish from the symptoms of Reiter's syndrome, a high degree of clinical suspicion was required to accurately diagnose syphilis, a curable and potentially fatal disease
— id: 67352, year: 2006, vol: 332, page: 90, stat: Journal Article,

Prostaglandin E2 synthesis and secretion: the role of PGE2 synthases
Park, Jean Y; Pillinger, Michael H; Abramson, Steven B
2006 Jun;119(3):229-240, Clinical immunology
Prostaglandin E2 (PGE2) is a principal mediator of inflammation in diseases such as rheumatoid arthritis and osteoarthritis. Nonsteroidal anti-inflammatory medications (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors reduce PGE2 production to diminish the inflammation seen in these diseases, but have toxicities that may include both gastrointestinal bleeding and prothrombotic tendencies. In cells, arachidonic acid is transformed into PGE2 via cyclooxygenase (COX) enzymes and terminal prostaglandin E synthases (PGES). Accumulating data suggest that the interaction of various enzymes in the PGE2 synthetic pathway is complex and tightly regulated. In this review, we summarize the synthesis and secretion of PGE2. In particular, we focus on the three isoforms of the terminal PGES, and discuss the potential of targeting PGES as a more precise strategy for inhibiting PGE2 production
— id: 64649, year: 2006, vol: 119, page: 229, stat: Journal Article,

Early-phase PGE(2) production in IL-1-stimulated chondrocytes: Coordinated nuclear localization of COX-1, heat shock protein 90 (Hsp90) and cytosolic prostaglandin e synthase (cPGES)
Park, JY; Marjanovic, N; Attur, M; Al-Mussawir, H; Dave, M; Abeles, AM; Krasnokutsky, S; Pillinger, MH; Abramson, SB
2006 SEP ;54(9):S90-S91, Arthritis & rheumatism
— id: 70103, year: 2006, vol: 54, page: S90, stat: Journal Article,

Editorial: Propylthiouracil and antineutrophil cytoplasmic antibody associated vasculitis: The detective finds a clue
Pillinger, MH; Stand, R
2006 AUG ;36(1):1-3, Seminars in arthritis & rheumatism
— id: 67866, year: 2006, vol: 36, page: 1, stat: Journal Article,

COX-2 inhibitor-mediated disruption of cholesterol transport is abrogated by addition of prostaglandin D-2 or E-2: Anti-atherogenicity of a functional prostaglandin system
Reiss, AB; Zhang, HW; Edelman, SD; Fernandez, P; Cronstein, BN; Pillinger, MH; Ragolia, L; Carsons, S; Chan, ESL
2006 SEP ;54(9):S403-S404, Arthritis & rheumatism
— id: 70118, year: 2006, vol: 54, page: S403, stat: Journal Article,

Farnesyltransferase inhibitors, but not statins, inhibit matrix metalloproteinase-1 (MMP-1) secretion from rheumatoid synovial fibroblasts
Abeles, AM; Marjanovic, N; Al-Mussawir, HE; Abramson, SB; Pillinger, MH
2005 SEP ;52(9):S453-S454, Arthritis & rheumatism
— id: 59284, year: 2005, vol: 52, page: S453, stat: Journal Article,

Simvastatin and geranyl-geranyl transferase inhibitor exhibit chondroprotective effects
Attur, M; Al-Mussawir, H; Abeles, AM; Pillinger, MH; Abramson, SB
2005 SEP ;52(9):S59-S59, Arthritis & rheumatism
— id: 59270, year: 2005, vol: 52, page: S59, stat: Journal Article,

Prostaglandin E2 exerts catabolic effects in OA cartilage: Evidence for signaling via the EP4 receptor
Attur, M; Dave, M; Patel, J; Pillinger, MH; Abramson, SB
2005 SEP ;52(9):S707-S707, Arthritis & rheumatism
— id: 59298, year: 2005, vol: 52, page: S707, stat: Journal Article,

