sign in sign up
<<
Home , Hemarthrosis

588 Annals ofthe Rheumatic Diseases 1991; 50: 588-591

REVIEW Ann Rheum Dis: first published as 10.1136/ard.50.8.588 on 1 August 1991. Downloaded from

Haemophilic

Rajan Madhok, John York, Roger D Sturrock

Haemophilic arthritis is a relatively rare arthro- 90% of severely affected patients have this pathy, but several aspects of its management complication.2 Three stages are recognised: and pathogenesis are of interest to rheuma- acute haemarthrosis, chronic synovitis, and tologists. Firstly, the number of haemophiliac degenerative arthritis. patients has increased simultaneously with Haemarthroses occur most commonly into availability of clotting factor. concentrates, and , elbows, and ankles. Patients are often most severely affected patients are likely to have aware of a bleed before any clinical signs. Once arthritis amenable to prevention or amelioration a haemarthrosis is established the is tense, by approaches familiar to rheumatologists. painful, and held in flexion. One joint often Secondly, the pathogenesis is unclear, and a becomes a focus for recurrent . further understanding may provide insights into Onset of the synovitic stage is often difficult the responses of joint tissues to . Thirdly, to establish. The patient presents with persis- the histopathology of haemophilic arthritis tent swelling in the absence of pain in a target represents one extreme of changes seen in joint. Swelling is due to synovial hypertrophy rheumatoid synovium, and thus haemophilic and usually refractory to clotting factor concen- arthritis may highlight common mechanisms in trate infusions. Joint aspiration may show an joint destruction. inflammatory exudate mixed with . Early degenerative arthritis is considered to be present if chronic synovitis persists for more Why haemophiliac patients bleed into than six months.3 describes two disorders-haemo- philia A due to factor VIlIc deficiency and due to factor IX deficiency. Both Pathology factors are glycoproteins, encoded by X Acute joint bleeding produces a transient acute http://ard.bmj.com/ chromosome genes that form part of the intrin- inflammatory synovitis, and resolution of these sic plasma clotting system. Specifically, factors changes is often slow.4 With repeated haem- VIIIc and IX activate . The clinical arthroses synoviocyte hypertrophy and hyper- manifestations of both disorders are therefore plasia supervene, which are supported by an similar. intense neovascularisation of the synovial mem- The predisposition to musculoskeletal bleed- brane. A characteristic feature is deposition of ing in haemophilia compared with other con- iron in superficial and subsynovial layers. A on September 25, 2021 by guest. Protected copyright. genital and acquired disorders can- perivascular mononuclear cell infiltrate and not be entirely explained by a single cause. fibrosis is also present. At the joint periphery Mechanical factors are important as suggested the inflamed synovium is organised into a by the onset of haemarthrosis with weight fibrous pannus, which is locally invasive. bearing; more frequent occurrence of bleeds Cartilage loss also occurs in weightbearing into legs than arms; and the propensity of joints areas, and at such sites chondrocytes contain on the dominant side to be more severely haemosiderin. In the later stages there is com- affected. The inherent absence of tissue plete loss of cartilage and subchondral bone is thromboplastin in synovium combined with an exposed with cyst formation. This is followed impaired intrinsic coagulation pathway may be by collapse and sclerosis of the joint. another factor.' The early pathological features have been described in spontaneous haemophilia in dogs, and changes similar to haemophilic arthritis Clinical manifestations have been reproduced in experimental animals The frequency of bleeding episodes parallels with injections of autologous blood`'0 Some plasma factor concentrations.2 Severe defects aspects of haemophilic arthritis remain unclear, (<1 1U/1) are characterised by spontaneous however. Firstly, the response of joint tissues to bleeding-the most common sites being joints, intra-articular blood is incompletely under- Centre for Rheumatic muscles, and renal tract. Factor concentrations stood-changes include synovitis and sub- Diseases, University 1 in after but the component or Department of Medicine, between and 5 IU/l result bleeding synovial angiogenesis, 10 Alexandra Parade, minor trauma. In mild deficiency (5-50 IU/1), components of blood that initiate and per- Glasgow G31 2ER bleeding occurs after severe trauma or surgery. petuate synovitis are not known. Secondly, R Madhok concentrations remain stable throughout mediators participating in cartilage breakdown J York Factor R D Sturrock life, except in rare variants. are uncertain. Thirdly, the way in which iron most enters chondrocytes is not yet explained. An Correspondence to: Joint disease is the single important Dr Madhok. cause of morbidity in haemophilia and up to understanding of these mechanisms may Haemophilic arthris 589

