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Limited evidence exists regarding the validity of clinical examination for the detection of shoulder pathology. We therefore wished to establish the sensitivity, specificity, positive predictive value and negative predictive value of clinical tests and magnetic resonance imaging (MRI) in the diagnosis of rotator cuff disorders against findings at arthroscopy. Using recognised tests for specific shoulder lesions, 117 patients with shoulder symptoms awaiting surgery were examined in a standard manner. The diagnoses were categorised and compared with abnormalities found on MRI and at surgery. Results were cross-tabulated to determine the above parameters. Ninety-four patients formed the study group with a mean age of 51 years. The median duration of symptoms was 45 weeks. For clinical examination, sensitivity and specificity to detect a tear or rupture of supraspinatus were 30 % (16/54) and 38 % (15/40) and, for the detection of any pathology, were 94 % (67/71) and 22 % (5/23), respectively, compared with arthroscopy. Correspondingly, the sensitivity of MRI compared with arthroscopy to detect a tear or rupture of supraspinatus was 90 % (28/31) with a specificity of 70 % (46/53), whereas for the detection of any abnormality, the sensitivity was 92 % (65/71) with a specificity of 48 % (11/23). The sensitivity of detecting any rotator cuff abnormality is high when examination and MRI is compared with arthroscopy with the specificity being greater with MRI than examination. In patients with shoulder symptoms severe enough to consider surgery, clinical assessment followed by specific imaging may help define the pathology in order to direct appropriate management.

ObjectivesAdult-acquired flat foot secondary to a dysfunctional posterior tibialis tendon (PTT) is often treated by surgical transfer of the flexor digitorum longus tendon (FDLT). In this study, the authors compared normal PTT, stage II dysfunctional PTT and replacement FDLT, aiming to define changes in collagen modification, glycosaminoglycan (GAG) and the expression of matrix and metalloproteinase mRNA.MethodsNormal PTTs were obtained from patients with no history of tendon problems. Samples of dysfunctional PTT and replacement FDLT tissue were obtained from patients undergoing surgical reconstruction. Tissue samples were analysed for total collagen and GAG, pentosidine and collagen cross-links. Total RNA was assayed for mRNA encoding matrix proteins and metalloproteinases, using real-time reverse transcription PCR. Differences between clinical groups were assessed using non-parametric statistics.ResultsDysfunctional PTT contained higher levels of GAG and lower levels of pentosidine than normal PTT or FDLT. In contrast, collagen in FDLT contained fewer ketoimine and more aldimine cross-links than either normal or dysfunctional PTT. mRNA encoding types I and III collagens, aggrecan, biglycan, matrix metalloproteinase (MMP)-2, -13 and -23, and a disintegrin and metalloproteinase (ADAM)-12L each showed increased levels in dysfunctional PTT compared with either normal PTT or (except MMP-13) FDLT. In contrast, MMP-3 and ADAM with thrombospondin domain (ADAMTS)-5 mRNA were lower in both dysfunctional PTT and FDLT than in normal PTT, while ADAMTS-1 mRNA was lower in dysfunctional PTT than in FDLT.ConclusionsStage II dysfunctional PTT shows biochemical and molecular changes consistent with a chronic remodelling of the extracellular matrix, rather than rupture, while the replacement FDLT resembles normal PTT in many, but not all, parameters.

Objective To profile the messenger RNA (mRNA) expression for the 23 known genes of matrix metalloproteinases (MMPs), 19 genes of ADAMTS, 4 genes of tissue inhibitors of metalloproteinases (TIMPs), and ADAM genes 8, 10, 12, and 17 in normal, painful, and ruptured Achilles tendons. Methods Tendon samples were obtained from cadavers or from patients undergoing surgical procedures to treat chronic painful tendinopathy or ruptured tendon. Total RNA was extracted and mRNA expression was analyzed by quantitative real-time reverse transcription–polymerase chain reaction, normalized to 18S ribosomal RNA. Results In comparing expression of all genes, the normal, painful, and ruptured Achilles tendon groups each had a distinct mRNA expression signature. Three mRNA were not detected and 14 showed no significant difference in expression levels between the groups. Statistically significant (P < 0.05) differences in mRNA expression, when adjusted for age, included lower levels of MMPs 3 and 10 and TIMP-3 and higher levels of ADAM-12 and MMP-23 in painful compared with normal tendons, and lower levels of MMPs 3 and 7 and TIMPs 2, 3, and 4 and higher levels of ADAMs 8 and 12, MMPs 1, 9, 19, and 25, and TIMP-1 in ruptured compared with normal tendons. Conclusion The distinct mRNA profile of each tendon group suggests differences in extracellular proteolytic activity, which would affect the production and remodeling of the tendon extracellular matrix. Some proteolytic activities are implicated in the maintenance of normal tendon, while chronically painful tendons and ruptured tendons are shown to be distinct groups. These data will provide a foundation for further study of the role and activity of many of these enzymes that underlie the pathologic processes in the tendon.