The inflammatory mediator leukotriene B4 (ltb4) exerts catabolic effects on chondrocyte metabolism
Attur, M; Gomez, PF; Patel, J; Al-Mussawir, H; Pillinger, MH; Abramson, SB
2005 SEP ;52(9):S59-S59, Arthritis & rheumatism
— id: 59269, year: 2005, vol: 52, page: S59, stat: Journal Article,

The second annual New York rheumatology objective structured clinical examination (ROSCE): Successful expansion demonstrates feasibility as a large scale rating tool
Berman, J; Fields, T; Azar, N; Pillinger, MH; Lazaro, D; Putterman, C; Bass, A; Reyes, C; Paget, S
2005 SEP ;52(9):S688-S688, Arthritis & rheumatism
— id: 59297, year: 2005, vol: 52, page: S688, stat: Journal Article,

Cox-2-selective inhibitors interfere with cholesterol transport: A possible mechanism for atherogenic effects
Chan, ESL; Zhang, HW; Fernandez, P; Cronstein, BN; Pillinger, MH; Ragolia, L; Carsons, S; Reiss, AB
2005 SEP ;52(9):S354-S354, Arthritis & rheumatism
— id: 59279, year: 2005, vol: 52, page: S354, stat: Journal Article,

Adenosine A(2A) receptor (A(2A)R) mediates dermal fibrosis in scleroderma
Fernandez, P; Montesinos, C; Desai, A; Pillinger, MH; Reiss, AB; Cronstein, BN; Chan, ESL
2005 SEP ;52(9):S364-S364, Arthritis & rheumatism
— id: 59280, year: 2005, vol: 52, page: S364, stat: Journal Article,

Resolution of inflammation: prostaglandin E2 dissociates nuclear trafficking of individual NF-kappaB subunits (p65, p50) in stimulated rheumatoid synovial fibroblasts
Gomez, Paul F; Pillinger, Michael H; Attur, Mukundan; Marjanovic, Nada; Dave, Mander; Park, Jean; Bingham, Clifton O 3rd; Al-Mussawir, Hayf; Abramson, Steven B
2005 Nov 15;175(10):6924-6930, Journal of immunology
NF-kappaB transcription factors regulate inflammatory responses to cytokines such as IL-1beta and TNF-alpha. We tested whether PGE2 regulated nuclear localization of individual NF-kappaB subunits, p65 and p50, in synovial fibroblasts harvested from patients with rheumatoid arthritis (RA). IL-1beta/TNF-alpha stimulated the translocation of p65 and p50 from the cytosol to the nucleus of human RA synovial fibroblasts, as well as NF-kappaB activation measured by luciferase reporter assay. PGE2 (10 nM, 6 h) enhanced p50, but inhibited p65 translocation and NF-kappaB activation. In contrast, depletion of endogenous PGE2 by ibuprofen (100 microM) and celecoxib (5 microM) enhanced p65, but inhibited p50 nuclear translocation as well as binding to NF-kappaB DNA binding sites. PGE2 also blocked IL-1beta/TNF-alpha-stimulated ERK activation, and the ERK inhibitor, PD98059, mimicked PGE2 in blocking p65, but enhancing p50 nuclear translocation, suggesting that the effects of PGE2 on p65 and p50 are mediated via effects on ERK. PGE2 also enhanced the expression of IkappaBalpha in an ERK-independent manner, suggesting that PGE2 inhibits NF-kappaB activation by both ERK-dependent and -independent mechanisms. Our data indicate that PGE2 may act to attenuate cytokine-induced inflammatory responses in RA synovial fibroblasts via regulation of the localization of specific NF-kappaB family dimers
— id: 61340, year: 2005, vol: 175, page: 6924, stat: Journal Article,

Expression and subcellular localization of COX 1 and 2 and their associated terminal synthases, cPGES and mPGES, in Il-1-stimulated chondrocytes
Pillinger, MH; Attur, M; Marjanovic, N; Dave, M; Abeles, AM; Merola, J; Krasnokutsky, S; Abramson, SB
2005 SEP ;52(9):S475-S475, Arthritis & rheumatism
— id: 59288, year: 2005, vol: 52, page: S475, stat: Journal Article,