provide insights into the pathogenesis of more arthritis, but the incidence has increased

common inflammatory , such as in patients with HIV-1 related immuno- Ann Rheum Dis: first published as 10.1136/ard.50.8.588 on 1 August 1991. Downloaded from . deficiency. 18 Haemophilic synovitis represents one Systemic corticosteroid treatment has been extreme of the continuum of histological evaluated in dampening the intra-articular in- changes present in rheumatoid arthritis. In both flammatory response in acute haemarthrosis, rheumatoid and haemophilic arthritis it has but the benefits are short lived and because of been suggested that iron perpetuates synovitis frequent side effects their use is limited and not and mediates tissue damage.'0'2 In both rheu- advocated. " matoid and haemophilic arthritis microbleeding Although treatment for haemophilia has is well recorded, and synovial iron deposition greatly improved, the influence of clotting correlates closely with the extent of erosive factor replacement therapy on the progression disease and is associated with a poorer prog- of haemophilic arthritis is not known. Two nosis.'3 4 Differences include the relative uncontrolled studies reported that arthritis absence of a chronic inflammatory response and progresses despite adequate early treatment of the presence of iron with chondrocytes in haemarthrosis, and even patients receiving haemophilic arthritis.'5 A possible sequence of prophylactic infusions develop episodes of events in haemophilic arthritis may be that synovitis.20 21 To determine further the intra-articular bleeding initially provokes a non- influence of clotting factor on the outcome of specific inflammatory response, and macro- arthritis in haemophilia an international co- phages accumulate around synovial iron operative study has been started. An interim deposits, release monokines, and stimulate analysis at four years showed that progression production of latent collagenases and pros- seems to be directly related to the frequency of tanoids from synovium. With repeated haem- joint bleeds. Treatment with dose regimens of arthroses the synovium proliferates, and the greater than 1000 units/kg a year confers some continued leak of red blood cells from the advantage in progression, but more than 2000 hypertrophied, vascular synovium produces a units/kg a year offer no additional advantage. cycle of synovitis--bleeding--synovitis. The The early use of clotting factor concentrates, increased iron load results in further synovio- therefore, seems to delay rather than prevent cyte hyperplasia, pannus formation, and macro- haemophilic arthritis. A small subgroup of phage accumulation. patients was identified in whom no joint disease The cartilage loss is multifactorial, initiated was found. These patients had used signifi- by sequestered polymorphonuclear cells and the cantly more clotting factor concentrate and had increased amounts of plasmin in the inflamed been receiving prophylactic treatment more synovium," and perpetuated by the synovial often than those who had progressive disease response, mediating damage directly in areas (Aledort, personal communication). where pannus forms.'0 In areas free from On the other hand, the lifelong dependence pannus the deposition of iron within chrondro- on blood products has placed patients with http://ard.bmj.com/ cytes may play an important part.'0 15 haemophilia at increased risk of blood borne viral infections. Hepatitis due to hepatitis B and the non A, non B agents is invariably found in Treatment regularly treated haemophiliac patients, and The aims in treating haemophilic arthritis are chronic liver disease is an increasingly common similar to those of any inflammatory arthro- cause of morbidity.22 23 HIV-1 induced pathy: symptom relief, prevention of the pro- immunodeficiency is now the most common on September 25, 2021 by guest. Protected copyright. gression of the joint damage, and maintenance cause of death in patients with severe haemo- of function. In haemophilic arthritis these goals philia.24 The risk of infections with these agents can be achieved by early treatment of haem- in the future has been significantly reduced, arthrosis and by limiting the effects of chronic however, with newer methods of fractionating synovitis. In the subject with degenerative and sterilising clotting factor concentrates. The changes function is amenable to correction by recent availability of screening tests for hepatitis surgical/physical methods with adequate hae- C should further reduce the incidence of mostatic cover. hepatitis.

