CLINICAL DETERMINANTS OF QUALITY OF LIFE IN PAGET'S DISEASE OF BONE.

A.L. LANGSTON1, M.K. CAMPBELL1, W.D. FRASER2, G. MACLENNAN1, P. SELBY3 and S.H. RALSTON4 FOR THE PRISM TRIAL GROUP.

1 Health Services Research Unit, University of Aberdeen, UK 2 Department of Clinical Biochemistry, University of Liverpool, UK 3 Department of Medicine, University of Manchester, UK 4 Rheumatic Diseases Unit, University of Edinburgh, UK.

Paget's disease of bone (PDB) is a common condition but its impact on health related quality of life and the clinical determinants of quality of life are unknown. Here we analysed the clinical; determinants of health related quality of life in a large cohort of PDB patients attending secondary care referral centres in the United Kingdom. Relevant clinical details on patterns of skeletal involvement, previous treatment and complications were collected by questionnaire in 1324 subjects with PDB who were enrolled in a randomised controlled trial of intensive bisphosphonate therapy versus symptomatic treatment (the PRISM study). Health related quality of life was assessed by completion of the Short-Form Health Survey Questionnaire (SF36). Clinical predictors of quality of life were assessed by univariate and multivariate regression analysis. The physical component summary score of SF36 was significantly reduced in PDB compared with population norms (36.3 ± 11.3 vs. 50) and univariate analysis identified several predictors of a reduced score including; bone pain due to PDB (p<0.001); age (p<0.001); time since diagnosis (p=0.004); number of bones involved (p=0.032); female gender (p=0.007), previous bisphosphonate therapy (p<0.001), previous orthopaedic surgery (p=0.013) and being widowed, single or divorced (p=0.008). On multivariate analysis, independent predictors of reduced physical scores were; pain due to PDB, previous bisphosphonate therapy and increasing age (p<0.001). Mental component summary scores were relatively normal in PDB (48.7 ± 11.8 vs. 50). Surprisingly, patients who had prior bisphosphonate therapy and normal serum total alkaline phosphatase (ALP) levels had the worst physical summary scores and more bodily pain than the remainder of the study population (p<0.001). We conclude that PDB has a negative impact on health related quality of life, which mainly affects physical functioning. Pagetic bone pain was less frequent in patients with normal ALP who have previously received bisphosphonates, but paradoxically quality of life and total bodily pain were worse in this group. The study emphasises the complex nature of pain in PDB and emphasises the importance of taking quality of life measures into account when planning therapeutic interventions.

DIETARY N-3 FATTY ACIDS AS NON-STEROIDAL ANTI-INFLAMMATORY DRUG SPARING AGENTS IN RHEUMATOID ARTHRITIS

B. GALARRAGA1, H.M. YOUSSEF2, M. HO1, A. HILL1, C. HALL2, S. OGSTON3, G. NUKI2 and J.J.F. BELCH1.

1Vascular and Inflammatory Diseases Research Unit, University Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee; 2Rheumatic Diseases Unit, Western General Hospital, Edinburgh, 3 Public health Section, Community Health Science Division, University of Dundee, Dundee.

Background: Non-steroidal anti-inflammatory drugs (NSAID) are frequently used in the management of patients with rheumatoid arthritis (RA). Dose dependant gastrointestinal and cardiovascular side effects are common, limiting their use. N-3 essential fatty acids have previously demonstrated some anti-inflammatory and NSAID sparing properties. The objective of this study was to determine whether fish oil supplementation reduces the daily NSAID requirement of patients with RA.

Methods: This was a dual centre, double blind placebo controlled, randomised study of 9 months duration. Ninety-seven patients with RA were randomised to take either 10g of marine oil (Seven Seas Ltd) containing 2.2g of n-3 essential fatty acids (32% docosahexaenoic acid, 68% eicosapentaenoic acid) a day or air filled identical placebo capsules. NSAID daily requirement, clinical and laboratory parameters of RA disease activity and safety checks were done at 0, 4, 12, 24 and 36 weeks. At 12 weeks patients were instructed to gradually reduce and if possible stop their NSAID intake. Reduction of NSAID intake by at least 30% without an associated flare in disease activity was the primary endpoint.

Results: Both groups were matched for baseline characteristics. 29/49 patients who received marine oil and 23/48 of the placebo treated patients completed the study. 17 out of 29 (59%) patients in the active group and 5 out of 23 (22%) patients in the placebo group were able to reduce their daily NSAID requirement by more than 30%. (p= 0.08 Chi-squared test). There was a significant improvement in the visual analogue scale of pain in the active group (p=0.032 Mann-Whitney test), but no differences between the groups were observed in the remaining clinical parameters of RA disease activity or in the type or number of side effects observed. Plasma measurements of eicosapentanoic acid and returned tablet counts suggested good compliance.

Conclusions: More than half of the patients who took marine oil supplements for 9 months were able to reduce NSAI therapy without any change in disease activity. This study confirms that fish oil supplements containing N-3 fatty acids can be NSAID sparing agents in RA patients.

