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416 Annals ofthe Rheumatic Diseases 1992; 51: 416-419

Bone abnormalities and severe arthritis in

R G Cooper, A J Freemont, M Riley, P J L Holt, D C Anderson, M I V Jayson

Abstract (normal value <10 MU/1) suppressing to 2 2 Two patients with pachydermoperiostosis MU/l during a standard glucose tolerance test; were studied in whom the predominant chest and skull radiographs were normal. In features at presentation were severe and view of the normal endocrine results, the disabling and in asso- patient was referred to a rheumatologist. ciation with distal long bone pain. Analysis Subsequent investigations showed that IgM of synovial fluid from the knee showed , antinuclear factor, and non-inflammatory changes. In one patient a erythematosus cells were negative and that bicortical iliac crest bone biopsy specimen, plasma calcium, inorganic phosphate and taken after labelling with demeclocycline, alkaline phosphatase, and serum iron, iron showed appositional rates which were in- binding capacity, immunoglobulin levels and creased in cortical bone but reduced in liver function tests (serum aspartate amino- trabecular bone. This mismatching resulted in transferase and serum alanine aminotransferase, trabecular osteoporosis, which occurred in and bilirubin) were normal. Twenty four hour association with increased numbers of osteo- urinary calcium excretion was also normal clasts, fidings which suggest differential (4- 1-5 2 mmol), but that of hydroxyproline was functional changes affecting the two bony increased to 35-45 mg/M2 (normal 20 mg/M2). University of envelopes. A radiological examination showed a periosteal Manchester, reaction along the distal ulnae, tibiae, and Rheumatic Diseases Centre, Hope Hospital, fibulae and a bone scan using labelling with Salford, United Kingdom Pachydermoperiostosis, or primaryhypertrophic strontium 87 confirmed increased isotope R G Cooper osteoarthropathy, was first described in 1935.' uptake at these sites. A synovial biopsy sample M I V Jayson It is an inherited disease which is autosomal from the right knee showed venous dilatation University of and it is without whereas a biopsy sample Manchester, dominant with variable penetration Department of phenotypically more severe in men. The disease of from the ankle showed gross dermal Medicine is characterised clinically by digital clubbing, thickening with hypertrophy of the sweat (Endocrinology), periostitis, and hypertrophic skin changes glands. A biopsy sample ofthe tibial metaphysis, Hope Hospital, Salford, United Kingdom (pachydermia), which may cause marked after labelling with demeclocycline, showed D C Anderson furrowing of the brow, seborrhoea with hyper- normal osteoid seams with minimal separation University of hidrosis, and or arthritis.2A The of the labelled lines, indicating that the hyper- Manchester, onset of symptoms, which is often preceded by ostosis was relatively inactive. Department of the Pachydermoperiostosis was diagnosed, the , symptomless clubbing, is usually during Manchester Royal second decade of life.4 Although up to 40% of increased hydroxyproline excretion reflecting Infirmary, Oxford Road, patients may develop synovial effusions these the increased metabolic rates of and Manchester, are if bone. In view of the severity of the patient's United Kingdom usually symptomless and, painful, usually M Riley respond to non-steroidal anti-inflammatory joint pain, which had responded poorly to University of drugs (NSAIDs).4 We report two patients with treatment with NSAIDs, a trial with high doses Manchester, primary hypertrophic osteoarthropathy in whom of was thought to be justified Department of bone changes were investigated histologically (enteric coated prednisolone, 50 mg/day) and , Manchester Royal and in whom severe joint pain was the initial the effects were monitored biochemically using Infirmary, Oxford Road, reason for presentation and which was refractory the excretion levels of urinary hydroxyproline. Manchester, to treatment. These decreased towards normal values rapidly United Kingdom but the symptoms continued intermittently and P J L Holt improved only gradually. By 1979 the patient University of Manchester, Case reports still had disabling joint pain and his 24 hour PATIENT 1 urinary hydroxyproline excretion was still Research Centre, In 1971 a healthy 16 year old white boy raised, at 32 mg/M2, but he was now working Manchester, United Kingdom presented to an endocrinologist with severe full time and the prednisolone, which had been A J Freemont joint pain in association with excessive growth. gradually reduced, was discontinued. The D C Anderson There was no relevant family history. Physical patient subsequently continued to have joint Correspondence to: examination showed a tall (196 cm) adolescent symptoms, which were not progressive, and he Dr R G Cooper, Rheumatic Diseases Centre, with marked digital clubbing, gross periarticular remains otherwise well. University of soft tissue hypertrophy around the , Manchester, Hope Hospital, , and , and bilateral knee joint Eccles Old Road, effusions. Acromegaly was suspected clinically. PATIENT 2 Salford M6 8HD, United Kingdom. Initial investigations showed: haemoglobin 126 In 1989 a 17 year old healthy white boy Accepted for publication g/l, erythrocyte sedimentation rate 26 mm/hour, developed severe pain and swelling of his knees 18 June 1991 baseline plasma growth hormone 2-6 MU/I and ankles after playing football. There was no Bone abnormalities and arthritis in pachydermoperiostosis 417

