Geraldine M. McCarthy

EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee For International Clinical Studies Including Therapeutics (ESCISIT)

Objective: To develop evidence based recommendations for the management of gout. Methods: The multidisciplinary guideline development group comprised 19 rheumatologists and one evidence based medicine expert representing 13 European countries. Key propositions on management were generated using a Delphi consensus approach. Research evidence was searched systematically for each proposition. Where possible, effect size (ES), number needed to treat, relative risk, odds ratio, and incremental cost-effectiveness ratio were calculated. The quality of evidence was categorised according to the level of evidence. The strength of recommendation (SOR) was assessed using the EULAR visual analogue and ordinal scales. Results: 12 key propositions were generated after three Delphi rounds. Propositions included both non-pharmacological and pharmacological treatments and addressed symptomatic control of acute gout, urate lowering therapy (ULT), and prophylaxis of acute attacks. The importance of patient education, modification of adverse lifestyle (weight loss if obese; reduced alcohol consumption; low animal purine diet) and treatment of associated comorbidity and risk factors were emphasised. Recommended drugs for acute attacks were oral non-steroidal anti-inflammatory drugs (NSAIDs), oral colchicine (ES = 0.87 (95% confidence interval, 0.25 to 1.50)), or joint aspiration and injection of corticosteroid. ULT is indicated in patients with recurrent acute attacks, arthropathy, tophi, or radiographic changes of gout. Allopurinol was confirmed as effective long term ULT (ES = 1.39 (0.78 to 2.01)). If allopurinol toxicity occurs, options include other xanthine oxidase inhibitors, allopurinol desensitisation, or a uricosuric. The uricosuric benzbromarone is more effective than allopurinol (ES = 1.50 (0.76 to 2.24)) and can be used in patients with mild to moderate renal insufficiency but may be hepatotoxic. When gout is associated with the use of diuretics, the diuretic should be stopped if possible. For prophylaxis against acute attacks, either colchicine 0.5–1 mg daily or an NSAID (with gastroprotection if indicated) are recommended. Conclusions: 12 key recommendations for management of gout were developed, using a combination of research based evidence and expert consensus. The evidence was evaluated and the SOR provided for each proposition.

EULAR evidence-based recommendations for the management of fibromyalgia syndrome

Objective: To develop evidence-based recommendations for the management of fibromyalgia syndrome. Methods: A multidisciplinary task force was formed representing 11 European countries. The design of the study, including search strategy, participants, interventions, outcome measures, data collection and analytical method, was defined at the outset. A systematic review was undertaken with the keywords “fibromyalgia”, “treatment or management” and “trial”. Studies were excluded if they did not utilise the American College of Rheumatology classification criteria, were not clinical trials, or included patients with chronic fatigue syndrome or myalgic encephalomyelitis. Primary outcome measures were change in pain assessed by visual analogue scale and fibromyalgia impact questionnaire. The quality of the studies was categorised based on randomisation, blinding and allocation concealment. Only the highest quality studies were used to base recommendations on. When there was insufficient evidence from the literature, a Delphi process was used to provide basis for recommendation. Results: 146 studies were eligible for the review. 39 pharmacological intervention studies and 59 non-pharmacological were included in the final recommendation summary tables once those of a lower quality or with insufficient data were separated. The categories of treatment identified were antidepressants, analgesics, and “other pharmacological” and exercise, cognitive behavioural therapy, education, dietary interventions and “other non-pharmacological”. In many studies sample size was small and the quality of the study was insufficient for strong recommendations to be made. Conclusions: Nine recommendations for the management of fibromyalgia syndrome were developed using a systematic review and expert consensus.

Proinflammatory Activation of Macrophages by Basic Calcium Phosphate Crystals via Protein Kinase C and MAP Kinase Pathways: A Vicious Cycle of Inflammation and Arterial Calcification?

Basic calcium phosphate (BCP) crystal deposition underlies the development of arterial calcification. Inflammatory macrophages colocalize with BCP deposits in developing atherosclerotic lesions and in vitro can promote calcification through the release of TNF alpha. Here we have investigated whether BCP crystals can elicit a proinflammatory response from monocyte-macrophages. BCP microcrystals were internalized into vacuoles of human monocyte-derived macrophages in vitro. This was associated with secretion of proinflammatory cytokines (TNFα, IL-1β and IL-8) capable of activating cultured endothelial cells and promoting capture of flowing leukocytes under shear flow. Critical roles for PKC, ERK1/2, JNK, but not p38 intracellular signaling pathways were identified in the secretion of TNF alpha, with activation of ERK1/2 but not JNK being dependent on upstream activation of PKC. Using confocal microscopy and adenoviral transfection approaches, we determined a specific role for the PKC-alpha isozyme. The response of macrophages to BCP crystals suggests that pathological calcification is not merely a passive consequence of chronic inflammatory disease but may lead to a positive feed-back loop of calcification and inflammation driving disease progression.