Objectives. Fluoroquinolone antibiotics may cause tendon pain and rupture. We reported previously that the fluoroquinolone ciprofloxacin potentiated interleukin (IL)-1b-stimulated expression of matrix metalloproteinases (MMP)-3 and MMP-1 in human tendon-derived cells. We have now tested additional fluoroquinolones and investigated whether they have a similar effect on expression of MMP-13. Methods. Tendon cells were incubated for two periods of 48 h with or without fluoroquinolones and IL-1b. Total ribonucleic acid (RNA) was assayed for MMP messenger RNA by relative quantitative reverse transcriptase polymerase chain reaction, with normalization for glyceraldehyde-3-phosphate dehydrogenase mRNA. Samples of supernatant medium were assayed for MMP output by activity assays. Results. MMP-13 was expressed by tendon cells at lower levels than MMP-1, and was stimulated typically 10- to 100-fold by IL-1b. Ciprofloxacin, norfloxacin and ofloxacin each reduced both basal and stimulated expression of MMP-13 mRNA. In contrast, ciprofloxacin and norfloxacin increased basal and IL-1b-stimulated MMP-1 mRNA expression. Both the inhibition of MMP-13 and the potentiation of MMP-1 expression by fluoroquinolones were accompanied by corresponding changes in IL-1b-stimulated MMP output. The non-fluorinated quinolone nalidixic acid had lesser or no effects. Conclusions. Fluoroquinolones show contrasting effects on the expression of the two collagenases MMP-1 and MMP-13, indicating specific effects on MMP gene regulation.

OBJECTIVES: To investigate the prevalence of calcium phosphate mineral salt accumulation in degenerative supraspinatus 'tendinitis' compared with a normal sample of human tendons, and to determine whether there is an association of calcium salt deposition with pathological changes in the tendon extracellular matrix. METHODS: Cadaver tendons (supraspinatus and common biceps tendons, n = 96) and fragments of supraspinatus tendons obtained during shoulder surgery (n = 31) were analysed for calcium content by atomic absorption spectroscopy, phosphorous content using a spectrophotometric assay, and matrix composition (collagen, glycosaminoglycans and DNA) using standard biochemical techniques. RESULTS: We established baseline values of calcium concentration in macroscopically normal cadaver tendons (mean 1.1 (SD 0.35) micrograms/mg dry wt, n = 60) and found that 33% (nine of 27) of ruptured tendons from patients with 'degenerative tendinitis' contained an excess of calcium (more than 2SD greater than the normal sample mean). Five of these specimens had increased concentrations of phosphorous and calcium:phosphorous (molar) ratios consistent with a variety of possible calcium crystals, including calcium pyrophosphate, hydroxyapatite, and tricalcium phosphate, in addition to mixed or amorphous calcium phosphate deposits. Four of these specimens contained normal concentrations of phosphorous, consistent with deposits of calcium oxalate or calcium carbonate, although this was not confirmed biochemically. In contrast, surgical specimens (n = 4) from patients with 'calcifying tendinitis' (radiographically detected calcium deposits) all contained salts with a mineral composition consistent with hydroxyapatite. The presence and identity of crystal deposits was subsequently confirmed in five specimens by radiographic microanalysis. Analysis of the tendon matrix demonstrated a number of significant differences between normal and degenerate (ruptured) tendons, including a reduction in collagen content, an increase in sulphated glycosaminoglycans (predominantly dermatan sulphate) and an increase in DNA (cellular) content. However, there were no significant differences between degenerate tendons that were 'calcified' and those degenerate specimens that contained normal concentrations of calcium. CONCLUSIONS: Although there was a relatively high prevalence of calcium salts in degenerate tendons, which might contribute to the pathological process (such as increased matrix collagen degradation), these data are consistent with the hypothesis that 'dystrophic calcification' of degenerate tendon matrix is a pathological entity distinct from cell mediated 'calcifying tendinitis'. Calcification is probably one possible outcome (or end point) of chronic tendon injury, although the possibility exists that in many cases, the presence of calcium salts may contribute to the tendon matrix degeneration.