relevant family history. The joints did not withdrawn and treatment with sulphasalazine settle with rest. Rheumatological examination was begun, but without success. In view of the revealed a healthy patient with marked digital severity of his continued problems, which had clubbing and an affecting precluded his finishing A level and business his knees and ankles with bilateral knee joint degree studies, a second rheumatological opinion effusions. As a testicular swelling was also was sought. found, a paramalignant syndrome was suspected The patient now also described hyperhidrosis and a testicular exploration was performed with 60 minutes of morning stiffness and pain and a biopsy sample taken; the histology was affecting the small joints of his fingers and . normal. Other investigations with normal His general health remained good, his weight results included haemoglobin, erythrocyte was steady, and his bowel action normal. sedimentation rate, IgM rheumatoid factor, Physical examination now showed of antinuclear factor, a chest radiograph, and com- the proximal and distal interphalangeal joints of puted tomography examination of the abdomen. his fingers and toes, and tender bony swellings Treatment with an NSAID was begun, but gave of the distal radius, ulna, tibia, and fibula little symptomatic relief, and two months later bilaterally. Further investigations showed a the patient developed severe upper abdominal baseline growth hormone level of 2-8 MU/1, pain. A perforated duodenal was confirmed decreasing to 0 5 MU/I (normal <10) during a on admission to hospital and vagotomy and glucose tolerance test. A chest radiograph was pyloroplasty were performed. The NSAID was normal. Examination of the synovial fluid showed a very low white cell count (100/mm3) which was within the normal range. Unusually, however, the predominant cell was densely stained with non-specific esterase-that is, the cells were macrophages. This contrasts with normal subjects in whom synoviocytes pre- dominate. In all other aspects the fluid resembled that of a non-inflammatory . Radio- graphs of his , feet, femora, and pelvis showed exuberant periosteal deposition of new bone (fig 1) and a bone scan using labelling with technetium confirmed increased uptake in the distal ends of his limb long bones (fig 2). A small bowel enema and duodenal biopsy sample were normal. A full thickness iliac crest bone biopsy sample, following labelling with deme- clocycline, showed hyperactive cortical bone deposition, but with marked trabecular osteo- porosis in association with increased numbers of (fig 3, table). A diagnosis of pachy- dermoperiostosis was made. As the patient's joint symptoms were severe and persistent a trial of high dose prednisolone Figure I Plain radiograph ofthe ofpatient 1. lPeriosteal reaction is seen along the distal radius and ulnar extending across the arrested growth plate and onto the epiphvsis, afeature thought to be specificforprimary hypertrophic osteoarthropathv only.'

