Chronic synovitis and HLA B27 in patients with severe haemophilia

RESEARCH LETTERS patient they were closed in inspiration and expiration. In one patient, one valve opened with every expiration and closed in inspiration. The improvement in lung function was greater in patients with radiographic signs of collapse than in those without (figure 2). In two patients the FEV1 had improved by 80–100% 1 week after the procedure, which was maintained at 4 weeks. That the intended lobar collapse was achieved in only four of the eight patients might have been because patients with very severe emphysema had large collateral air flow between the target and non-target lobes. The finding that the volume did not change in the patient in whom one of the valves opened with every expiration (suggesting substantial collateral ventilation) lends support to this hypothesis. However, even without lobar collapse, blocking air entry into the most emphysematous lobes achieved a small but consistent benefit, especially in the TLCO. The mechanisms for such an effect are not clear; a possibility is that the TLCO improves because of reduced dead-space ventilation in the target region. The ipsilateral pneumothorax in two of our patients was probably caused by tearing in either the expanding or collapsing lung and not by the procedure itself. The pneumothoraces occurred days after the procedure and always after radiographic signs of collapse were noted. We believe that the presence of concomitant pleural adhesions lead to the lung tearing in both collapsing or re-expanding lobes. Observation after the procedure is important, but the overall risk of pneumothorax needs to be better defined in a larger trial. The absence of postobstructive pneumonia, albeit during a short follow-up period, is reassuring. Emphysematous airways should be sterile at the time of insertion and complete (not partial) occlusion blocks entry of pathogens in the target lobe. Furthermore, the valve is designed to allow clearance of secretions. The unilateral approach allows the possibility of a further palliative intervention if needed, and with more experience, bilateral insertion could be attempted. An advantage of lungvolume reduction with endobronchial valves is that the procedure can be reversed and other treatments tried if necessary. An earlier version of the same endobronchial valve has been used in patients suitable for LVRS.4 The procedure was safe in those patients, but the device used did not reduce radiological volume in any of the patients treated, probably because of poor valve closure. Thus the design of the valve was modified before our study. Patient selection may also have been a factor. Different technologies based on much the same idea have been reported with good safety and efficacy results in animal models of emphysema.5 Our study did not include any form of control treatment. A randomised controlled study will be needed, but a placebo effect probably would not account for improvements in some variables, in particular the radiology and the TLCO. Second, some of the other variables did not significantly change, and a randomised trial of endobronchial valve therapy needs to be powered to detect clinically important differences. Our results suggest that volume reduction can be achieved with unilateral bronchoscopically placed valve implants in patients with severe emphysema with acceptable short-term safety and worthwhile functional benefits. Conflict of interest statement T Toma and D Geddes received an honararium for time spent attending two FDA meetings in Washington DC, USA, to discuss research protocols with the Emphasys valve system. T Toma’s salary is supported by the Royal Brompton Emphysema Research Fund. M Polkey has received assistance to attend international congresses and honoraria for speaking from several drug companies, including AstraZeneca, GSK, Cephalon, and 3M. Acknowledgements This work was supported by an unrestricted grant from Royal Brompton Emphysema Research Fund and Emphasys. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing the report. 1 2 3 4 5 Geddes D, Davies M, Koyama H, et al. Effect of lung-volume-reduction surgery in patients with severe emphysema. N Engl J Med 2000; 343: 239–45. Patients at high risk of death after lung-volume-reduction surgery. N Engl J Med 2001; 345: 1075–83. Toma TP. Lung-volume reduction. Lancet 2001; 357: 1621. Snell GI, Smith JA, Silvers AJ, et al. Bronchoscopic volume reduction: a pilot study. ACCP meeting. 