The objective of this study was to develop European League Against Rheumatism/American College of Rheumatology classification criteria for polymyalgia rheumatica (PMR). Candidate criteria were evaluated in a 6-month prospective cohort study of 125 patients with new-onset PMR and 169 non-PMR comparison subjects with conditions mimicking PMR. A scoring algorithm was developed based on morning stiffness > 45 minutes (2 points), hip pain/limited range of motion (1 point), absence of rheumatoid factor and/or anti-citrullinated protein antibody (2 points), and absence of peripheral joint pain (1 point). A score >= 4 had 68% sensitivity and 78% specificity for discriminating all comparison subjects from PMR. The specificity was higher (88%) for discriminating shoulder conditions from PMR and lower (65%) for discriminating RA from PMR. Adding ultrasound, a score >= 5 had increased sensitivity to 66% and specificity to 81%. According to these provisional classification criteria, patients >= 50 years old presenting with bilateral shoulder pain, not better explained by an alternative pathology, can be classified as having PMR in the presence of morning stiffness > 45 minutes, elevated C-reactive protein and/or erythrocyte sedimentation rate, and new hip pain. These criteria are not meant for diagnostic purposes.

Forty-four patients with polymyalgia rheumatica and/or giant cell arteritis (PMR/GCA) were followed from presentation, through remissions and relapses for a median duration of 36 months. Clinical disease activity, ESR, CRP and alpha 1-antichymotrypsin (alpha 1-ACT) were measured. Before treatment ESR, CRP and alpha 1-ACT were all significantly raised, compared with age- and sex-matched controls. On clinical remission with prednisolone treatment, ESR and CRP fell to control levels but alpha 1-ACT behaved quite differently, remaining raised for 18 months or until prednisolone treatment could be withdrawn. At 18 month follow-up of PMR/GCA, and alpha 1-ACT level of < or = 0.7 g/l was associated with a reduced risk of subsequent relapse (P = 0.006). At clinical relapse during treatment, ESR was not raised compared with controls, and CRP, although significantly higher than controls (P = 0.015), remained less than 6 mg/l in the majority of patients. The three laboratory investigations were, therefore, of limited value in confirming relapses of PMR/GCA during prednisolone treatment, but alpha 1-ACT may be useful as an indicator of underlying disease activity and hence as a guide to the speed that the prednisolone dosage should be reduced.

The metalloproteinases are a family of enzymes that can degrade all the components of the extracellular matrix. These potent enzymes are often found in proenzyme forms and require activation before the substrate can be digested. To prevent unlimited connective tissue destruction a number of inhibitors exist to limit their activity. In a previous study it was found that metalloproteinases in proenzyme form and metalloproteinase inhibitors were often present in rheumatoid synovial fluids. Two of these inhibitors were identified in rheumatoid synovial fluid as alpha 2 macroglobulin and tissue inhibitor of metalloproteinase (TIMP), the specific metalloproteinase inhibitor. A third inhibitory peak was unidentified. In the study reported here it was shown that this third inhibitor can be purified using gelatin-Sepharose chromatography and consists of TIMP-2 bound to progelatinase (relative molecular weight 72,000) in a similar way to that found in concentrated connective tissue culture medium. The importance of these proteinase inhibitors in synovial fluid is discussed.