Annexin-1 peptide Ac2-26 stimulates matrix metalloproteinase secretion in rheumatoid arthritis synovial fibroblasts
Tagoe, CE; Marjanovic, N; Jacobson, DR; Pillinger, MH
2005 SEP ;52(9):S45-S46, Arthritis & rheumatism
— id: 59268, year: 2005, vol: 52, page: S45, stat: Journal Article,

The neutrophil: function and regulation in innate and humoral immunity
Burg ND; Pillinger MH
2001 Apr;99(1):7-17, Clinical immunology
The neutrophil is a critical effector cell in humoral and innate immunity and plays vital roles in phagocytosis and bacterial killing. Discussed here are the neutrophil components necessary for these processes and the diseases in which these components are either lacking or dysfunctional, illustrating that normal neutrophil function is vital for health.
— id: 21216, year: 2001, vol: 99, page: 7, stat: Journal Article,

Regulation of expression of granulocyte-macrophage colony-stimulating factor in human bronchial epithelial cells: roles of protein kinase C and mitogen-activated protein kinases
Reibman J; Talbot AT; Hsu Y; Ou G; Jover J; Nilsen D; Pillinger MH
2000 Aug 1;165(3):1618-1625, Journal of immunology
GM-CSF has a major role in the immune and inflammatory milieu of the airway. Airway epithelial cells (AEC) are among the first targets of environmental stimuli and local cytokines, in response to which they can produce GM-CSF. The regulation of GM-CSF is only minimally understood in AEC. We hypothesized that GM-CSF expression in AEC would result from activation of protein kinase C (PKC) and subsequent activation of the extracellular signal-regulated kinase (MAPKerk1/2) pathway, so we investigated signal transduction pathways in human primary culture bronchial epithelial cells (HBECs). TNF-alpha, IL-1beta, and PMA induced the release of GM-CSF in HBECs. The robust response to PMA was not detected in SV40 adenovirus-transformed normal human bronchial epithelial cells (BEAS-2B). PMA and TNF-alpha stimulation of GM-CSF required activation of PKC (inhibition by staurosporine and bisindolylmaleimide I). GM-CSF expression was up-regulated by a nonphorbol PKC activator, but not by an inactive PMA analogue. PMA-induced GM-CSF production in HBECs did not require a Ca2+ ionophore and was not inhibited by cyclosporin A. Activation of MAPKerk1/2 via PKC was associated with and was required for GM-CSF production induced by PMA and TNF-alpha. The data demonstrate regulation of GM-CSF in HBECs by PKC pathways converging on the MAPKerk1/2 pathway and further define cell-specific regulation critical for local airway responses
— id: 11588, year: 2000, vol: 165, page: 1618, stat: Journal Article,

Phosphatidylinositol 3-kinase mediates chemoattractant-stimulated, CD11b/CD18-dependent cell-cell adhesion of human neutrophils: evidence for an ERK-independent pathway
Capodici C; Hanft S; Feoktistov M; Pillinger MH
1998 Feb 15;160(4):1901-1909, Journal of immunology
We examined the role of phosphatidylinositol 3-kinase (PI 3-K) in FMLP-stimulated cell-cell adhesion of human neutrophils. The specific PI 3-K inhibitors wortmannin and LY294002 inhibited neutrophil homotypic aggregation stimulated by chemoattractants such as FMLP (50% inhibitory concentration (IC50) approximately 11 nM and 13 microM, respectively) but not PMA. Wortmannin also inhibited FMLP-stimulated adhesion of neutrophils to human endothelial cell monolayers, suggesting a common signaling pathway for homotypic and heterotypic adhesion. Neither CD11b/CD18 expression nor expression of an activation-specific epitope of CD11b/CD18 was affected by wortmannin in FMLP-stimulated cells. Moreover, wortmannin also inhibited the aggregation of egranulate neutrophil cytoplasts that lack the capacity for CD11b/CD18 up-regulation. Although wortmannin inhibited neutrophil lysosomal enzyme release, it had no effect on FMLP-stimulated up-regulation of CD35 in intact neutrophils, suggesting discrepant signaling pathways for specific granule degranulation and secretory vesicle release. Aggregation of human neutrophils is associated with activation of the mitogen-activated protein kinases Erk1 and -2, and Erk is activated in response to PI 3-K in some cell types. However, wortmannin inhibited FMLP stimulation of neutrophil Erk only at concentrations (IC50 > or = 1 microM) inconsistent with an effect on PI 3-K. Our data indicate that PI 3-K mediates neutrophil adhesion by a mechanism independent of CD11b/CD18 up-regulation, suggesting that PI 3-K acts either parallel to, or downstream of, Erk
— id: 7522, year: 1998, vol: 160, page: 1901, stat: Journal Article,