AUDIT OF FEASIBILITY AND IMPLEMENTATION OF THE SCOTTISH EARLY WARNING SCORING ON A RHEUMATOLOGY WARD

DICHELLE WONG, VEENA B DHILLON, C MICHAEL LAMBERT

Rheumatic Diseases Unit, University of Edinburgh

Purpose There is often documented deterioration of physiological parameters before patients become critically ill. The Scottish Early Warning Scoring (SEWS) chart is a colour-coded chart for documenting patient physiological parameters including pulse, respiratory rate, oxygen saturation, temperature and blood pressure. SEWS dictates the frequency of observations and the threshold for prompting medical review.

A 1-month audit was used to assess the feasibility of implementing SEWS routinely in rheumatology in-patients at the Edinburgh Western General Hospital (WGH). A 6-month prospective study was used to record patient outcome and to assess whether patients at risk of deterioration are identified for early interventions that might prevent catastrophic deterioration or admission to critical care units.

Methods The rheumatology nursing team was trained in the use of SEWS. Rheumatology in-patients at WGH during September 2004 had observations documented using SEWS charts. The charts were examined retrospectively to assess the rate of complete documentation of physiological parameters. Questionnaires were used to assess staff satisfaction.

During the 6-month study, SEWS was used to guide the frequency of measuring observations and the threshold for prompting medical review. SEWS charts and clinical notes of rheumatology in-patients at WGH from November 2004 to May 2005 were examined.

Results During the 1-month audit, 84.2% of patients (n=19) had complete documentation of physiological parameters using SEWS. 85% of the nursing team agreed that a tool is required to identify sick patients; 100% agreed that the SEWS score was easy to calculate; 77% agreed that SEWS was helpful in identifying sick patients and 85% agreed that SEWS prompted earlier intervention.

Data was collected from 117 patients during the 6-month prospective study. Eighty-eight patients had a maximum SEWS score of 2 or less; 8 patients with a score of 3; 2 with a score of 4; 2 with a score of 5 and 1 with a score of 6 (see Figure 1). All the patients with SEWS score of 3 or more were identified and reviewed by medical staff. Seven of these patients required additional intervention. There was no mortality and no transfers to critical care units.

Conclusions SEWS charts were feasible to use on the Rheumatology ward. There was a high rate of full documentation of physiological parameters after the introduction of SEWS. SEWS charts were an easy-to-use bedside tool for alerting nursing and medical teams that patients are at risk of deteriorating.

Patients with high SEWS scores were reviewed, and additional treatment was initiated when appropriate. Early identification of ill patients and intervention was achieved.

Figure 1. The maximum SEWS score during admission. (Emergency = patients admitted as emergency; Elective= patients admitted electively)

GUEST LECTURE: "OPTIMISING THE USE OF CONVENTIONAL DMARD TREATMENT IN RA".

PROF. HILARY A CAPELL MB, BCH, BA, MD, FRCP Professor/Consultant Rheumatologist

Born in Johannesburg, South Africa, Dr Capell graduated from the University of Witwatersrand in 1972. She came to the United Kingdom in 1974 and after further general professional training in Glasgow, obtained the MRCP in 1975. Her interest in rheumatology arose after experience with Watson Buchanan and his colleagues in the Centre for Rheumatic Diseases, then in Baird Street in Glasgow. She has held the post of Consultant Rheumatologist and Honorary Senior Lecturer in the Centre for Rheumatic Diseases, now in the Royal Infirmary in Glasgow, since 1979. Currently Lead Clinician in Rheumatology in North Glasgow University Hospitals NHS Trust.

THE ROLE OF SERUM OSTEOCALCIN AND ß-CROSSLAPS IN ASSESSMENT OF WOMEN WITH POSTMENOPAUSAL AND STEROID INDUCED OSTEOPOROSIS

H. M. YOUSSEF, M. O. SHERIF1 and E. ABO-HASHEM2

Department of Rheumatology and Rehabilitation, 1Pharmacy Department, Mansoura Emergency Hospital and 2Department of Clinical Pathology; Faculty of Medicine, Mansoura University, Egypt.

Correspondence Address: Hazem M. Youssef, Fife Rheumatic Diseases Unit, Cameron Hospital, Windygates, Fife KY8 5RR, Scotland, UK. Tel. 01592 226828, Fax. 01592 715851, e-mail: hazemyoussef@nhs.net

Objectives. Biochemical markers of bone turnover are not widely used in clinical practice despite their potential value in the assessment of patients with osteoporosis. The aim of this study was to evaluate the use of two serum markers of bone turnover, osteocalcin (OC) a bone formation marker and ß-CrossLaps (ß-CTx) a bone resorption marker in assessment of patients with postmenopausal osteoporosis (PMO) and steroid induced osteoporosis (SIO) and to study their role in monitoring of some therapeutic interventions.