Objective. To compare the levels of collagenase, tissue inhibitor of metalloproteinases (TIMP), and collagenase—TIMP complex in synovial fluid (SF) from patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA). This study aims to clarify existing data from previously used enzyme or inhibitor activity assays performed following separation by gel filtration, by using a 1-step enzyme-linked immunosorbent assay (ELISA) for each component. Methods. Total collagenase, free TIMP, and collagenase—TIMP complex were measured using a newly developed, specific double-antibody sandwich ELISA. Results. Levels of both collagenase and TIMP were significantly higher in RA patients (collagenase 1,560 ± 150 ng/ml [mean ± SEM], TIMP 1,610 ± 130 ng/ml; n = 80) than OA patients (collagenase 420 ± 90 ng/ml, TIMP 1,050 ± 60 ng/ml; n = 80), with the difference being especially striking for collagenase. Sixteen RA fluids had detectable levels of collagenase—TIMP complex, compared with only 3 OA fluids. Conclusion. The level of total collagenase in SF is greater in RA than OA, while levels of free TIMP show more overlap between the 2 diseases; this may simply reflect the increased inflammation seen in RA, or it may reflect a different disease mechanism.

Liver involvement in polymyalgia rheumatica/giant cell arteritis (PMR/GCA) before treatment and during follow-up of up to 3 1/2 years was assessed in 74 patients clinically, with liver function tests, isotope scans and blood flow studies. Twenty-seven patients had elevated alkaline phosphatase levels which fell to normal after 2.6 weeks treatment. Both PMR and GCA patients were affected, the latter more commonly. Isotope scans were abnormal in 7 of 29 patients and remained abnormal on follow-up. The arterial fraction of hepatic flow was significantly reduced in GCA patients in comparison with those having PMR only; values became normal after treatment. These abnormalities may be due to hepatic arteritis.

A community survey of identifiable symptomatic shoulder disorders in a sample of 644 elderly people over age 70 (318 male and 326 female) revealed a prevalence of 21%. Shoulder disorders were more common in women (25%, versus 17% in men). Approximately 70% of the cases of shoulder pain involved the rotator cuff. Fewer than 40% of the subjects sought medical attention for these symptoms. Increased medical awareness is needed, since the elderly often do not volunteer information about such symptoms.

OBJECTIVE: To assess immunologically relevant outcomes in a cohort of rheumatoid arthritis (RA) patients with prolonged therapy-induced lymphopenia. METHODS: Morbidity (infection or malignancy) and mortality were assessed in 53 RA patients who were treated with the lymphocytotoxic monoclonal antibody alemtuzumab between 1991 and 1994. Data were obtained by interview, medical record review, and Office for National Statistics mortality monitoring. Lymphocyte subsets were enumerated by flow cytometry. A retrospective, matched-cohort study of mortality was performed with 102 control subjects selected from the European League Against Rheumatism database of patients with rheumatic disorders. RESULTS: Lymphopenia persisted in the patients: median CD3+CD4+, CD3+CD8+, CD19+, and CD56+ lymphocyte counts measured at a median followup of 11.8 years from the first administration of alemtuzumab were 0.50 x 10(9)/liter, 0.26 x 10(9)/liter, 0.11 x 10(9)/liter, and 0.09 x 10(9)/liter, respectively. Twenty-seven of 51 cases and 46 of 101 controls with available data had died, yielding a mortality rate ratio of 1.20 (95% confidence interval 0.72-1.98). Causes of death were similar to those that would be expected in a hospital-based RA cohort. No opportunistic infections were noted, and only 3 infections were documented following 36 elective orthopedic procedures. CONCLUSION: Despite continued lymphopenia 11.8 years after therapy, our patient cohort did not exhibit excess mortality or unusual infection-related morbidity, and surgery was well tolerated. These data should be reassuring for clinicians and patients who are considering lymphocytotoxic or other immunomodulatory therapy for RA.

Objectives. To determine the expression of mRNA encoding the proteoglycans aggrecan, versican, biglycan and decorin in mid-tendon samples of chronic painful Achilles tendinopathy and ruptured Achilles tendons, compared with normal tendons. Methods. Total RNA isolated from frozen tendon samples (14 normal, 13 painful, 14 ruptured) was assayed by relative quantitative reverse transcription polymerase chain reaction for aggrecan, versican, biglycan and decorin mRNA, normalized using 18S rRNA. Differences between sample groups were tested by univariate analysis of variance with age as co-variate. Results. In normal tendon samples expression of each of the proteoglycan mRNA decreased with increasing age. Decorin mRNA was the most highly-expressed of the proteoglycan mRNA, while versican mRNA expression was higher (3.8-fold) than that of aggrecan. In painful tendinopathy both aggrecan and biglycan mRNA expression increased (more than 10-fold and 5-fold, respectively) compared with normal tendon samples, but levels of versican and decorin mRNA were not significantly changed. In ruptured tendons the levels of aggrecan, biglycan and versican mRNA were not changed compared with normal tendon samples, but decorin mRNA decreased markedly. Conclusions. Increased aggrecan and biglycan mRNA expression in painful tendinopathy resembles the pattern in fibrocartilaginous regions of tendon, and may reflect an altered mechanical environment at the site of the lesion. Increased aggrecan mRNA expression may underlie the increase in glycosaminoglycan observed in painful tendinopathy.