Integrin-dependent homotypic adhesion of neutrophils. Arachidonic acid activates Raf-1/Mek/Erk via a 5-lipoxygenase- dependent pathway
Capodici C; Pillinger MH; Han G; Philips MR; Weissmann G
1998 Jul 1;102(1):165-175, Journal of clinical investigation
AA stimulates integrin-dependent neutrophil adhesion, a critical early step in acute inflammation. However, neither the signaling pathway(s) of AA-stimulated adhesion, nor whether AA acts directly or through the generation of active metabolites, has been elucidated. Previously, we have observed a tight association between neutrophil Erk activation and homotypic adhesion in response to chemoattractants acting through G protein-linked receptors. We now report a similar association between homotypic adhesion and Erk activation in response to AA. Erk activation was cyclooxygenase independent and required AA metabolism to 5(S)- hydroperoxyeicosatetraenoic acid (5-HpETE) via 5-lipoxygenase, but not the further lipoxygenase-dependent metabolism of 5-HpETE to leukotrienes. AA stimulation of Erk was accompanied by Raf-1 activation and was sensitive to inhibitors of Raf-1 and Mek. Whereas activation of Erk by AA was pertussis toxin sensitive, [3H]-AA binding to neutrophils was not saturable, suggesting that an AA metabolite activates a G protein. Consistent with this hypothesis, Erk activation by 5(S)-hydroxyeicosatetraenoic acid (5-HETE; lipoxygenase-independent metabolite of 5-HpETE) was also pertussis toxin sensitive. These data suggest that a 5-lipoxygenase metabolite of AA, e.g., 5-HETE, is released from AA-treated cells to engage a plasma membrane-associated, pertussis toxin-sensitive, G protein-linked receptor, leading to activation of Erk and adhesion via the Raf-1/Mek signal transduction pathway
— id: 7521, year: 1998, vol: 102, page: 165, stat: Journal Article,

Wegener's granulomatosis in a patient receiving propylthiouracil for Graves' disease
Pillinger M; Staud R
1998 Oct;28(2):124-129, Seminars in arthritis & rheumatism
CONTEXT: The use of propylthiouracil (PTU) in patients with Graves' disease has been associated with multiple complications including rash, leukocytoclastic vasculitis, pulmonary hemorrhage, glomerulonephritis, and the presence of perinuclear antineutrophilic cytoplasmic antibodies (pANCA). OBJECTIVES: To report the association of Wegener's granulomatosis (WG) with the use of PTU in a patient with Graves' disease and to review the spectrum of systemic vasculitis seen in patients with Graves' disease taking PTU. DESIGN: Retrospective review of data collected in a patient with WG. In addition, a Medline search (1980 to present) for PTU-associated vasculitis was conducted. RESULTS: We report WG in a patient treated with PTU who fulfilled the criteria of the American College of Rheumatology for this disease. Furthermore, his serum was positive for cytosolic antineutrophil cytoplasmic antibodies (cANCA) and anti-proteinase-3 (PR3) antibodies by indirect immunofluorescence and enzyme linked immunosorbent assay (ELISA), respectively. WG is associated with high morbidity and mortality and usually requires extensive therapy with prednisone and cyclophosphamide. Our patient, however, did not need specific therapy except discontinuation of PTU to make a full recovery. In previous reports, PTU has been associated with different forms of vasculitis, but this is a the first description of classic WG in a patient treated with PTU. CONCLUSIONS: PTU is capable of causing WG in susceptible patients with Graves' disease. Our patient did not require specific therapy for vasculitis and improved after discontinuation of PTU
— id: 7425, year: 1998, vol: 28, page: 124, stat: Journal Article,