ACUTE HAEMARTHROSIS CHRONIC SYNOVITIS Management of acute haemarthrosis is directed The aim in treating haemophilic synovitis is to at stopping bleeding with replacement treat- prevent further cartilage damage. At present ment and provision of adequate analgesia. Early treatment remains empirical and is directed at treatment of bleeding can be achieved by the interrupting the cycle of bleeding--synovitis-- provision of clotting factor concentrates for bleeding. Further haemarthrosis may be pre- home treatment. vented by prophylactic replacement treatment. Arthrocentesis is not generally recommended The synovitis, however, is more difficult to in the management of haemarthrosis. This suppress, and both surgical and radiochemical procedure has not been shown to slow down the have been tried.253' The im- progression of haemophilic arthritis. 7 Joint mediate to short term benefits of surgical aspiration should be considered in a large tense synovectomy in reducing bleeds are encourag- haemarthrosis for symptomatic relief or if joint ing, but, unfortunately, the procedure is associ- sepsis is suspected. was pre- ated with stiffness and loss of motion. Few long viously a rare complication df haemophilic term results have been published.32 More 590 Madhok, York, Strock

Sugical treamen opions in haemophilic arthitis Joint affected Synovecmy Arthrodesis Ann Rheum Dis: first published as 10.1136/ard.50.8.588 on 1 August 1991. Downloaded from Shoulder Rarely indicated Good pain relief Little experience Elbow Good pain relief. Often combined Rarely indicated Little experience with newer with radial head excision prosthesis Hip Results comparable with other inflammatory arthropathies Reduces frequency of haemarthrosis/ Consider if arthoplasty fails Procedure of choice associated with loss of function Ankle/subtalar Rarely indicated Procedure of choice Results unsatisfactory