Calcium Phosphate Crystals Induce Cell Death in Human Vascular Smooth Muscle Cells: A Potential Mechanism in Atherosclerotic Plaque Destabilization

Vascular calcification is associated with an increased risk of myocardial infarction; however, the mechanisms linking these 2 processes are unknown. Studies in macrophages have suggested that calcium phosphate crystals induce the release of proinflammatory cytokines; however, no studies have been performed on the effects of calcium phosphate crystals on vascular smooth muscle cell function. In the present study, we found that calcium phosphate crystals induced cell death in human aortic vascular smooth muscle cells with their potency depending on their size and composition. Calcium phosphate crystals of approximately 1 &mgr;m or less in diameter caused rapid rises in intracellular calcium concentration, an effect that was inhibited by the lysosomal proton pump inhibitor, bafilomycin A1. Bafilomycin A1 also blocked vascular smooth muscle cell death suggesting that crystal dissolution in lysosomes leads to an increase in intracellular calcium levels and subsequent cell death. These studies give novel insights into the bioactivity of calcified deposits and suggest that small calcium phosphate crystals could destabilize atherosclerotic plaques by initiating inflammation and by causing vascular smooth muscle cell death.

EULAR revised recommendations for the management of fibromyalgia

Objective The original European League Against Rheumatism recommendations for managing fibromyalgia assessed evidence up to 2005. The paucity of studies meant that most recommendations were ‘expert opinion’. Methods A multidisciplinary group from 12 countries assessed evidence with a focus on systematic reviews and meta-analyses concerned with pharmacological/non-pharmacological management for fibromyalgia. A review, in May 2015, identified eligible publications and key outcomes assessed were pain, fatigue, sleep and daily functioning. The Grading of Recommendations Assessment, Development and Evaluation system was used for making recommendations. Results 2979 titles were identified: from these 275 full papers were selected for review and 107 reviews (and/or meta-analyses) evaluated as eligible. Based on meta-analyses, the only ‘strong for’ therapy-based recommendation in the guidelines was exercise. Based on expert opinion, a graduated approach, the following four main stages are suggested underpinned by shared decision-making with patients. Initial management should involve patient education and focus on non-pharmacological therapies. In case of non-response, further therapies (all of which were evaluated as ‘weak for’ based on meta-analyses) should be tailored to the specific needs of the individual and may involve psychological therapies (for mood disorders and unhelpful coping strategies), pharmacotherapy (for severe pain or sleep disturbance) and/or a multimodal rehabilitation programme (for severe disability). Conclusions These recommendations are underpinned by high-quality reviews and meta-analyses. The size of effect for most treatments is relatively modest. We propose research priorities clarifying who will benefit from specific interventions, their effect in combination and organisation of healthcare systems to optimise outcome.

Microcalcifications Associated with Breast Cancer: An Epiphenomenon or Biologically Significant Feature of Selected Tumors?

Radiographic mammary calcifications occur in 30–50% of breast cancers and constitute one of the most important diagnostic markers of both benign and malignant lesions of the breast. The presence of oxalate-type microcalcification appears to be a reliable criterion in favor of the benign nature of the lesion or, at most, of a lobular carcinoma in situ. In contrast, calcium hydroxyapatite (HA) crystals are associated with both benign and malignant breast tumors. Although the diagnostic value of microcalcifications in breast cancer is of great importance, the genesis of these calcifications is unclear. Despite numerous histological ultrastructure studies of HA deposits in breast carcinomas, to date there have been limited investigations of the potential role of these crystals in breast cancer. We review the literature examining the biological effects of HA crystals in breast cancer cell lines, specifically the mechanism of HA-induced mitogenesis and upregulation of gene expression.

Detection of calcium phosphate crystals in the joint fluid of patients with osteoarthritis – analytical approaches and challenges

Clinically, osteoarthritis (OA) is characterised by joint pain, stiffness after immobility, limitation of movement and, in many cases, the presence of basic calcium phosphate (BCP) crystals in the joint fluid. The detection of BCP crystals in the synovial fluid of patients with OA is fraught with challenges due to the submicroscopic size of BCP, the complex nature of the matrix in which they are found and the fact that other crystals can co-exist with them in cases of mixed pathology. Routine analysis of joint crystals still relies almost exclusively on the use of optical microscopy, which has limited applicability for BCP crystal identification due to limited resolution and the inherent subjectivity of the technique. The purpose of this Critical Review is to present an overview of some of the main analytical tools employed in the detection of BCP to date and the potential of emerging technologies such as atomic force microscopy (AFM) and Raman microspectroscopy for this purpose.