Modes of action of aspirin-like drugs: salicylates inhibit erk activation and integrin-dependent neutrophil adhesion
Pillinger MH; Capodici C; Rosenthal P; Kheterpal N; Hanft S; Philips MR; Weissmann G
1998 Nov 24;95(24):14540-14545, Proceedings of the National Academy of Sciences of the United States of America
The anti-inflammatory effects of high-dose salicylates are well recognized, incompletely understood and unlikely due entirely to cyclooxygenase (COX) inhibition. We have previously reported a role for activation of the kinase Erk in CD11b/CD18 integrin-dependent adhesiveness of human neutrophils, a critical step in inflammation. We now report the effects of salicylates on neutrophil Erk and adhesion. Exposure of neutrophils to aspirin or sodium salicylate (poor COX inhibitor) inhibited Erk activity and adhesiveness of formylmethionyl-leucyl-phenylalanine- and arachidonic acid-stimulated neutrophils, consistent with anti-inflammation but not COX inhibition (IC50s = 1-8 mM). In contrast, indomethacin blocked neither Erk nor adhesion. Inhibition of Mek (proximal activator of Erk) also blocked stimulation of Erk and adhesion by formylmethionyl-leucyl-phenylalanineand arachidonic acid. Salicylate inhibition of Erk was independent of protein kinase A activation and generation of extracellular adenosine. These data are consistent with a role for Erk in stimulated neutrophil adhesion, and suggest that anti-inflammatory effects of salicylates may be mediated via inhibition of Erk signaling required for integrin-mediated responses
— id: 7745, year: 1998, vol: 95, page: 14540, stat: Journal Article,

Mechanisms of neutrophil adhesion: Inhibitors of ERK block neutrophil aggregation and adhesion to endothelial cell monolayers
Rosenthal, P; Capodici, C; Weissmann, G; Pillinger, MH
1998 SEP ;41(9):S243-S243, Arthritis & rheumatism
— id: 53744, year: 1998, vol: 41, page: S243, stat: Journal Article,

Reiter's syndrome among Asian shipboard immigrants: the case of The Golden Venture
Solitar BM; Lozada CJ; Tseng CE; Lowe AM; Krajewski WM; Blanchard K; Pillinger M; Weissman G
1998 Apr;27(5):293-300, Seminars in arthritis & rheumatism
OBJECTIVE: To assess the incidence of Reiter's syndrome aboard The Golden Venture, a ship carrying illegal immigrants from China to the United States. METHODS: After identification of an index case, we conducted telephone interviews with medical staff at immigrant detention centers in Pennsylvania, New York, and Virginia. When a potential case was identified at one facility, we performed a site inspection, reviewing the medical records of all detainees and performing histories and physicals on all those with joint and/or ocular complaints. RESULTS: We identified two patients, both HLA B27 positive, with Reiter's syndrome. The observed incidence (0.87%) approximated the predicted incidence but may have underestimated the actual incidence. We review the history of shipboard Reiter's syndrome, and discuss the pathogenic roles of HLA B27 and particular infectious agents. CONCLUSION: Continued transportation of illegal immigrants from China and other parts of the world is likely to result in occasional clusters of Reiter's syndrome. Physicians treating immigrant populations should remain aware of the possibility of reactive arthritis
— id: 7801, year: 1998, vol: 27, page: 293, stat: Journal Article,