Figure 3 Reverse prints offull thickness, bicortical bone biopsy specimensfrom the posterior iliac crests of (A) a normal subject and (B)patient 2. The outer cortices lie at the bottom ofthe print in both instances. A comparison Figure 2 Bone scan ofpatient 2 using bisphosphonate labelled with technetium, showing ofthe biopsy specimens showed markedly thickened cortices, markedly increased uptake in the distal radius and ulnar. This was not due to the epiphysial especially the inner cortex, in patient 2, but with trabecular growth plate, which wasfused on plain radiographs. thinning as a result ofrelative osteoporosis. 418 Cooper, Freemont, Riley, et al

Histomorphometric results for trabecular and cortical bone out inflammation."b Radiological studies have from patient 2. Results for normal controls given as indicated that, for primary and secondary mean (SD) hypertrophic osteoarthropathy alike, the degree Histomorphometric findings Patient 2 Normal age and of periosteal reaction depends on the duration of sex matched controls (n=10) the disease rather than its cause. 7 There are no previous reports of bone histology in primary Trabecular bone volume (%) 16-1 23-1 (4-5) Total osteoid surfaces (%) 20-0 18-2 (5 4) hypertrophic osteoarthropathy. Our results, Total resorptive surfaces (%) 50 3-6 (1-7) summarised in the table and fig 3, indicated a Mineralising seams (%) 81-4 76-9 (12-4) count (/mm') 0-467 Median 01045 trabecular osteoclast count an orderofmagnitude (range 0-001- greater than that seen in normal bone, in 0-1%) Appositional rate (gg/day) combination with a reduced appositional rate Trabecular bone 044 1 which contrasts with an increased appositional Cortical bone 1-17 0 70 (0-12) rate in cortical bone. This mismatching of osteoclast and activity appears to be the cause of reduced trabecular bone mass, was begun empirically. This provided little despite normal osteoid thickness, combined relief except when given in doses in excess of with markedly increased cortical bone mass in 20 mg, and was therefore discontinued. Intra- both Haversian and periosteal new bone. These articular steroid injections did not help. The findings suggest differential functional changes patient is currently trying to return to his affecting the two bony envelopes which has not business degree studies. been shown previously. The natural history of primary hypertrophic osteoarthropathy appears to be self limiting, an Discussion active adolescent phase being followed by a Hypertrophic osteoarthropathy was first des- quiescent adult phase.'2 Our first patient fits cribed during the late nineteenth century in this pattern well as, at 35 years of age, his association with severe lung infections,5 6 but symptoms are considerably reduced, even has since been regarded an ominous clinical sign though the pain and were severe portending bronchial and other neoplasms. during the active phase of his disease. The Digital clubbing occurs in most patients with second patient remains a problem with respect hypertrophic osteoarthropathy7 and the two to treatment because of the severity of his abnormalities occur in similar thoracoabdominal symptoms, and his difficulties in tolerating diseases,8 including congenital cyanotic heart drugs given by mouth. These patients highlight disease and cystic fibrosis.9 10 The skeletal the difficulties in treating patients when morphological abnormalities seen in clubbing symptoms are severe. The known data indicate and hypertrophic osteoarthropathy are iden- that the associated joint problem is non- tical,' suggesting a common cause. inflammatory, so the use of systemic steroids is In recent reviews ofclubbing and hypertrophic difficult to justify, especially considering the osteoarthropathy, neurogenic and hormonal expected natural history ofprimary hypertrophic causative mechanisms were suggested." The osteoarthropathy. Indeed, the trabecular osteo- 'neurogenic theory' proposes that afferents porosis presently shown possibly represents a arising from diseased internal organs travel via contraindication. the vagus nerve and induce clubbing and hyper- trophic osteoarthropathy by reflex, whereas the We gratefully acknowledge the assistance of J B Weiss, who performed the hydroxyproline assays, including establishing a 'hormonal theory' proposes that hormone-like normal reference range in the required age group. substances, capable of inducing clubbing and hypertrophic osteoarthropathy, are normally present in plasma but are inactivated during 1 Touraine A, Solente G, Gole L. Un syndrome osteodermo- pathique: la pachydermie plicaturee avec pachyperiostose pulmonary passage. In patients with broncho- des extremities. Presse Med 1935; 43: 493-504. genic carcinomas, tumour derived hormone-like 2 Rimoin D L. Pachydermoperiostitis (idiopathic clubbing and periostitis). Genetic and physiological considerations. substances can presumably gain direct access to N EnglJ Med 1%5; 272: 924-31. the systemic circulation. " Where shunts or 3 Martinez-Lavin M, Pineda C, Valdez T, et al. Primary hypertrophic osteoarthropathy. Semin Arthritis Rheum direct systemic access do not result from serious 1988; 17: 156-62. internal disorders, such as in primary hyper- 4 Vogl A, Goldfischer S. Pachydermoperiostitis: primary or idiopathic hypertrophic osteoarthropathy. AmJ_ Med 1%2; trophic osteoarthropathy, an overproduction of 33: 166-87. hormone-like substances is proposed.'2 What- 5 Bamberger E. Ueber knockenveranderungen bei chronischen lungenund herzkrankheiten. Z Klin Med 1891; 18: 193- ever the composition of the putative hormone- 217. like substances, and growth hormone abnor- 6 Marie P. De L'osteoarthropathie hypertrophiante pneumo- nique. Rev Med (Paris) 1890; 10: 1-36. malities appear to have been excluded,'3 their 7 Locke E. Secondary hypertrophic osteoarthropathy and its effects are widespread and can be detected in relation to simple club fingers. Arch Intern Med 1915; 15: 659-77. dermal and epidermal endothelial and connective 8 Mendlowitz M. Clubbing and hypertrophic osteoarthropathy. tissues. Wide field nail bed microscopy also Medicine (Baltimore) 1942; 21: 269-306. 9 Martinez-Lavin M, Bobadilla M, Casanova J, Ahie F, shows capillary dilatation and periungual skin Martinez M. Hypertrophic osteoarthropathy in cyanotic histology shows endothelial hyperplasia, congenital heart disease. Arthritis Rheum 1982; 25: 1186-93. 10 Cohen A, Yulish B, Wasser K, Vignos P J, Jones P K, Sorin hyalinosis, and sclerosis.'4 ' S B. Evaluation of pulmonary hypertrophic osteoarthro- In primary hypertrophic osteoarthropathy pathy in cystic fibrosis. Am J Dis Child 1986; 140: 74-7. 11 Pineda C J, Guerra J Jr, Weisman M H, Resnick D, synovial fluid studies have shown non-in- Martinez-Lavin M. The skeletal manifestations of club- flammatory microscopic appearances whereas bing: a study of patients with cyanotic congenital heart disease and hypertrophic osteoarthropathy. Semin Arthritis synovial histological examinations show hyper- Rheum 1985; 14: 263-73. cellularity and vascular thickening, but with- 12 Martinez-Lavin M. Digital clubbing and hypertrophic osteo- Bone abnormalities and arthritis in pachydermoperiostosis 419