Methods. Thirty-six women with PMO and thirty-six women with SIO were included in the study. All patients had been recently diagnosed and had received no bone protection therapy prior to the study. Serum calcium, phosphate, alkaline phosphatase and parathyroid hormone levels were checked in all patients to exclude other metabolic bone disease. In each group, patients were assigned to receive alendronate (10 mg + 500 mg calcium carbonate/ day), HRT (conjugated estrogen + norgestrel) or calcium & vitamin D alone (1200 mg of calcium carbonate + 800 IU cholecalciferol/ day). Fasting serum levels of OC and ß-CTx were checked by electrochemiluminescence immunoassay (ECLIA) before and 3 months after treatment in each of the 6 subgroups. Results were compared with those in a control group of 15 healthy age matched premenopausal and postmenopausal women with normal bone densities.

Results. In patients with PMO, pre treatment levels of OC and ß-CTx were significantly elevated in comparison to controls (mean ± S.D.) (48.94 ± 8.5 vs 37.76 ± 11.15 ng/ml, P <0.001 and 6.76 ± 1.92 vs 5.02 ± 2.58 ng/ml, P = 0.01, respectively). The levels of both markers decreased significantly after treatment with alendronate (32.57 ± 9.34 vs 48.78 ± 6.59 ng/ml, P <0.001 and 2.86 ± 1.80 vs 7.75 ± 1.16 ng/ml, P <0.001, respectively). ß-CTx but not OC levels decreased significantly after treatment with HRT (4.69 ± 2.55 vs 6.02 ± 2.63 ng/ml, P = 0.026 and 44.12 ± 10.45 vs 45.06 ± 9.77 ng/ml, P = 0.43, respectively). There were no significant changes in the levels of either marker after treatment with calcium & vitamin D. In patients with SIO, pre treatment levels of OC were significantly lower than controls (11.9 ± 5.19 vs 37.76 ± 11.15 ng/ml, P < 0.001). The mean level of ß-CTx was slightly higher in patients than controls but the difference was not statistically significant. The levels of OC increased significantly after treatment with alendronate and with calcium & vitamin D (13.16 ± 1.55 vs 10.38 ± 0.89, P < 0.001 and 15.18 ± 8.17 vs 12.59 ± 6.75 ng/ml, P = 0.001, respectively), but not with HRT. There was a significant reduction in ß-CTx levels after treatment with alendronate and HRT (4.67 ± 2.02 vs 6.64 ± 2.43, P = 0.02 and 3.96 ± 1.54 vs 5.1 ± 2.44 ng/ml, P = 0.01, respectively) but not with calcium & vitamin D. No significant correlation was found between the levels of OC or ß-CTx and the bone mineral density in the studied patients.

Conclusion. Serum OC and ß-CTx may be helpful in assessing the rate of bone turnover in patients with osteoporosis prior to therapy; and our findings are consistent with bone turnover being greater in PMO than in SIO. Both markers are helpful in monitoring the response (and adherence to treatment) in patients with PMO and SIO as early as three months after starting antiresorptive therapy.

A SERIES OF CASES OF HENOCH-SCHÖNLEIN PURPURA PRESENTING IN ADULTHOOD

I. MORRISON, S.M. FRASER and E. MORRISON

Department of Rheumatology, Southern General Hospital, Glasgow

The incidence of Henoch-Schönlein Purpura (HSP) is less in adulthood than childhood but the disease has been felt to be more severe; one retrospective study comparing presentation in childhood with those >20 years showed more frequent and severe renal involvement in the adult group and a greater use of aggressive therapies including steroids and cytotoxics.¹ The prognosis is good overall with up to 90% of adults recovering completely. The majority of the morbidity of HSP has been attributed to renal disease. We report the cases of 3 middle-aged patients (41F, 45M, 48M) who have recently presented to our unit with HSP and given cause for significant clinical concern. Although each has had renal involvement, one of our patients had skin-threatening cutaneous vasculitis and two severe GI involvement necessitating close surgical involvement and consideration of emergency laparotomy. Two of the 3 required high dose oral steroid therapy. Each has recovered and they remain under close outpatient review. We conclude that while renal involvement can give rise to long-term complications in a minority of adult HSP patients, in our series of 3 patients presenting in middle age, it was involvement of other systems which was the driver of clinical concern and need for escalation of therapies.

¹Blanco, R, Martinez-Taboada, VM et al Arthritis Rheum 1997; 40:859

ASSESSING RISK OF TUBERCULOSIS (TB) IN PATIENTS ON ANTI-TUMOUR NECROSIS FACTOR ? (TNF-?) THERAPIES: IMPACT OF THE BRITISH THORACIC SOCIETY (BTS) GUIDELINES 

J. ARGYLE, K. WILSON, P. REYNOLDS and M. DUNCAN

Background: Patients embarking on anti TNF-a therapies are at risk of reactivation of TB. Changes to current screening practices for TB are necessary following publication of the BTS Guidelines1 and withdrawal of Heaf strength Tuberculin PPD.

Aim: To review screening results from our current practice and assess the impact of changing to follow BTS Guidelines.