Objectives. Versican is the principal large proteoglycan expressed in mid-tendon, but its role in tendon pathology is unknown. Our objective was to define the expression of versican isoform splice variant messenger ribonucleic acid (mRNA) in normal Achilles tendons, in chronic painful tendinopathy and in ruptured tendons. Methods. Total RNA isolated from frozen tendon samples (normal n ¼ 14; chronic painful tendinopathy n ¼ 10; ruptured n ¼ 8) was assayed by relative quantitative reverse transcriptase polymerase chain reaction (RT-PCR) for total versican, versican variants V0, V1, V2, V3 and type I collagen � 1 mRNA, normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Differences between sample groups were tested by Wilcoxon statistics. Results. Painful and ruptured tendons showed a significant decrease (median 2-fold) in the expression of versican mRNA, in contrast to an increased expression (median 8-fold) of type I collagen � 1 mRNA in painful tendons. Versican splice variants V0 and V1 mRNA were readily detected in normal samples, V3 levels were substantially lower, and V2 levels were more variable. Each of V1, V2 and V3 mRNA showed significant decreases in expression in painful and ruptured tendons, but V0 was not significantly changed. Conclusions. Changes in versican expression relative to that of collagen, and alterations in the balance of versican splice variants, may contribute to changes in matrix structure and function in tendinopathies.

Objective. Fluoroquinolone antibiotics such as ciprofloxacin can induce tendon pathology and have various effects on tendon-derived cells in culture. We are investigating whether ciprofloxacin modifies signalling responses in tendon cells. Methods. Human Achilles tendon-derived cells were preincubated with or without ciprofloxacin (50g/ml) and were then challenged with interleukin-1 (IL-1, 1 ng/ml) for up to 48 h. Prostaglandin E2 (PGE2) output was assayed by ELISA. The expression of cyclooxygenase-2 (COX-2) was examined by Western blotting. Results. IL-1 stimulated a substantial and prolonged increase in the output of PGE2. Preincubation with ciprofloxacin reduced IL-1-induced PGE2 output at all times tested; the reduction at 48 h was 69% (99% confidence interval 59–79%; 15 experiments). Norfloxacin and ofloxacin also reduced PGE2 output. However, ciprofloxacin did not affect the induction of COX-2 by IL-1, measured at 4 or 48 h. Conclusions. Ciprofloxacin reduces IL-1-induced PGE2 output in tendon-derived cells. The reduction in PGE2 output could modulate various cellular activities of IL-1, and may be implicated in fluoroquinolone-induced tendinopathy.

Objective To determine whether the fluoroquinolone antibiotic ciprofloxacin, which can cause tendon pain and rupture in a proportion of treated patients, affects the expression of matrix metalloproteinases (MMPs) in human tendon-derived cells in culture. Methods Cell cultures were derived from 6 separate tendon explants, and were incubated in 6-well culture plates for 2 periods of 48 hours each, with ciprofloxacin (or DMSO in controls) and interleukin-1β (IL-1β), alone and in combination. Samples of supernatant medium from the second 48-hour incubation were assayed for MMPs 1, 2, and 3 by Western blotting. RNA was extracted from the cells and assayed for MMP messenger RNA (mRNA) by semiquantitative reverse transcription–polymerase chain reaction, with normalization for GAPDH mRNA. Results Unstimulated tendon cells expressed low or undetectable levels of MMP-1 and MMP-3, and substantial levels of MMP-2. IL-1β induced a substantial output of both MMP-1 and MMP-3 into cell supernatants, reflecting increases (typically 100-fold) in MMP mRNA, but had only minor effects on MMP-2 expression. Ciprofloxacin had no detectable effect on MMP output in unstimulated cells. Preincubation with ciprofloxacin potentiated IL-1β–stimulated MMP-3 output, reflecting a similar effect on MMP-3 mRNA expression. Ciprofloxacin also potentiated IL-1β–stimulated MMP-1 mRNA expression, but did not potentiate the output of MMP-1, and had no significant effects on MMP-2 mRNA expression or output. Conclusion Ciprofloxacin can selectively enhance MMP expression in tendon-derived cells. Such effects might compromise tendon microstructure and integrity.