2001; Paper 25. Ingenito EP, Berger RL, Henderson AC, Reilly JJ, Tsai L, Hoffman A. Bronchoscopic lung volume reduction using tissue engineering principles. Am J Respir Crit Care Med 2003; 167: 771–78. Department of Thoracic Medicine, National Heart and Lung Institute, London, UK (T P Toma MD); Departments of Respiratory Medicine (N Hopkinson MRCP, M Polkey MRCP, Prof D M Geddes FRCP), Radiology (Prof D M Hansell MD), Anaesthesia (C Morgan FRCA, J Hillier FRCA, and Thoracic Surgery (P Goldstraw FRCS), Royal Brompton Hospital, London Correspondence to: Prof Duncan M Geddes, Department of Respiratory Medicine, Royal Brompton Hospital, London SW3 6NP, UK (e-mail: [email protected]) Chronic synovitis and HLA B27 in patients with severe haemophilia Kanjaksha Ghosh, Umapathy Shankarkumar, Shrimati Shetty, Dipika Mohanty Chronic synovitis affects about 10% of patients with severe haemophilia in India. This disease has some features in common with ankylosing spondylitis, which has been linked to HLA B27. We therefore aimed to test whether there is an association between HLA B27 and chronic synovitis. We studied 473 patients with severe haemophilia (33 of whom had chronic synovitis), and 1175 healthy controls using a standard serological technique and the reverse line strip assay. 64% (21 of 33) of patients with haemophilia and chronic synovitis were positive for HLA B27, compared with 5% (23 of 440) of those with severe haemophilia, but not chronic synovitis (odds ratio 31·6 [95% CI 9·28–39·38], p<0·0001), and 9% (100 of 1175) of healthy controls (18·81 [9·6–27·7], p<0·0001). We conclude that there is a strong association between HLA B27 and chronic synovitis in Indian patients with severe haemophilia and screening in this population could allow treatment and prevention of the complication. Lancet 2003; 361: 933–34 Chronic synovitis in patients with severe haemophilia has striking similarities to the chronic synovitis seen in cases of Without chronic synovitis (n=440) Contributors T Toma, M Polkey, and D Geddes prepared the protcol, recruited patients, inserted the valves, monitored patients, gathered and analysed data, and prepared the report. N Hopkinson prepared the protocol, recruited the patients, measured lung function, analysed the data, and prepared the report. J Hillier and C Morgan prepared the anaesthetic protocol, anaesthetised the patients, and monitored their recovery. D Hansell prepared the CT scanning protocol, analysed the radiographic images, and prepared the report. P Goldstraw prepared the protocol, inserted the valves, analysed the data, and prepared the report. D Geddes also supervised the study. THE LANCET • Vol 361 • March 15, 2003 • www.thelancet.com Median age (years [range]) Mean number bleeds per year (SD) Inhibitors HIV-1 positive HBsAg positive HCV positive 14·8 (8–44) 8·2 (7·6) 36 (8%) 20 (5%) 38 (9%) 108 (25%) With chronic synovitis (n=33) 13·5 (6–41) 9·5 (9·2) 3 (9%) 1 (3%) 4 (12%) 9 (27%) Table 1: Characteristics of patients with haemophilia 933 For personal use. Only reproduce with permission from The Lancet Publishing Group. RESEARCH LETTERS Controls (n=1175) Haemophilia without chronic synovitis (n=440) Haemophilia with chronic synovitis (n=33) B27 positive B27 negative Odds ratio (95% CI) p 100 23 21 1075 417 12 0·59 (0·51–0·67)* 18·81 (9·6–27·7)† 31·6 (9·28–39·38)‡ 0·0267 <0·0001 <0·0001 *Controls vs haemopilia without chronic synovitis. †Controls vs haemopilia with chronic synovitis. ‡Haemopilia without chronic synovitis vs haemopilia with chronic synovitis. Table 2: Presence of HLA B27 in controls and haemophilia patients with and without chronic synovitis seronegative spondylarthritis, which is strongly linked to HLA B27.1–3 It is fairly common (about 10%) in patients with severe haemophilia. We sought to test the association between HLA B27 and chronic synovitis in patients with severe haemophilia. All haemophiliacs in Mumbai, India are registered with the Haemophilia Society, and attend the comprehensive haemophilia care unit at the Institute of Immunohaematology at least once every 6 months. We recruited 473 patients with severe haemophilia, with a mean age of 16·8 years (SD 7·6) who attended the unit from April, 1994 to November, 2001. We avoided selection bias because our cohort study included all patients with severe haemophilia in Mumbai. During the same period, we selected 1175 healthy individuals from Mumbai; they had a mean age of 36·2 years (13·2) and were unrelated to our patients. These control individuals were tissue typed as part of another study of HLA polymorphisms in the population that ran concurrently with ours. Both studies were approved by the institute’s ethics committee, and written informed consent was obtained from all patients and controls. Serological and molecular HLA typing were done by an investigator (US), who was not aware of whether samples were from controls or patients. We did standard coagulation tests and determined HLA status in these patients using a serological method—ie, simultaneous testing for the presence of at least three HLA B27 monospecific antisera (Anti HLA-ABC, Biotest, Dreieich, Germany). We extracted DNA from the blood samples of all participants who were identified as HLA B27 positive by the serological method. The HLA subtype was further tested with PCR-sequence specific primers (Histotype DNA-B27, Biologische Analysen System, Lich, Germany) by use of the reverse line