Methods: We reviewed records for all our patients treated with anti-TNF-a therapy since 2004. Current practice is to screen all patients with history, examination, chest X-ray (CXR) and Heaf test. Patients identified with latent TB are treated according to Centers for Disease Control Guidelines.2 Patient records were reassessed according to the BTS Guidelines, and discrepancies identified.

Results: 22 patients commenced therapy, predominantly for Rheumatoid arthritis (n=18). 18 (82%) are female, median age 60 years (range 20 - 74). All patients are white, 21 born in UK. 19 patients (86%) were on immunosuppressives. No patient had a history of TB. 2 patients had abnormal CXRs, both showing calcified granulomata. 19 patients underwent tuberculin tests. 3 patients were not tested (1 refused, 1 no reagent available, 1 no test advised).

5 patients (1 abnormal CXR, 1 abnormal CXR & positive Heaf test, 3 positive Heaf tests) were treated with anti-TB therapy. All commenced Etanercept after 1 month of therapy and none has evidence of active TB at median follow-up 8 months (range 5-12).

Utilising BTS Guidelines, 2 patients with abnormal CXRs would have had anti-TB therapy, completed in full prior to anti-TNF-a therapy. 19 patients would be unsuitable for tuberculin testing, including 3 of those with positive Heaf tests. These 3 patients would have been under observation only. 3 of our 22 patients would have required a tuberculin test.

Discussion: We have identified a high incidence of latent TB (23%) in this small West of Scotland series. We are concerned about the applicability of the BTS Guidelines to our patient population. Tuberculin testing may still be appropriate despite the use of immunosuppressive drugs. Future alternatives include using interferon-gamma immunological tests for TB.

Conclusions: Changing practice to implement BTS Guidelines will only identify a minority of patients with latent TB. It is important to ensure BTS Guidelines are appropriate, to reduce the risks of clinical TB in our patients on anti-TNF-a therapy.

References: 1 BTS Guidelines. Thorax 2005; 60:800-805 2 CDC, Division of Tuberculosis Elimination. Factsheet: treatment of LTBI. 2004.

PSORIATIC ARTHRITIS - DOCUMENTATION OF PUVA EXPOSURE MUST BE ACCURATELY RECORDED

L.L. WONG, R.D. BAXTER, D.W. MCCAREY, J.A. HUNTER AND M.M. GORDON

Gartnavel General Hospital1and University of Glasgow2

Background Psoriatic arthritis (PsA) is the second most common peripheral inflammatory arthropathy in Rheumatology clinics. Recent advances have seen new agents licensed for treatment for PsA including biological agents.

Methods Consecutive patients attending a rheumatology unit over a four week period were identified. Using the BSR guidelines on anti-TNF therapy in PsA, we sought to identify which patients fulfilled the criteria. Data was collected on demographics, pattern of disease, previous and current treatment and contraindications to anti-TNF treatment.

Results 50 patients age 15-78ys (median 48yrs) were identified. 50% were male, 94% Caucasian and 60% had erosive disease. Median PsA duration was 9 years. Pattern of arthritis (Moll & Wright): 62% had asymmetrical polyarthritis, 30% seronegative RA and 60% patients had = 3 tender and swollen joints.

All patients received NSAIDs before DMARDs. At time of study, 16% were on NSAIDs only and 38% had received =2 DMARDs. 9.5% had received =5 DMARDs, 5 patients on Etanercept. Commonest 1st DMARD was Sulphasalazine (76%) followed by Methotrexate (19%). The most frequent reason for DMARD failure was toxicity (29/42). In 34%, anti-TNF was contraindicated due to unknown quantities of PUVA treatment but in 64% there was no contraindication. Overall, 3/50 satisfied the BSR guidelines but were not receiving such therapy. 3 others would qualify if gold were recognised in the guidelines.

Conclusions In our cohort, 16% of patients would be eligible for anti- TNF treatment of whom 10% are receiving this therapy. Although 60% met the required number of tender and swollen joints, previous PUVA would be a contraindication in more than a third due to lack of documentation. PUVA is therefore an important potential contraindication and documentation of total doses administered is important.

KEYNOTE LECTURE: "REGULATION OF AUTOIMMUNE ARTHRITIS" MOHINI GRAY, ARC Clinician Scientist and Honorary Consultant Rheumatologist

MRC Centre for Inflammation Research, University of Edinburgh, UK.

The interaction of apoptotic cells (AC) with cells of the immune system is both immunosuppressive and anti-inflammatory. It is not known if AC have a role in modulating the course of autoimmune mediated, chronic inflammation. The data that I will discuss shows that AC given up to 1 month prior to the clinical onset of collagen induced arthritis protected mice from severe joint inflammation and bone and cartilage destruction. The mechanism for this was by the inhibition of pathogenic antibody production. We also found that antigen specific CD4+T cells from AC treated mice secreted significantly more of the immunosuppressive cytokine IL-10 and that inhibition of IL-10 in-vivo reversed the beneficial effect of AC on autoantibody production. This data shows that AC have a profound influence on the course of an aggressive autoimmune disease and the mechanism of this benefit arises from a modulation of the adaptive immune response to the auto-antigen.

