Mary Gayed

BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding—Part I: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids

Centre for Rheumatology Research, UCL Division of Medicine, University College London, London, Department of Rheumatology, University Hospitals of Leicester, Leicester, Womens Health, University College London Hospital, London, Obstetrics and Gynaecology, Frimley Park Hospital, Surrey, Department of Rheumatology, University Hospital Birmingham NHS Foundation Trust, Birmingham, Department of Rheumatology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK, Department of Rheumatology, Copenhagen University Hospital, Rigshospitalet, Denmark, Department of Rheumatology, Burton Hospitals NHS Trust, Burtonupon-Trent, Rheumatic and Musculoskeletal Disease Unit, Our Lady’s Hospice and Care Services, Dublin, Ireland, Department of Rheumatology, University College London Hospital, London, Department of Rheumatology, Aneurin Bevan University Health Board, Newport, UK, Department of Rheumatology, Sandwell and West Birmingham Hospitals NHS Trust and Division of Immunity and Infection, University of Birmingham, Birmingham, UK

Lupus and cancer

Individuals with systemic lupus erythematosus (SLE) have an increased susceptibility to certain types of cancer. Of particular concern are haematologic malignancies, specifically non-Hodgkin lymphoma, where a three- to four-fold increased risk is seen in SLE, compared with the general population. There is some evidence that immunosuppressive exposures play a role, although there appear to be other factors driving the risk. Lupus disease activity, with resultant dysregulated lymphocyte proliferation, may itself be a mediator of the association between SLE and lymphoma. Aside from haematologic malignancy risk, lung cancer also is increased in SLE compared with the general population, and smoking likely drives this risk in large part. Last but not least, cervical dysplasia is a concern in women with SLE, particularly with exposure to immunosuppressants; routine screening for this complication should not be neglected.

The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults

NICE has accredited the process used by the BSR to produce its guidance on the management of systemic lupus erythematosus in adults. Accreditation is valid for 5 years from 10 June 2013. More information on accreditation can be viewed at www.nice.org.uk/accreditation. For full details on our accreditation visit: www.nice.org.uk/accreditation. Rheumatology Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Rheumatology Department, City Hospital, Sandwell and West Birmingham Hospitals NHS Trust, Rheumatology Department, University Hospitals Birmingham NHS Foundation Trust, Birmingham, Royal National Hospital for Rheumatic Diseases, Bath, Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute for Inflammation and Repair, University of Manchester, Manchester Academic Health Sciences Centre, The Kellgren Centre for Rheumatology, NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester, Louise Coote Lupus Unit, Guy’s Hospital, London, Laurie Pike Health Centre, Modality Partnership, Birmingham, Department of Rheumatology, Freeman Hospital, Newcastle upon Tyne, Department of Medicine, University of Cambridge, Lupus and Vasculitis Unit, Addenbrooke’s Hospital, Cambridge, Lupus Research Unit, The Rayne Institute, St Thomas’ Hospital, Division of Women’s Health, King’s College London, Section of Renal Medicine and Vascular Inflammation, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, London, LUPUS UK, Romford, Essex and Centre for Rheumatology, University College London, London, UK

The cost of care of systemic lupus erythematosus (SLE) in the UK: annual direct costs for adult SLE patients with active autoantibody-positive disease

Objectives The aim of the Systemic LUpus Erythematosus Cost of Care In Europe (LUCIE) study was to evaluate the annual direct medical costs of managing adults with active autoantibody-positive disease on medication for SLE in secondary care. This paper presents the UK analyses only. Methods A cost-of-illness study was conducted from the perspective of the National Health Service. Health resource utilization data were retrieved over a two-year period from four centres in England and unit cost data were taken from published sources. Results At baseline, 86 patients were included, 38 (44.2%) had severe SLE and 48 (55.8%) had non-severe SLE. The mean (SD) SELENA-SLEDAI score was 7.7 (5.7). The mean (SD) annual direct medical cost of was estimated at £3231 (£2333) per patient and was 2.2 times higher in patients with severe SLE compared with patients with non-severe SLE (p < 0.001). Multivariate model analyses showed that renal disease involvement (p = 0.0016) and severe flares (p = 0.0001) were associated with higher annual direct costs. Conclusions Improvement of the overall stability of SLE and early intervention to minimize the impact of renal disease may be two approaches to mitigate the long-term direct cost of managing SLE patients in the UK.