recently, arthroscopic synovectomy has been remains prevention, and the availability of attempted, but in both surgical and arthro- monoclonal antibody purified and recombinant scopic synovectomy33 postoperative bleeding factor concentrates free of infectious agents has been a problem. combined with a comprehensive approach to Radiocolloids reduce the frequency of subse- treatment make this goal attainable. Further quent bleeds but seem not to confer any studies of the pathogenesis of haemophilic additional advantages.30 We have often used arthritis may clarify mechanisms of joint intra-articular corticosteroid treatment and damage in the more common arthropathies. found that the subsequent use of clotting factor concentrate was reduced and the subjective We are grateful to Ann Tierney for typing the manuscript. We thank Dr M Steven, Dr G DO Lowe, and Professor C D Forbes intensity and duration of synovitis was dimin- for helpful discussions. ished. Favourable results have also been re- ported with osmic acid (York, personal com- 1 Harrold D J. The defect of blood coagulation in joints. J Clin munication). If intra-articular treatment is to be Pathol 1961; 14: 305-8. used our policy is to perform the procedure 2 Forbes C D. Clinical aspects of the haemophilias and their treatment. In: Ratnoff 0 D, Forbes C D, eds. Disorders of under prophylactic clotting factor concentrate hemostasis. Orlando, Florida: Grune and Stratton, 1984; cover, and patients remain non-weight-bearing 177-241. 3 Arnold W D, Hilgartner M W. Haemophilic . for at least 24 hours. In patients positive for Current concerns of pathogenesis and management. J Bone antibody to HIV-1 the increased risk of joint joint Surg [Am) 1977; 59: 287-305. 4 Forbes C D, Greig W R, Prentice C R M. Radioisotope knee sepsis should be borne in mind. Surgical syno- scans in haemophilia and christmas disease. J Bone Joint vectomy should be considered if synovitis per- Surg [Br] 1972; 54: 468-75. S Swanton M C. Hemophilic arthritis in dogs. Lab Invest 1959; sists for six months. 8: 1269-77. D-Penicillamine has been shown to reduce the 6 Hoaglund F T. Experimental hemarthrosis. The response of canine knees to injection of autologous blood. J BoneJoint mononuclear cell infiltrate in an animal model Surg [Am] 1967; 49: 285-98. of haemophilic arthritis.34 Anecdotal experience 7 Wolf C R, Mankin H J. The effect of experimental in four patients treated with D-penicillamine for hemarthrosis in articular cartilage on the rabbit knee joint. J7 Bone Joins Surg [Am] 1965; 47: 1203-10. http://ard.bmj.com/ a median of 10 weeks showed promising results 8 Roy S. Ultrastructure of articular cartilage in experimental hemarthrosis. Archives of Pathology 1968; 86: 69-75. in three.34 9 Convery R F, Woo L-Y S, Akeson W H, Arneil D, Malcom L L. Experimental hemarthrosis in the knee joint of the mature canine. Arthritis Rheum 1976; 19: 59-67. 10 Madhok R, Bennett D, Sturrock R D, Forbes C D. DEGENERATIVE ARTHRITIS Mechanisms of joint damage in an experimental model of hemophilic arthritis. Arthritis Rheum 1988; 31: 148-55. Degeneration of the joint in haemophiliac 11 Stein H, Duthie R B. The pathogenesis of chronic haemo- patients results in pain and progressive impair- philic arthropathy. J BoneJointSSg [Br] 1981; 63: 601-7. 12 Blake D R, Hall N D, Bacon P A, Dieppe P A, Halliwell B, on September 25, 2021 by guest. Protected copyright. ment of function. Adequate analgesia in such Gutteridge J M C. The importance of iron in rheumatoid patients can be difficult to provide and is often disease. Lancet 1981; ii: 1142-4. 13 Bennett R M, WilliamsE D, Lewis S H, Holt P J L. Synovial influenced by previous drug habituation. The iron deposition in rheumatoid arthritis. Arthritis Rheum efficacy and safety of non-steroidal anti-inflam- 1973; 16: 298-304. 14 Blake D R, Gallagher P J, Potter A R, Bell M J, Bacon P A. matory agents has been evaluated.3l39Ibu- The effect of synovial iron on the progression of rheuma- profen has the advantage of a short half life and toid disease: a histologic assessment of patieats with early rheumatoid synovitis. Arthitis Rheum 1984; 27: 495-501. flexible dosage regimen; its effect on the gastro- 15 Hough A J, Banfield W J, Sokoloff L. Cartilage in haemo- intestinal tract is a limiting factor, however. Its philic arthropathy. Arch Pathol Lab Med 1976; 100: 91-5. 16 Storti E, Magrini V, Ascari E. Synovial fibrinolysis and cautious use in selected patients may be haemophilic haemarthrosis. BMJ 1971; 4: 812. beneficial. 17 Ingram G I C, Matthews J A, Bennett A E. Controlled trial of joint aspiration in acute haeftiophilic arthrosis. Br J Corrective orthopaedic surgery, including Haematol 1972; 23: 649-54. replacement arthroplasties of hips,40 knees,4' 18 Ellison Reller B L. Differentiating pyogenic arthritis from spontaneous hewarthrosis in patients with hemophilia. and elbows,42 has been successfully undertaken West J Med 1986; 144: 42-5. in patients with haemophilia. It requires inten- 19 Kisker C T, Burke C. Double blind studies on the use of steroids in the treatment of acute haemarth is in patients sive monitoring to maintain haemostasis, how- with haemophilia. N Engi J Med 1970; 282: 639-42. ever, and should be undertaken only in centres 20 Ali A M, Gandy R H, Britten M I, et al. Joint haemorrhage in haemophilia: Is full advantage taken of plasma therapy.? where facilities and experience are available. BMJ 1967; iii: 828-31. The table shows possible surgical options. The 21 Levine P H. Efficacy of self therapy in haemophilia: a study of 72 patients with and B. N Engi J Med only haemostatic contraindication is the 1974; 291: 1381-4. presence of a high titre inhibitor. 22 Fletcher M L, Trowel J M, Crgske J, et al. Non-A, non-B hepatitis after transfusion of factor VIII in infrequently treated patients. BMJ 1983; 287: 1754-7. In conclusion, several aspects of haemophilic 23 Aledort L M, Levine P H, Hilgartner M, et al. A study of liver biopsies and liver disease among haemophiliacs. Blood arthritis are amenable to treatment. Manage- 1985; 66: 367-72. ment of chronic haemophilic synovitis remains a 24 Darby S C, Rizza C R, DollR, Spooner R J D, Stratton I M, Thakrar B. Incidence of AIDS and excess mortality problem, but approaches familiar to rheumato- associated with HIV in haemophiliacs in the United logists may be helpful. The best treatment Kingdom: a report on the behalf of the directors of Haemophilic artitis 591