ANGIOTENSIN II RECEPTOR BLOCKERS AS POTENTIAL ANTI-INFLAMMATORY AGENTS

M.M. CHEE1, M.E. PERRY2, A.G. PRICE3 , R.D. STURROCK1, W.R. FERRELL1 and J.C. LOCKHART3 1Centre for Rheumatic Diseases, Glasgow Royal Infirmary, 2Department of Rheumatology, Gartnavel General Hospital, Glasgow, Scotland, UK, 3School of Engineering & Science, University of Paisley, Scotland, UK Objective Angiotensin II (AngII) plays an important role in regulating blood pressure via the renin-angiotensin-aldosterone system. Subsequently, it was found to have pro-inflammatory properties and long-term effects on tissue structure. Studies on angiotensin converting enzyme inhibitors (ACEi) and AngII receptor blockers (ARB) have suggested that their therapeutic effects are mediated by inhibiting AngII. In theory, ACEi and ARB could be used as anti-inflammatory agents. Captopril is already established as having anti-inflammatory properties, mediated by the thiol moiety unique to the drug. The purpose of this study was to establish in an animal model of arthritis whether ARBs have anti-inflammatory effects and in a retrospective audit to establish the anti-inflammatory effects of ARB by comparing inflammatory markers of rheumatoid arthritis patients who were on ACEi (ramipril or lisinopril), or ARB or neither

Study Method Adjuvant monoarthritis was induced under anaesthesia in the rat knee joint (n=6) treated with vehicle or the selective AT1 receptor antagonist losartan (15mg/kg s.c. alternate days), these being administered both prophylactically and therapeutically. Joint swelling was monitored as an indicator of inflammation. Patients were identified from 2 centres - Glasgow Royal Infirmary (GRI) and Gartnavel General Hospital (GGH). Data were collected by patient questionnaire at GRI and by computer database at GGH. Data included disease modifying anti-rheumatic drug (DMARD) therapy, ACEi (ramipril and lisinopril) and ARB use, and corresponding C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) values. Results of CRP and ESR values of all patients were consolidated and statistical analysis performed.

Results Rat joint swelling was significantly (P<0.0001) reduced (>50%) by losartan treatment, both with prophylactic and therapeutic (day 12) intervention. Mean (± SD) ESR from RA patients on ARB (n=42), was lower (25.1±22.5) than that from patients on ACEi 30.8±29.2, n=58) or those on no angiotensin inhibition therapy (control group: 40.1±29.4, n=38), and these differed significantly (P=0.02, 1-way ANOVA, log10 transformed). Post-hoc testing (Bonferroni) revealed only the ARB-treated group differed significantly (P=0.021) from the control group. Although a similar trend between groups was apparent for CRP, this was not significant using non-parametric statistics (data set not normalized by log10 transformation). Adjusting for statin use, the difference in ESR between groups remained significant (P=0.036, 1-way ANCOVA). Conclusions Inhibiting AngII has anti-inflammatory potential and ARB may be more effective than ACEi.

DO PATIENTS WITH RHEUMATOID ARTHRITIS RECEIVE CARDIOVASCULAR PROPHYLAXIS: WHO IS RESPONSIBLE?

N. BASU and A.G. MACDONALD

Introduction Cardiovascular disease is a major cause of morbidity and mortality in RA patients. Traditional risk factors, such as smoking, hypertension and hypercholesterolaemia, have a prominent role in this outcome, as do more novel risk factors such as systemic inflammation1. It would therefore seem sensible to closely monitor and treat modifiable risk factors such as cholesterol in this high-risk population. Meeting 'cholesterol targets' in the general population is an inherent part of the new primary care contract. However, rheumatoid patients may be deemed 'uncomfortable' to manage in the community because of their frequent multi-organ involvement and exposure to potentially toxic immunosuppressant medication. Temptation to defer responsibility to secondary care may be heightened by the regular and long-term relationships that patients develop with rheumatological services. This audit aims to examine whether this population receives sufficient cardiovascular prophylaxis in regards to hypercholesterolaemia compared with the general population.

Methods Case notes of all patients attending the rheumatology out patient clinics at Aberdeen Royal Infirmary were reviewed from 1 March 2006. Diagnosis of RA for > 1year and age>55 were used as an inclusion criteria, and the first 50 patients that matched this were collated. A control group of 50 consecutive patients with a diagnosis of soft tissue rheumatism or osteoarthritis with an age>55 were used for comparison. Data was extracted in order to calculate the 10 year cardiovascular disease risks using risk prediction charts2, and to assess other indications for statin therapy according to NICE guidelines applicable to the general population3.

Results The ages of the two cohorts were equivalent, 67.3 (55-85) years in the rheumatoid population and 64.4 (55-81) in the control group.