Soft tissue rheumatic complaints encompass disorders of tendon, ligament, bursa, fascia, joint capsule and isolated lesions of muscle. Some chronic pain syndromes such as fibromyalgia are also included. Although they represent a significant proportion of new patient consultations in rheumatology, they remain poorly understood with respect to their pathologies, epidemiology and management. The diverse spectrum of these often complex disorders is frequently underestimated.

OBJECTIVES—To investigate age related and site specific variations in turnover and chemistry of the collagen network in healthy tendons as well as the role of collagen remodelling in the degeneration of the supraspinatus tendon (ST-D) in rotator cuff tendinitis. METHODS—Collagen content and the amount of hydroxylysine (Hyl), hydroxylysylpyridinoline (HP), lysylpyridinoline (LP), and the degree of non-enzymatic glycation (pentosidine) were investigated in ST-D and in normal human supraspinatus (ST-N) and biceps brachii tendons (BT-N) by high-performance liquid chromatography. RESULTS—In BT-N, tendons that served as control tissue as it shows rarely matrix abnormalities, pentosidine levels rise linearly with age (20-90 years), indicating little tissue remodelling (resulting in an undisturbed accumulation of pentosidine). A similar accumulation was observed in ST-N up to 50 years. At older ages, little pentosidine accumulation was observed and pentosidine levels showed large interindividual variability. This was interpreted as remodelling of collagen in normal ST after age 50 years because of microruptures (thus diluting old collagen with newly synthesised collagen). All degenerate ST samples showed decreased pentosidine levels compared with age matched controls, indicating extensive remodelling in an attempt to repair the tendon defect. Collagen content and the amount of Hyl, HP, and LP of ST-N and BT-N did not change with age. With the exception of collagen content, which did not differ, all parameters were significantly (p

In recent years giant cell arteritis and polymyalgia rheumatica have increasingly been considered as closely related conditions. The two syndromes form a spectrum of disease and affect the same types of patient. The conditions may occur independently or may occur in the same patient, either together or separated in time. Polymyalgia rheumatica is a clinical syndrome of middle aged and elderly patients and is characterised by: Swollen temporal artery of patient with giant cell arteritis. #### Aetiology of polymyalgia rheumatica and giant cell arteritis Polymyalgia rheumatica—At present it is impossible to define the underlying pathological abnormality in polymyalgia rheumatica, and several different mechanisms may be responsible for a largely similar pattern of pain. Giant cell arteritis is limited to vessels with an internal elastic component. Both humoral and cellular immunological mechanisms have been implicated in its development, and the latter seem to be more important. Giant cell arteritis affects white people almost exclusively, but it has been reported in black Americans. In all studies both conditions are very rare under the age of 50 years. Reports from Olmsted County, Minnesota, and Gothenburg, Sweden, have shown that the incidence is increasing in women but not in men. About half of patients with giant cell arteritis have symptoms of polymyalgia rheumatica, whereas 15-50% of patients with polymyalgia rheumatica have giant cell arteritis. Problems with case definition and ascertainment complicate epidemiological observations. #### Epidemiology of giant cell arteritis