Basic calcium phosphate crystals activate human osteoarthritic synovial fibroblasts and induce matrix metalloproteinase-13 (collagenase-3) in adult porcine articular chondrocytes

OBJECTIVE To determine the ability of basic calcium phosphate (BCP) crystals to induce (a) mitogenesis, matrix metalloproteinase (MMP)-1, and MMP-13 in human osteoarthritic synovial fibroblasts (HOAS) and (b) MMP-13 in cultured porcine articular chondrocytes. METHODS Mitogenesis of HOAS was measured by [3H]thymidine incorporation assay and counts of cells in monolayer culture. MMP messenger RNA (mRNA) accumulation was determined either by northern blot analysis or reverse transcriptase-polymerase chain reaction (RT-PCR) of RNA from chondrocytes or HOAS treated with BCP crystals. MMP-13 secretion was identified by immunoprecipitation and MMP-1 secretion by western blot of conditioned media. RESULTS BCP crystals caused a 4.5-fold increase in [3H]thymidine incorporation by HOAS within 20 hours compared with untreated control cultures (p⩽0.05). BCP crystals induced MMP-13 mRNA accumulation and MMP-13 protein secretion by articular chondrocytes. In contrast, in HOAS, MMP-13 mRNA induced by BCP crystals was detectable only by RT-PCR, and MMP-13 protein was undetectable. BCP crystals induced MMP-1 mRNA accumulation and MMP-1 protein secretion by HOAS. MMP-1 expression was further augmented when HOAS were co-incubated with either BCP and tumour necrosis factor α (TNFα; threefold) or BCP and interleukin 1α (IL1α; twofold). CONCLUSION These data confirm the ability of BCP crystals to activate HOAS, leading to the induction of mitogenesis and MMP-1 production. MMP-13 production in response to BCP crystals is substantially more detectable in porcine articular chondrocytes than in HOAS. These data support the active role of BCP crystals in osteoarthritis and suggest that BCP crystals act synergistically with IL1α and TNFα to promote MMP production and subsequent joint degeneration.

Calcium hydroxyapatite promotes mitogenesis and matrix metalloproteinase expression in human breast cancer cell lines

Radiographic mammary microcalcifications are one of the most pertinent diagnostic markers of breast cancer. Breast tissue calcification in the form of calcium hydroxyapatite (HA) is strongly associated with malignant disease. We tested the hypothesis that calcium HA may exert biological effects on surrounding cells, thereby facilitating breast cancer progression. Our findings showed that HA crystals enhanced mitogenesis in breast cancer cell lines MCF‐7 and Hs578T and also in normal human mammary epithelial cells. HA crystals were also found to upregulate the production of a variety of matrix metalloproteinases (MMPs), including MMP‐2, ‐9, and ‐13 in MCF‐7 and MMP‐9 in human mammary epithelial cell lines. HA crystals were found to greatly augment prostaglandin E2 levels in Hs578T cells, and treatment with a cyclooxygenase inhibitor, aspirin, abrogated the HA‐induced mitogenesis. These results suggest that calcium HA crystals may play an active role in amplifying the pathological process involved in breast cancer.

Primary care-based dermatology practice: internists need more training.

Objective:To evaluate the ability of teachers in an internal medicine clinic to appropriately diagnose, treat, and refer for specific dermatologic disorders.Design:Prospective study.Setting:Medical school-affiliated primary care clinic.Patients/participants:Case presentations of 20 patients who had dermatologic problems were prepared in the form of photographs with accompanying histories. All cases were presented to 17 of 21 available faculty internists who answered questions concerning diagnosis and management of the cases on a questionnaire. The responses of three board-certified faculty dermatologists were used as a reference standard.Measurements and main results:The internists had had an average of three weeks’ total formal dermatology training. Overall, 60% of cases were correctly diagnosed by the internists and 89% of these were either treated appropriately or referred to dermatologists. In 40% of incorrectly diagnosed cases, internists failed to refer and the majority of these were treated inappropriately. Of referrals deemed appropriate by dermatologists, only 62% were made. Conversely, 33% of referrals were deemed unnecessary.Conclusions:Faculty internists were able to diagnose many common skin diseases despite having received little dermatology training. However, errors in diagnosis occurred frequently and when diagnoses were incorrect there was a tendency to mismanage. These data suggest that the current amount of dermatology training is inadequate to prepare future primary care physicians for their increased role in the management of skin disorders.