Only 50% of rheumatoid patients, in this cohort, requiring statins actually received such therapy. In contrast, 80% of the control group received an appropriate prescription. 11 controls and 5 rheumatoid patients had not undergone lipid screening in the previous 12 months and therefore could not be evaluated. The majority of these patients had at least one cardiovascular risk factor to warrant annual screening. Finally, no individual was inappropriately treated and no statin intolerance was recorded.

HYDROXYCHLOROQUINE IS ASSOCIATED WITH CARDIOMYOPATHY 

R.D. BAXTER, M.M. GORDON and J.A. HUNTER Gartnavel General Hospital, 1053 Great Western Road, Glasgow 

Key Message; Hydroxychloroquine should be considered in the differential diagnosis of otherwise unexplained dilated cardiomyopathy Summary of Case; a sixty year old man presented with fever, rigors and weight loss. Clinical examination was normal at presentation. The only abnormal investigation was a single lipoid non-caseating granuloma with surrounding eosinophils on bone marrow biopsy. Six months of empirical treatment with anti-tuberculous therapy was instigated although prolonged culture failed to detect AAFB. During the fifth month the patient developed features consistent with an inflammatory arthritis. X-rays showed no erosive features and he was commenced on anti-inflammatories. One month later he had a return of his original symptoms requiring high dose steroids. The working diagnosis was sarcoidosis and he was given hydroxychloroquine and steroids reduced. Fourteen months later, the patient was free from joint and systemic symptoms but described one week of orthopnoea .He had clinical and radiological evidence of pulmonary oedema and mitral regurgitation. ECG was abnormal and echo showed severe LV dysfunction and thrombus. He was treated appropriately. Endomyocardial biopsy was contraindicated during anticoagulant therapy. A diagnosis of HCQ-associated cardiomyopathy was suggested on clinical grounds, and in the absence of hyperferritinaemia, thyroid dysfunction, eosinophilia, hyperglycaemia or abnormal viral serology. Hydroxychloroquine cardiomyopathy may manifest as conduction abnormalities, restrictive, hypertrophic or dilated cardiomyopathy. Risk factors are difficult to characterise due to paucity of cases but age and renal impairment may be important. Recovery after cessation of treatment is variable; toxicity to cardiac and skeletal muscle can occur at standard doses. This case reminds us that HCQ is associated with cardiomyopathy and that severe cardiac decompensation can present with a short history but advanced ventricular dysfunction. Physicians should retain a high index of suspicion when faced with unexplained cardiac symptoms and undertake prompt investigation in the hope of resolution on stopping anti-malarial therapy. This case would also present an opportunity for discussion; the aetiology not only of the cardiomyopathy but also the underlying systemic disorder remains elusive.

BISPHOSPHONATE ASSOCIATED OSTEONECROSIS OF THE JAW - A CASE REPORT

RENGI MATHEW and VEENA DHILLON

Rheumatic Diseases Unit, University of Edinburgh

A 56 year old female was diagnosed with Rheumatoid Arthritis in 1997 and was started on sulphasalazine. Over the course of the next few years, she was treated with Methotrexate, Gold and Leflunomide as her disease was inadequately controlled. She had also been on Prednisolone since 2002. She was started on Fosamax 70 mg weekly by her GP in early 2004. By end 2005, she was referred to the Resistant Rheumatoid Arthritis Clinic for consideration of Biologic therapy as her arthritis remained poorly controlled. At this time, the patient reported a persistent dental abscess that had been ongoing for about a year. She had developed purulent discharge and draining sinuses in the left maxilla following removal of an upper left posterior tooth in July 2004. She was seen in the dental clinic in December 2005 and underwent removal of a non-vital molar tooth and curettage of necrotic bony debris in the adjacent maxilla with coverage by a soft tissue flap. Histology showed multiple fragments of vital and necrotic bone suggestive of osteonecrosis. In the absence of any other cause, this was believed to be associated with the use of bisphosphonates, and Fosamax was discontinued. When last reviewed in March 2006, she was improving from the maxillary osteonecrosis point of view and was left with only a very small pinpoint fistula in the left maxilla. CT scan showed no other areas of involvement.

Discussion Bisphosphonates are widely used in the treatment of multiple myeloma and metastatic disease to the bone from solid tumours, as well as in the chronic management of Osteoporosis and Paget's disease. An increased incidence of osteonecrosis of the jaw has been reported in patients treated with bisphosphonates, especially Pamidronate and Zolendronate. The incidence is reported to be between 4% and 10% among patients receiving chronic bisphosphonate therapy. A few cases of osteonecrosis associated with oral bisphosphonates have been reported of which Alendronate appears to be the main culprit. Pamidronate and Zolendronate are nitrogen containing bisphosphonates, are much more potent and are not metabolised. Therefore, they accumulate in bone and have an ongoing affect that results in bone necrosis. Majority of cases were initiated by tooth extraction or other dental procedures. The typical presenting lesions were either a non healing extraction socket or an exposed jaw bone. The risk of developing osteonecrosis appears to increase with time of the use of the medication. Management: Milder cases can be managed conservatively by antibiotics and local wound irrigation. Majority of patients required surgical procedures to remove all of the involved bone - sequestrectomies, marginal or segmental mandibular resections, partial or complete maxillectomy. Cessation of bisphosphonate therapy may not have a major impact on the progression of this process.