haemophilia centres in the United Kingdom. BMJ 1989; pathy of the knee. Scand Haematol 1984; 33 (suppl 40): 298: 1064-8. 263-70. 25 Storti E, Traldi A, Tosatti E, et al. Synovectomy, a new 34 Corrigan J J, Kolba K S, Gail E P, et al. Treatment of Ann Rheum Dis: first published as 10.1136/ard.50.8.588 on 1 August 1991. Downloaded from approach to haemophiliac arthropathy. Acta Haematol hemophilic arthropathy with D penicillamine: a pre- (Basel) 1%9; 41: 193-205. liminary report. Am Hematol 1985; 19: 255-64. 26 Stori E, Ascari E. Surgical and chemical synovectomy. Ann N 35 McIntyre B A, Philp R B, Inwood M J. Effect of ibuprofen Y Acad Sci 1975; 240: 316-7. on function in normal subjects and hemophiliac 27 Pietrogrande V, Dioguardi N, Mannucci P M. Short-term patients. Clin Pharmacol Ther 1978; 24: 616-21. evaluation of synovectomy in haemophilia. BMJ 1972; ii: 36 Inwood M J, Killackey B, Startup S J. The use and safety of 378-81. ibuprofen in the haemophiliac. Blood 1983; 61: 709-11. 28 Kay L, Stainsby D, Buzzard B, et al. The role of synovec- 37 Thomas P, Hepburn B, Kim H C, Saidi P. Nonsteroidal anti- tomy in the management of recurrent haemarthroses in inflammatory drugs in the treatment of hemophilic arthro- hamophilia. Br J Haematol 1981; 49: 53-60. pathy. Am Hematol 1982; 12: 131-7. 29 Ahlberg A, Pettersson H. Synoviorthesis with radioactive 38 Hasiba U, Scranton P E, Lewis J H, Spero J A. Efficacy and gold in haemophiliacs. Clinical and radiological follow-up. safety of ibuprofen for hemophilic arthropathy. Arch Intern Acta Ordhop Scand 1979; 50: 513-7. Med 1980; 140: 1583-5. 30 Erken E H W. Radiocolloids: joint protection in haemophiiia. 39 Steven M M, Small M, Pinkerton L, Madhok R, Sturrock R In: Dohring S, Schulitz M C, (eds). Orhopedic problems in D, Forbes C D. Non-steroidal anti-inflammatory drugs in haemophilia: symposiun Dusseldorf. Munich: Zuckschwerdt, haemophilic arthritis-a clinical and laboratory study. 1985: 153-7. Haemostasis 1985; 15: 204-9. 31 Fernadez-Palezzi F, de Bosch N, de Vargas A F. Radioactive 40 Houghton G R. Joint surgery in haemophilia. In: Forbes C synovectomy in haemophiliac haemarhrosis. Follow up of D, Lowe G D 0, eds. Unresolved probkms in haemophilia. fifty cases. ScandJ Haematol 1984; 33 (suppl 40): 291-300. Lancaster, UK: MTP Press, 1982: 217-33. 32 Gamba G, Molinari E, Grignani G, Geroldi D, Ascari E, 41 Small M, Steven M M, Freeman P A, et al. Total knee Ceciliani L. Long term evaluation of the results of arthroplasty in haemophilic arthritis. Bone Joint Surg synovectomy and of synoviorthesis in the treatment of [Br] 1983; 65: 163-5. haemophilic haemarthrosis. Haemaologica 1979; 64: 42 Gilbert M S, Arnold W D. Elbow surgery in haemophilia. In: 783y95. Seligsohn V, Rimon A, Horoszowski H, eds. Haemophilia. 33 Wiedel J D. Arthroscopic synovectomy in hemophilic arthro- Kent, UK: Castle House Publications, 1981: 195-9. http://ard.bmj.com/ on September 25, 2021 by guest. Protected copyright.