strip (RLS) assay.4 We tested serum from patients with chronic synovitis for antinuclear factor using ELISA and rheumatoid factor with a latex agglutination kit. HLA status of patients was concealed from the doctor (DM) who did clinical examinations. Patients with haemophilia were clinically assessed and we used a proforma to record disabilities, approximate number of bleeds per year, joints affected by synovitis, and the frequency and nature of replacement therapy. Table 1 shows characteristics of patients in the haemophilia group. Almost all patients had received replacement therapy with cryoprecipitate during an acute bleed, and those with chronic synovitis had all received factor concentrate. Of the 473 patients with severe haemophilia, 424 had factor VIII and 49 had factor IX deficiency. 33 patients had chronic synovitis, which presented as swelling of the joint with heat and redness, and absence of response to treatment with factor concentrate given for at least 7 consecutive days. These patients had had chronic synovitis for between 6 and 43 months. The prevalence of inhibitors in patients with synovitis was almost the same as that reported previously.5 There were three sibling pairs in the haemophilia group, and in every pair, one sibling had chronic synovitis and the other did not. In every case, the affected patients were HLA B27 positive, whereas the unaffected siblings were not. For 28 of the 33 patients with synovitis, one or more knee joints was affected, and of these patients, two also had an affected ankle, one also an elbow, and one also a shoulder. In five 934 patients, only the ankle joint was affected. None of the 33 patients tested positive for ANA or rheumatoid factor. Radiographs and MRI of all the patients with synovitis showed effusion and synovial thickening of the joints. Table 2 shows the frequency of HLA B27 in different groups. Patients with HLA B27 and severe haemophilia had a greater risk of developing chronic synovitis than did those without HLA B27 (relative risk 12·17, 95% CI 5·32–18·97) Molecular subtypes of HLA B27 in the controls and the haemophilia patients with chronic synovitis were distributed in a broadly similar fashion—ie, B*2704 (37%), B*2705 (30%), B*2707 (26%), B*2708 (7%) in controls, and B*2704 (20%), B*2705 (29%), B*2707 (4%) and B*2708 (47%) in patients with chronic synovitis. The B*2708 allele has not previously been described in the Indian population. In our study population, about 9% patients with severe haemophilia had chronic synovitis, and a large proportion (about 64%) of these patients showed HLA B27 on tissue typing. Thus, patients with severe haemophilia and HLA B27 have a greater risk of developing chronic synovitis than do those without the antigen. This conclusion is lent support by the fact that within three sibling pairs, chronic synovitis was associated with positive HLA B27 status. We do not know why or how HLA B27 is so strongly linked with ankylosing spondylitis, or chronic synovitis in patients with haemophilia. One explanation might be that patients who inherit HLA B27 cannot easily downregulate inflammatory mediators after bleeding in the joints, leading to chronic synovitis. Identification of an association between this antigen and chronic synovitis in patients with haemophilia could be clinically useful. Screening could identify those who are likely to develop chronic synovitis and aggressive treatment could be initiated to prevent this complication. Contributors K Ghosh conceived, designed the study, did statistical analysis and wrote the manuscript; U Shankarkumar did tissue typing; S Shetty did coagulation studies of the patients and assisted with statistical analysis; D Mohanty examined patients, and provided suggestions to improve the manuscript. Conflict of interest statement None declared. Acknowledgments The study was funded by the Indian Council of Medical Research (ICMR). 1 Rodriguez – Merchan EC. The destructive capabilities of the synovium in the haemophiliac joint. Haemophilia 1998; 4: 506–10. 2 Sengupta S, Sehgal S, Aikat BK, et al HLA B27 in ankylosing spondylitis in India. Lancet 1977; 1: 1209–10. 3 Shankarkumar U, Devaraj JP, Ghosh K, Mohanty D. Seronegative spondarthritis and human leucocyte antigen association. Br J Biomed Sci 2002; 59: 11–14. 4 Mack SJ, Geyer LN, Eilich HA. HLA class I reverse line blot typing protocol. In: HLA-2000 IHWG Technical Manual. Tilarus MGJ, ed. Seattle: Fred Hutchinson Cancer Research Center, 2000 5 Ghosh K, Shetty S, Kulkarni B et al. Development of inhibitors in patients with haemophilia from India. Haemophilia 2001; 7: 273–78. Institute of Immunohaematology, Floor 13, New Building, KEM Hospital Campus, Parel, Mumbai 400 012, India (K Ghosh MD, U Shankarkumar PhD, S Shetty PhD, Dipika Mohanty MD) Correspondence to: Dr Dipika Mohanty (e-mail: [email protected]) THE LANCET • Vol 361 • March 15, 2003 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet Publishing Group.