The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults: Executive Summary

NICE has accredited the process used by the BSR to produce its guidance on the management of systemic lupus erythematosus in adults. Accreditation is valid for 5 years from 10 June 2013. More information on accreditation can be viewed at www.nice.org.uk/accreditation. For full details on our accreditation visit: www.nice.org.uk/accreditation. Rheumatology Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Rheumatology Department, City Hospital, Sandwell and West Birmingham Hospitals NHS Trust, Rheumatology Department, University Hospitals Birmingham NHS Foundation Trust, Birmingham, Royal National Hospital for Rheumatic Diseases, Bath, Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute for Inflammation and Repair, University of Manchester, Manchester Academic Health Sciences Centre, The Kellgren Centre for Rheumatology, NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester, Louise Coote Lupus Unit, Guy’s Hospital, London, Laurie Pike Health Centre, Modality Partnership, Birmingham, Department of Rheumatology, Freeman Hospital, Newcastle upon Tyne, Department of Medicine, University of Cambridge, Lupus and Vasculitis Unit, Addenbrooke’s Hospital, Cambridge, Lupus Research Unit, The Rayne Institute, St Thomas’ Hospital, London, Division of Women’s Health, King’s College London, Section of Renal Medicine and Vascular Inflammation, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, London, LUPUS UK, Romford, Essex and Centre for Rheumatology, University College London, London, UK

Comment on: The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults: reply

follow-up. As a result, this subgroup had a much lower prednisone burden during the follow-up (average dose during the first 5 years of follow-up 2.8 vs 9.4 mg/day). Among them, damage accrual was significantly lower, with significant differences in glucocorticoid-related and cardiovascular damage and no differences in lupusrelated damage, thus reflecting a similarly good longterm control of SLE activity [8]. Thus, we believe that a different approach to the use of glucocorticoids in SLE can be made. Methyl-prednisolone pulses, at doses between 125 and 500 mg/day, should be the first option for moderate severe flares, rather than prednisone >30 mg/day, independent of body weight. Tapering to doses <7.5 mg/day must be accomplished within a few weeks in order to minimize the risk of adverse events. As recommended in the guideline, therapy with antimalarial drugs should be continued irrespective of the severity of SLE, and immunosuppressive drugs used also as glucocorticoid-sparing agents [1].

FRI0093 A Systematic Analysis of the Safety of Prescribing of Anti-Rheumatic, Immunosuppressive and Biologic Drugs in Men Trying to Conceive

Background Prescribing of anti-rheumatic and immunosuppressive drugs in men with active rheumatic disease trying to conceive is required to control disease activity. This increases the chance of successful conception. However it is complicated by concerns regarding the safety of these drugs. They arise from safety information based mainly on experimental and animal studies as human data is limited. Previous systematic reviews have identified a risk of oligospermia with sulfasalazine and gonadal toxicity with cyclophosphamide in men trying to conceive, as well as theoretical concerns for leflunomide and biologics. We have undertaken a systematic review to update information on this subject. Objectives This systematic review aims to update information on the safety fo prescribing these drugs in men trying trying to conceive. Methods A systematic search of PubMed and Embase was carried out using relevant keywords for pregnancy, men, conception and drugs commonly prescribed in patients with rheumatic disease from 1966 onwards. The drug categories included analgesics, disease modifying anti-rheumatic drugs, biologics and steroids. Review articles and non-English language papers were excluded. Results 21 studies were selected for detailed review, describing relevant drug use in men with rheumatic disease, inflammatory bowel disease, post-transplantation, psoriasis, multiple sclerosis and leukaemia. The studies included 3 case reports, 4 case series, 10 cohort studies and 1 case-controlled study. These studies identified 2214 drug exposures (705 NSAIDs, 517 steroids, 343 azathioprine, 287 ciclosporine, 100 methotrexate, 120 sulfasalazine, 44 etanercept, 66 infliximab, 13 hydroxychloroquine, 11 rituximab, 6 adalimumab, 2 leflunomide) in 1963 men trying to conceive, leading to 2112 pregnancies. There were limited reports of the effects upon fertility (in 133 men) and one retrospective questionnaire study1 of 30 men taking azathioprine reported an increased rate of infertility (>1yr to conception) of 15.2% vs 8.3% of controls. The confounding effects however, of underlying (Crohns) disease and the possibility of female infertility, were a limitation of this study. Of the 1778 live births, 33 congenital malformations were reported which were not specific to any drug. In the remaining 78 pregnancies that miscarried, the precise number of elective terminations was not stated in all studies. Conclusions This systematic review did not find an increased risk of adverse pregnancy outcomes in partners of men taking anti-rheumatic, immunosuppressive and biologic drugs whilst trying to conceive. However there remains insufficient evidence to advocate the safe use of these drugs. This information however, is useful when counselling men of potential risk particularly after accidental conception. References Teruel C et al. Outcomes of Pregnancies Fathered by IBD patients exposed to thiopurines. The American Journal of Gastroenterology 2010; 105:2003-2008 Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4289