Conclusion In view of the increasing and widespread use of bisphosphonate therapy, physicians and patients need to be aware of this potential complication which may result in significant morbidity and impaired quality of life for these patients.

FROM ANTI-INFLAMMATORIES TO ANTI-RESORPTIVES AND BACK AGAIN. 

ROB J. VAN 'T HOF Rheumatic Diseases Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK.

We have previously shown that the butanediol ester of biphenylcarboxylic acid (ABD56) inhibits osteoclast (OC) formation and activity in vitro and in vivo. However, the mechanism of action of this compound is presently unknown. As activation of the NF?B and AP-1 signal transduction pathways by RANKL have been shown to be essential pathways for osteoclast differentiation and survival, we studied whether inhibition of these pathways mediates the anti-resorptive effects of ABD56.

Exposing OC cultures to ABD56 1 hour prior to stimulation with RANKL completely abolished NF?B and AP-1 activation. In contrast, ABD56 did not inhibit M-CSF induced AP-1 activation or PTH-induced AP-1 and NF?B activation. Unlike M-CSF and PTH receptors, TNF receptor family members like RANK stimulate the NF?B and AP-1 pathways through recruitment of members of the TRAF family of adapter proteins. In mouse osteoclast cultures, pre-treatment with ABD56 inhibited the RANKL-stimulated recruitment of TRAF6 to RANK. As the recruitment of TRAFs is also crucial for the activation of other TNF receptor family members such as the TNF receptor, we investigated whether ABD56 affects TNF-induced signalling. In mouse macrophage cultures, pre-treatment with ABD56 inhibited the TNF-stimulated recruitment of TRAF2 to the TNF receptor, and abolished activation of the NF?B and AP-1 signalling pathways. The fact that ABD56 inhibits TNF-induced signalling suggested that apart from being an anti-resorptive compound, it might also be a novel anti-inflammatory compound. We investigated this using the collagen induced (CIA) and serum induced models of rheumatoid arthritis (RA). However, ABD56 is an ester and therefore liable to degradation by esterases. As we had developed more stable and potent versions of this compound in the meantime, we decided to test one of these, ABD345, were the ester link has been replaced by a ketone link. ABD345 almost completely prevented joint inflammation in the CIA model. In the serum induced model, however, ABD345 was only partially effective, delaying onset of inflammation by 3 days and the maximal disease score by approximately 30-40%.

In conclusion, ABD56 inhibits activation of the NF?B and AP-1 pathways by RANKL and TNF, by inhibiting the recruitment of adapter proteins from the TRAF family. ABD56 and derived compounds are potent inhibitors of bone resorption and inhibit joint inflammation in animal models of RA. ABD56 and related compounds therefore make up a new class of anti-resorptive and anti-inflammatory compounds that act through a novel mechanism of action. The compounds show promise as cost-effective small molecule alternatives for anti-TNF treatment in inflammatory conditions such as Rheumatoid Arthritis.