Inflammation and anti-inflammation: gating of cell/cell adhesion at the level of mitogen-activated protein kinases
Pillinger MH; Capodici C; Han G; Weissmann G
1997 Dec 15;832:1-12, Annals of the New York Academy of Sciences
— id: 7744, year: 1997, vol: 832, page: 1, stat: Journal Article,

Mitogen-activated protein kinase in neutrophils and enucleate neutrophil cytoplasts: evidence for regulation of cell-cell adhesion
Pillinger MH; Feoktistov AS; Capodici C; Solitar B; Levy J; Oei TT; Philips MR
1996 May 17;271(20):12049-12056, Journal of biological chemistry
We employed neutrophils and enucleate neutrophil cytoplasts to study the activation of the mitogen-activated protein kinases (MAPKs) p44erk1 and p42erk2 in neutrophils by inflammatory agonists that engage G protein-linked receptors. Formyl-methionyl-leucyl-phenylalanine (FMLP) rapidly and transiently activated MAPK in neutrophils and cytoplasts, consistent with a role in signaling for neutrophil functions. FMLP stimulated p2lras activation in neutrophils and Raf-1 translocation from cytosol to plasma membrane in cytoplasts, with kinetics consistent with events upstream of MAPK activation. Insulin, a protein tyrosine kinase receptor (PTKR) agonist, stimulated neutrophil MAPK activation, demonstrating an intact system of PTKR signaling in these post-mitotic cells. FMLP- and insulin-stimulated MAPK activation in cytoplasts were inhibited by Bt2cAMP, consistent with signaling through Raf-1 and suggesting a mechanism for cAMP inhibition of neutrophil function. However, Bt2cAMP had no effect on FMLP-stimulated MAPK activation in neutrophils. The extent of MAPK activation by various chemoattractants correlated with their capacity to stimulate neutrophil and cytoplast homotypic aggregation. Consistent with its effects on MAPK, Bt2cAMP inhibited FMLP-stimulated aggregation in cytoplasts but not neutrophils. Insulin had no independent effect but primed neutrophils for aggregation in response to FMLP. Our studies support a p2lras-, Raf-1-dependent pathway for MAPK activation in neutrophils and suggest that neutrophil adhesion may be regulated, in part, by MAPK
— id: 8311, year: 1996, vol: 271, page: 12049, stat: Journal Article,

Translocation of p21rac2 from cytosol to plasma membrane is neither necessary nor sufficient for neutrophil NADPH oxidase activity
Philips MR; Feoktistov A; Pillinger MH; Abramson SB
1995 May 12;270(19):11514-11521, Journal of biological chemistry
Activation of the membrane-associated NADPH oxidase of neutrophils requires several cytosolic factors including p47phox, p67phox and p21rac2. We compared NADPH oxidase activity with the membrane translocation of p47phox, p67phox, and p21rac2. In a cell-free system, GTP gamma S stimulated translocation of p47phox and p67phox to the plasma membrane only in the presence of arachidonate, and this translocation correlated with NADPH oxidase activity of the reisolated plasma membranes (R = 0.94 and 0.97, respectively). In contrast, GTP gamma S-stimulated p21rac2 translocation with or without arachidonate, and the extent of translocation did not correlate with oxidase activity (R = 0.17). Neutrophil cytoplasts were used to relate membrane translocation of p47phox, p67phox and p21rac2 to membrane oxidase activity in response to the inflammatory agonists. Whereas N-formyl-methionyl-leucyl-phenylalanine stimulated equimolar, transient membrane translocation of p47phox and p67phox which kinetically paralleled NADPH oxidase activity, relatively little p21rac2 translocated (moles of p47phox/p21rac2 = 16.6). Moreover, although phorbol 12-myristate 13-acetate stimulated both the stable translocation of p47phox and p67phox and sustained NADPH oxidase activity, it did not stimulate p21rac2 translocation. From these data we conclude that membrane translocation of p21rac2 does not regulate NADPH oxidase activity stoichiometrically
— id: 6712, year: 1995, vol: 270, page: 11514, stat: Journal Article,

