Faculty Bibliography

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

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

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

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

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

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

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