OBJECTIVES--To analyse the collagen composition of normal adult human supraspinatus tendon and to compare with: (1) a flexor tendon (the common biceps tendon) which is rarely involved in any degenerative pathology; (2) degenerate tendons from patients with chronic rotator cuff tendinitis. METHODS--Total collagen content, collagen solubility and collagen type were investigated by hydroxyproline analysis, acetic acid and pepsin digestion, cyanogen bromide peptide analysis, SDS-PAGE and Western blotting. RESULTS--The collagen content of the normal cadaver supraspinatus tendons (n = 60) was 96.3 micrograms HYPRO/mg dry weight (range 79.3-113.3) and there was no significant change across the age range 11 to 95 years. There was no significant difference from the common biceps tendon [93.3 (13.5) micrograms HYPRO/mg dry weight, n = 24]. Although extremely insoluble in both acetic acid and pepsin, much of the collagen was soluble after cyanogen bromide digestion [mean 47.9% (29.8)]. Seventeen per cent (10/60) of the 'normal' cadaver supraspinatus tendon sample contained more than 5% type III collagen, although none of the common biceps tendons had significant amounts. Degenerate supraspinatus and subscapularis tendons had a reduced collagen content [83.8 (13.9) micrograms/mg dry weight and 76.9 (16.8) micrograms/mg dry wt respectively) and were more soluble in acetic acid, pepsin and cyanogen bromide (p < 0.001). Eighty two per cent (14/17) of supraspinatus tendons and 100% (8/8) of subscapularis tendons from patients with tendinitis contained more than 5% type III collagen. CONCLUSIONS--The changes in collagen composition in rotator cuff tendinitis are consistent with new matrix synthesis, tissue remodelling and wound healing, in an attempt to repair the tendon defect, even in old and degenerate tendons. An increase in type III collagen in some 'normal' cadaver supraspinatus tendons is evidence that changes in collagen synthesis and turnover may precede tendon rupture. These changes may be the result of repeated minor injury and microscopic fibre damage or a consequence of local factors such as reduced vascular perfusion, tissue hypoxia, altered mechanical forces and the influence of cytokines. These collagenous changes may accumulate with age and substantially weaken the tendon structure, predisposing the tendon to rotator cuff tendinitis and eventual tendon rupture.

OBJECTIVES--To analyse the glycosaminoglycans of the adult human rotator cuff tendon matrix, to characterise changes in the glycosaminoglycan composition with age and in chronic rotator cuff tendinitis. METHODS--Rotator cuff (supraspinatus) tendons (n = 84) and common biceps tendons (n = 26) were obtained from cadavers with no history of tendon pathology (age range 11-95 years). Biopsies of rotator cuff tendons (supraspinatus and subscapularis tendons, n = 53) were obtained during open shoulder surgery to repair shoulder lesions (age range 38-80 years). Glycosaminoglycans were extracted by papain digestion and analysed by cellulose acetate electrophoresis, the carbazole assay for uronic acid and the dimethylmethylene blue dye-binding assay for sulphated glycosaminoglycans. Some digests were analysed for keratan sulphate by 5D4 monoclonal antibody ELISA. Soluble proteoglycans were extracted in 4M guanidine hydrochloride and analysed by 4-15% SDS PAGE. RESULTS--The mean (SD) sulphated glycosaminoglycan (GAG) content of the normal cadaver supraspinatus tendon was 12.3 (4.3) micrograms/mg dry weight, between three and ten times greater than in the common biceps tendon [1.2 (0.6) micrograms/mg dry weight]. The major GAG was chondroitin sulphate [6.9 (2.6) micrograms/mg dry weight], with a smaller proportion of dermatan sulphate [2.5 (1.2) micrograms/mg dry weight]. In contrast, the common biceps tendon contained predominantly dermatan sulphate [0.8 (0.2) microgram/mg dry weight] with less chondroitin sulphate [0.2 (0.2) microgram/mg dry weight]. There was no difference in the concentration of hyaluronan in these tendons [9.3 (2.8) micrograms/mg dry weight and 10.8 (4.3) micrograms/mg dry weight respectively] and there was no significant change of hyaluronan with age. Keratan sulphate was a small but significant component of the supraspinatus tendon [0.43 (0.33) microgram/mg dry weight, n = 25], whereas there was little or none in the common biceps tendon [0.04 (0.05) microgram/mg dry weight, n = 8] and there was no significant change across the age range. In the supraspinatus tendon, there was a significant decrease in total glycosaminoglycan, chondroitin sulphate and dermatan sulphate with age (p < 0.001), whether expressed relative to the tendon dry weight or total collagen content, and no change in the relative proportion of the different GAG types. There was, however, a large degree of variation within the samples. Supraspinatus tendons from patients with chronic tendinitis had a significantly increased concentration of hyaluronan [30.4 (10.1) micrograms/mg dry weight, p < 0.001], chondroitin sulphate [8.4 (1.8) micrograms/mg dry weight, p < 0.05] and dermatan sulphate [3.8 (1.1) micrograms/mg dry weight, p < 0.001] compared with normal cadaver supraspinatus tendons, although the keratan sulphate content was not significantly different [0.18 (0.05) microgram/mg dry weight]. CONCLUSIONS--The normal supraspinatus tendon has the proteoglycan/glycosaminoglycan of tendon fibrocartilage, which it is suggested is an adaptation to mechanical forces (tension, compression and shear) which act on the rotator cuff tendons in the shoulder, although other factors such as reduced vascularity, low oxygen tension and the influence of local growth factors may also be important. This functional adaptation may have important consequences for the structural strength of the supraspinatus tendon and to influence the ability of the tendon to repair after injury. The glycosaminoglycan composition of tendon specimens from patients with chronic tendinitis is consistent with acute inflammation and new matrix proteoglycan synthesis, even in relatively old tendon specimens and after at least one injection of corticosteroid.