Longterm outcomes of children born to mothers with SLE exposed to azathioprine in pregnancy

Background Azathiopine (AZA) is commonly used to ensure SLE disease control during pregnancy. There is little information regarding long term outcomes of these children. Objectives We aimed to assess if AZA exposure during pregnancy and lactation was associated with adverse outcomes for children born to mothers with lupus. Methods Women attending lupus clinics, with available pregnancy data, were consented to take part. A standard questionnaire developed for a multi-centre study was used to collect the data. Results Complete data was available for 287 children born alive to 200 women: 66% Caucasian, 15% South Asian, 10% Afro-Caribbean, 1% Chinese, 1% Hispanic, 4% other and 4% not stated. The median (range) age of women at delivery was 32 (19-44) yrs, and duration of disease was 6 (0.5-27) yrs. Two groups were studied: 89 children exposed to AZA during pregnancy &/or breast-feeding (group A) vs 198 children unexposed (group NA). Maternal renal disease (group A 38/67, 57% vs group NA 28/175, 16%), use of maternal prednisolone (group A 78/89, 87% vs group NA 93/198, 47%) and aspirin (group A 70/84, 83% vs group NA 132/200, 66%) were significantly increased in group A compared with group NA (p<0.005). No significant differences in exposure to hydroxychloroquine or heparin between the groups was identified. There was no significant difference in maternal pre-eclampsiaa, hypertension, anti Ro and/or anti-La antibodies, between the two groups. The presence of maternal lupus anticoagulant and/or anticardiolipin antibodies (ACA) was statistically higher in group A 44/73 (60%) vs group NA 79/178 (49%), p=0.03. However the presence of the antibodies individually was not different. Median age of children at enrolment in group A was 3.2, (range 0-17.1) vs group NA 3.1 (0-16.2) years. The median birth weight in group A was 2.8 (0.6-4.4)kg vs 3.1 (0.7-4.7) kg in group NA and gestational age in group A was 36.3 (27-42) wks vs 38 (25-42) wks in NA. These were both statistically significant. Using univariate analysis children exposed to AZA had a significantly increased rate of hospital admissions for infection (group A 25/89, 28% vs group NA 28/198, 14%, p=0.005), but not for overall hospital admissions (group A 29/84, 35% vs group NA 45/192, 23%, p=0.07) or out- patient visits. When the effect of AZA was adjusted by multifactor logistic regression for maternal renal disease and prednisolone use, the relationship became non-significant (OR 1.73 (0.85-3.5), p=0.13, however, due to the lower sample size its power was <80%. Conclusions This study shows that women with SLE who take AZA during pregnancy are more likely to have had renal disease, ACA and/or lupus anticoagulant and to use prednisolone. The median birthweight and duration of pregnancy was lower. There appeared to be an increased risk of hospital admission due to infection in the children of group A mothers. However, after adjusting for markers of maternal lupus disease severity this relationship disappeared. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.1616