arthropathy: a unifying hypothesis. J Rheumatol 1987; 14: trophic osteoarthropathy. Scand 16: 6-8. 205-12. J Rheumatol 1987; 13 Dupont B, Hoyr I, Borgestov S, Nerup J. Plasma 16 Lauter hormone and growth S, Vasey F, Huttner I, Osterland C K. Pachydermo- hypertrophic osteoarthropathy in carcinoma periositis. Studies on the synovium. Rheumatol 1978; of the bronchus. Acta Med Scand 1970; 188: 25-30. 88-9. J 5: 14 Matucci-Cerinic M, Cinti S, Morroni M. 17 Pineda C stitis Pachydermoperio- J, Martinez-Lavin M, Goobar J E, Sartoris D J, (primary hypertrophic osteoarthropathy): report of a Clopton P, Resnick D. Periostitis in hypertrophic osteo- case with evidence of endothelial and connective tissue arthropathy: relationship to disease duration. Am Radiol involvement. Ann Rhewum Dis 1989; 48: 240-6. 1987; 148: 773-8. J 15 Matucci-Cerinic M, Lotti T, Jaiic I, Lollo D, Brunetti L, 18 Resnick D. In: Resnick D, ed. Bone and Imaging. Orlic D. Cutaneous fibrinolytic activity in primary hyper- London: Saunders, 1989: 1239-41. Joint