Prenylcysteine-directed carboxyl methyltransferase activity in human neutrophil membranes
Philips MR; Pillinger MH
1995 ;256:49-63, Methods in enzymology
— id: 12854, year: 1995, vol: 256, page: 49, stat: Journal Article,

Activation-dependent carboxyl methylation of neutrophil G-protein gamma subunit
Philips MR; Staud R; Pillinger M; Feoktistov A; Volker C; Stock JB; Weissmann G
1995 Mar 14;92(6):2283-2287, Proceedings of the National Academy of Sciences of the United States of America
The gamma subunits of heterotrimeric guanine nucleotide-binding regulatory (G) proteins (G gamma) are post-translationally processed at their C termini by prenylation, proteolysis, and carboxyl methylation. Whereas prenylation of G gamma is required for membrane association of G proteins, the role of carboxyl methylation is unknown. Here we show that human neutrophils express G gamma 2 but not G gamma 3 or G gamma 7 and that carboxyl methylation of G gamma 2 is associated with signal transduction. In a reconstituted cell-free system, neutrophil G gamma 2 was labeled by the methyl donor S-[methyl-3H]adenosyl-L-methionine. Carboxyl methylation was confirmed by alkaline hydrolysis and quantitation of volatile [3H]methanol. Neutrophil G gamma 2 methylation was stimulated by activation of G protein with guanosine 5'-[beta, gamma-thio]triphosphate. We estimate that after 1 hr of G-protein activation at least 6% of the total pool of G gamma 2 was carboxyl-methylated. The inflammatory agonist fMet-Leu-Phe stimulated guanosine 5'-[beta,gamma-thio]triphosphate-dependent carboxyl methylation. Methylation of G gamma 2 was inhibited by the carboxyl methyltransferase inhibitor N-acetyl-S-trans,trans-farnesylcysteine at concentrations that affected signal transduction in neutrophils. These results demonstrate that activation of neutrophil Gi is associated with alpha-carboxyl methyl esterification of G gamma 2 and suggest that carboxyl methylation of G gamma may play a role in signal transduction
— id: 6713, year: 1995, vol: 92, page: 2283, stat: Journal Article,

CARBOXYL METHYLATION OF RHO-FAMILY RAS-RELATED PROTEINS IN HUMAN NEUTROPHILS IS ASSOCIATED WITH ACTIN POLYMERIZATION
PHILIPS, MR; FEOKTISTOV, AS; PILLINGER, MH
1995 SEP ;38(9):159-159, Arthritis & rheumatism
— id: 86687, year: 1995, vol: 38, page: 159, stat: Journal Article,

The neutrophil in rheumatoid arthritis
Pillinger MH; Abramson SB
1995 Aug;21(3):691-714, Rheumatic diseases clinics of North America
The destructive capacity of the neutrophil has long been appreciated, and the presence of extraordinary numbers of neutrophils in the synovial fluid of patients with RA supports a role for these cells in the pathogenesis of joint destruction. In this article, we reviewed the current state of knowledge of neutrophil function in the inflammatory response, and emphasized the subjects of neutrophil/endothelial adhesion and the role of chemoattractants and cytokines in neutrophil mobilization. We also discussed the mechanisms of action of neutrophil destruction of cartilage and the interplay of signals between the neutrophil and the chondrocyte. The capacity of many of the drugs used to treat RA to interfere with one or several of these processes underscores the importance of the neutrophil in RA and suggests that future therapeutic strategies could target neutrophil activation within the synovial space
— id: 8014, year: 1995, vol: 21, page: 691, stat: Journal Article,

Crosstalk in signal transduction via EP receptors: prostaglandin E1 inhibits chemoattractant-induced mitogen-activated protein kinase activity in human neutrophils
Pillinger MH; Philips MR; Feoktistov A; Weissmann G
1995 ;23:311-316, Advances in prostaglandin thromboxane & leukotriene research
— id: 6714, year: 1995, vol: 23, page: 311, stat: Journal Article,