Chapter 80 – Rheumatic Disease

March 01, 2004 ABSTRACT: The basic screening studies for rheumatic diseases are a complete blood cell count, a determination of the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level, a rheumatoid factor assay, an antinuclear antibody (ANA) test, a measurement of serum uric acid level, and a urinalysis. Test results must be interpreted within a clinical context; for example, a positive ANA assay suggests the possibility of a rheumatic disorder, but it is not specific for any diagnosis. Tests that reveal the nature and extent of target-organ involvement, such as renal function studies in patients with systemic lupus erythematosus, can help guide the selection of therapy. Laboratory results also reflect disease activity; the ESR and CRP level are useful gauges of the activity of most inflammatory rheumatic disorders. Finally, laboratory monitoring can help you minimize the significant toxicity associated with many of the drugs used to manage rheumatic diseases.

SAT0236 Role of serological markers at baseline and follow-up in predicting biopsy proven lupus nephritis

Background Studies have shown that 30-50% of SLE patients (pts) develop lupus nephritis (LN). Patients with high affinity anti-dsDNA antibodies (abs) are more likely to develop LN. The Farr radioimmunoassay is the best method of detecting these abs but is rarely available. Instead ELISA tests for anti-dsDNA abs that detect abs of variable affinity and Crithidia test for high affinity abs are used. It is unclear if the Crithidia test needs to be repeated at every visit with C3 and C4 & anti-dsDNA abs by ELISA to assess lupus activity and the risk of developing LN. Objectives To audit the relationship between anti-dsDNA abs by ELISA & Crithidia, & low C3 & C4 at baseline & follow-up in SLE pts with and without biopsy proven LN. Methods Data was recorded prospectively from 1989 including lupus activity, renal biopsy (WHO classification), anti-dsDNA abs by ELISA & Crithidia, C3 and C4 levels. Pts were excluded if not seen in the clinic before 1st renal biopsy, had <2 visits to the clinic or had missing baseline &/or followup data. Pts that developed Class III/IV ±class V were combined. Pure class V LN was analysed separately. Results Of 309 pts, 290 (94%) were eligible: 93%female, 7% male,12.7% Afro-Caribbean, 17% South Asian, 63%Caucasian, 2% Chinese & 3% recorded as mixed/other. The mean±sd age was 49±15.1 & disease duration 17.5±8.3 years. There were 43 eligible pts with renal biopsies. Distribution of each WHO class of LN was Class II 16%, Class III/IV 63%, and Class V 9%. The 27 pts that developed Class III/IV LN (LNIII/IV) were compared with remaining 263 pts. At baseline, 78% of LN III/IV patients had anti ds-DNA abs by ELISA and Crithidia, vs 20% positive (pos) for both without LN III/IV, see table 1; 81% of LN III/IV were pos for each anti-DNA abs test vs 33% without LN III/IV ELISA pos and 22% Crithidia pos. Low C3 & C4 was present in 63% with LN III/IV and 7% without LN III/IV, and 63% with LN III/IV had pos ELISA & low C3/C4 vs 5% without LN III/IV. Pos ELISA, Crithidia and low C3/C4 was found in 78% with LN III/IV vs 5% without LN III/IV. There was no significant relationship between any anti-dsDNA antibody or complement test singly or in combination at baseline and the subsequent development of class V lupus nephritis. Over time more patients developed anti-dsDNA abs measured by ELISAand Crithidia. Developing Crithidia pos later was not helpful in identifying those more at risk of LN III/IV than baseline measurement. The combination of anti-dsDNA by ELISA with low C3/C4 was sensitive for identifying those at risk of LN III/IV. Conclusions This audit suggests that the combination of anti-ds DNA abs by ELISA and Crithidia together with low C3/C4 results at baseline can help to identify patients at most risk of developing class III/IV LN. Results do not support the need to measure anti-dsDNA abs by Crithidia serially, but do support the combination of ELISA, C3 & C4. Disclosure of Interest None Declared