JUVENILE ONSET GOUT AS A POSSIBLE MANIFESTATION OF AN EREDITARY KIDNEY DISORDER 

S. BOYLE, V.B. DHILLON, G. NUKI, N. TURNER Rheumatic Diseases Unit, University of Edinburgh

Mr CW is a 40yr old male of Chinese descent who has lived in the UK for many years. He was diagnosed with a juvenile onset seronegative inflammatory arthropathy in 1995 at 2 successive London hospitals. Since then, he had been treated with a number of DMARDS, including Myocrisin, Sulfasalazine, Methotrexate, and Leflunamide with very little benefit. Prednisolone had afforded some relief in conjunction with NSAIDS. His joint problems began at 10yrs of age where he presented with a painful swollen ankle of 1 weeks duration. Initially one joint was affected at a time, though throughout his teenage years, the "attacks" of pain and swelling have increased in frequency and duration with the subsequent involvement of his ankles, knees, hands and elbows. He was reviewed at the Western General Hospital for the first time in April 2005 where he had complained of painful swollen knees, ankles, MCP, PIP's, wrists, shoulders, and elbows with 1-2 hours of early morning stiffness. He has a family history of hypertension, with no family history of gout or renal disease. He has a brother and two sisters who are well, and has 2 daughters aged 5 and 7yrs with no significant medical history. He has worked as a postmaster since 2001, and does not smoke or drink alcohol. Examination revealed bilateral PIP and MCP joint synovitis with nodules over the PIP, MCP joints and wrists. There were a number of punched out lesions over both ankles containing what appeared to be tophaceous material. Swabs showed large numbers of urate crystals consistent with origin from a tophus. He was Rheumatoid factor negative, whilst bilateral hand radiography revealed degenerative and scattered erosive changes involving PIP and MCP joints, not typical of either a gouty arthritis or inflammatory erosive arthropathy. Feet radiography shows erosive changes at the right first MCP joint, with associated degenerative changes. At the time of presentation at our clinic, he had evidence of moderate renal impairment: urea 9.2 creatinine 142, eGFR 51ml/min/1.73m²,and hyperuricaemia (urate 0.64) Abdominal ultrasound showed "the right kidney to be 10.4cm, and left 9.9cm with minor cortical irregularity involving the left kidney, with the appearance of "bilaterally bright" renal pyramids demonstrating acoustic shadowing. No renal tract calculi were identified." He has been more appropriately labeled "polyarticular tophaceous gout" and has subsequently been treated with colchicine and allopurinol (recently increased to 300mg daily).His level of renal impairment has fluctuated with urea 8.3-10.4 and creatinine 119-220 since being reviewed in our clinic. He had a urine protein excretion of 0.3g/24hrs, creatinine clearance 76mls/min, and eGFR 62mls/min/1.73m² in February 2006. Summary Mr CW is a 40 year old male with a 30 year history of juvenile onset gout and renal impairment with ultrasound changes suggestive of a possible underlying subtle kidney disorder. Conclusion The question arises as to whether the ultrasound findings and renal impairment have occurred secondary to his hyperuricaemia (e.g. urate nephropathy, nephrocalcinosis) or indeed a primary phenomenon in which case a range of differentials are possible i.e. Medullary Sponge Kidney, Renal Tubular Acidosis and the inherited tubulo-interstitial nephritides (NPH-MCKD complex) characterized by mutations in the genes encoding uromodulin (UMOD). Unfortunately screening for this gene is not available at present. Further detailed investigations of uric acid metabolism and renal urate excretion are ongoing.

FIFE RHEUMATIC DISEASES UNIT (FRDU) GENERAL PRACTITIONER NEWSLETTER 

S. CULLINANE AND ALL CONTRIBUTING MEMBERS OF THE FRDU

Introduction: The Fife Rheumatic Diseases Unit (FRDU) was established in 1994, within a Primary Care NHS trust. At the outset the unit was developed as a multi-disciplinary community focused Rheumatology service.

The management of patients with inflammatory joint disease in Fife occurs predominantly in the community setting, ideally in the patients' home.

In Fife we have always been fortunate in having an excellent working relationship with General Practitioners. Despite this it had become apparent that certain queries or concerns had a common theme. This had been conventionally addressed by formal education programmes often only attended by a small group of interested, well-informed GP's. This meant that the wider group of GP's was often neglected in education terms.

In an attempt to improve primary care (GP) understanding and management of Rheumatological problems, a pilot series of "newsletters" were planned from July 2002.

The aims of the initial pilot project were:

· To improve understanding of Rheumatological problems, which in Fife are predominantly managed in the community setting.

· To streamline patient management from primary care to specialist referral. In Fife we were aware that people with inflammatory arthritis were not being referred early to specialist care, an issue we hoped to address with the newsletter.

In July 2002 the first issue of the newsletter was produced and e-mailed to all GP's on the network directory The newsletter included, a topic of Rheumatological interest, department personnel and contact numbers and details of the Departments in-service meetings with an invitation for interested GP's to attend.

Monthly newsletters were issued for the following twelve months, in the same format.

In the first twelve months all members of the Rheumatology team contributed a "topic of the month". All had to be Rheumatological based and written to the current level of evidence. This ensured not only evidence based articles, but allowed the FRDU team to continue practicing to current evidence or best practice.

In June 2003 all registered GP's, were contacted by internal mail with a simple questionnaire for completion. A self-addressed envelope was included for return in the internal mail system.

Results: 237 questionnaires were sent out in June 2003, four weeks later the responses were analysed.

139 (59%) GP's replied; 98 (41%) GP's did not reply. Of the 59% who replied

· 14% (19) had never or not recently received a copy.

 · 5% (7) had received the newsletter but rarely or never read it. 

· 81% (113) received the newsletter and read it all or most of the time. 

32 GP's added comments, which included future topics of interest, and amendments to style and content detail. e.g. Use and design of splints, useful pre-referral tests, referral guidelines and managing a flare in rheumatoid arthritis. . The newsletter continued to be produced following guidelines. · Contact details and waiting times - to continue · Yearly list issued to all surgeries with table of previous copies for request, if required · Paper copies to be sent to surgeries with IT problems or incompatible systems · Guidelines booklet to be produced by the Department as a reference. This booklet was produced and is used as a Departmental manual. It is also available to download on the GP's LMC Website. The guidelines booklet includes: · Information regarding DMARDS · Pre-referral guidelines and investigations, including criteria for urgency of referral · Adverse drug reactions and actions to be taken

We continue to receive positive feedback from GP's and plan to repeat the feedback questionnaire at five years (July 2007). The newsletter is now an integral part of the FRDU professional development. We have formalized an education programme to supplement newsletters and incorporate practical skills e.g. joint injection. A pilot joint injection programme has been developed and will be offered in the near future.

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