CROSSTALK IN SIGNAL-TRANSDUCTION VIA EP RECEPTORS - PROSTAGLANDIN E(1) INHIBITS CHEMOATTRACTANT-INDUCED MITOGEN-ACTIVATED PROTEIN-KINASE ACTIVITY IN HUMAN NEUTROPHILS
PILLINGER, MH; PHILIPS, MR; FEOKTISTOV, A; WEISSMANN, G
1995 FEB ;23(2):311-316, Advances in prostaglandin & thromboxane research
— id: 87404, year: 1995, vol: 23, page: 311, stat: Journal Article,

Characterization of a plasma membrane-associated prenylcysteine-directed alpha carboxyl methyltransferase in human neutrophils
Pillinger MH; Volker C; Stock JB; Weissmann G; Philips MR
1994 Jan 14;269(2):1486-1492, Journal of biological chemistry
Signal transduction in human neutrophils requires prenylcysteine-directed carboxyl methylation of ras-related low molecular weight GTP-binding proteins. We now report the subcellular localization and characterization of a neutrophil prenylcysteine alpha carboxyl methyltransferase. The highest carboxyl methyltransferase activity copurified with biotinylated neutrophil surface membranes, supporting a plasma membrane localization of the enzyme. Neutrophil nuclear fractions contained little or no methyltransferase activity. Methyltransferase activity was detergent-sensitive but could be reconstituted by removal of detergent in the presence of phosphatidyl choline and an anionic phospholipid. N-Acetyl-S-trans,trans-farnesyl-L-cysteine (AFC) and N-acetyl-S-all-trans-geranylgeranyl-L-cysteine (AGGC) were effective substrates for neutrophil prenylcysteine-directed methyltransferase; Vmax values for AFC and AGGC (16.4 and 22.1 pmol of methylated/mg protein/min, respectively) are among the highest yet reported. Although both GTP gamma S and the chemoattractant fMet-Leu-Phe stimulated methylation of ras-related proteins, neither affected methylation of AFC. These data suggest that neutrophil plasma membranes contain a phospholipid-dependent, prenylcysteine-directed carboxyl methyltransferase of relatively high specific activity that modifies ras-related protein substrates in the GTP-bound, activated state
— id: 6485, year: 1994, vol: 269, page: 1486, stat: Journal Article,

Carboxyl methylation of Ras-related proteins during signal transduction in neutrophils
Philips MR; Pillinger MH; Staud R; Volker C; Rosenfeld MG; Weissmann G; Stock JB
1993 Feb 12;259(5097):977-980, Science
In human neutrophils, as in other cell types, Ras-related guanosine triphosphate-binding proteins are directed toward their regulatory targets in membranes by a series of posttranslational modifications that include methyl esterification of a carboxyl-terminal prenylcysteine residue. In intact cells and in a reconstituted in vitro system, the amount of carboxyl methylation of Ras-related proteins increased in response to the chemoattractant N-formyl-methionyl-leucyl-phenylalanine (FMLP). Activation of Ras-related proteins by guanosine-5'-O-(3-thiotriphosphate) had a similar effect and induced translocation of p22rac2 from cytosol to plasma membrane. Inhibitors of prenylcysteine carboxyl methylation effectively blocked neutrophil responses to FMLP. These findings suggest a direct link between receptor-mediated signal transduction and the carboxyl methylation of Ras-related proteins
— id: 13250, year: 1993, vol: 259, page: 977, stat: Journal Article,

LIGATION OF THE NEUTROPHIL FORMYL PEPTIDE RECEPTOR INDUCES CARBOXYL METHYLATION OF G-GAMMA
STAUD, R; PILLINGER, MH; WEISSMANN, G; PHILIPS, MR
1992 SEP ;35(9):S137-S137, Arthritis & rheumatism
— id: 74222, year: 1992, vol: 35, page: S137, stat: Journal Article,