OBJECTIVES--Rotator cuff tendinitis and lateral epicondylitis are common in clinical practice but the underlying pathology is poorly understood. The study examined both normal and biopsy tendon specimens histologically, to determine the mechanisms involved in tendon degeneration. METHODS--Rotator cuff tendons from 83 cadavers aged 11-94 and tendon biopsy specimens from 20 patients with lateral epicondylitis aged 27-56 years were examined histologically. RESULTS--The microscopic changes found in the tendon biopsies from the elbow were similar to those found in the cadaveric rotator cuff tendons. Abnormalities ranged from minor blood vessel wall changes and loss of tenocytes to calcification. The most frequent abnormality was glycosaminoglycan infiltration and fibrocartilaginous transformation. There appeared to be some sequence in the changes observed which were milder in younger patients. Only 17% of cadaver tendons, below the age of 39 were abnormal but abnormalities increase in later life to around 40-50%. CONCLUSIONS--There was an increasing incidence of degenerative changes in tendons with age. The changes observed in biopsy samples of common extensor tendons were the same as those seen in aged supraspinatus tendons, but these changes were not seen in control common extensor tendons.

Monoclonal antibodies have been raised against purified human fibroblast collagenase and characterised. One of these antibodies has been used in combination with a polyclonal anticollagenase antibody in a double antibody sandwich ELISA to measure collagenase. The assay range was 2-50 ng/ml collagenase. The assay measures total collagenase, i.e. pro- and active enzyme as well as collagenase in complex with TIMP. The level of collagenase has been measured in sera samples from patients with rheumatoid arthritis and compared with age- and sex-matched controls. The levels measured were: rheumatoid arthritis, 69 +/- 29 ng/ml; normal, 49 +/- 14 ng/ml.

A 22-year-old male taking dexamethasone following resection of a medulloblastoma developed an acutely painful swollen knee from which salmonella enteritidis was cultured. He had no gastrointestinal symptoms; one stool culture was positive. Active metalloproteinases without inhibitors were detected in the synovial fluid, a characteristic finding in septic joints. S. enteritidis infecting joints is extremely rare despite being the second most frequent salmonella species after S. typhimurium causing infections in man. The recent findings of S. enteritidis in eggs, and poultry points to one more source of infection. Immunosuppression is likely to facilitate infection.

The joints of 56 patients with polymyalgia rheumatica were examined for evidence of inflammatory synovitis. x Rays, isotope scans, and thermography supplemented clinical examination. Control sternoclavicular joints were examined at necropsy. Peripheral and axial synovitis were uncommon and the results contrast with the findings of several recent studies.

Tendon pathology has many manifestations, from spontaneous rupture to chronic tendinitis or tendinosis; the etiology and pathology of each are very different, and poorly understood. Tendon is a comparatively poorly vascularised tissue that relies heavily upon synovial fluid diffusion to provide nutrition. During tendon injury, as with damage to any tissue, there is a requirement for cell infiltration from the blood system to provide the necessary reparative factors for tissue healing. We describe in this review the response of the vasculature to tendon damage in a number of forms, and how and when the revascularisation or neovascularisation process occurs. We also include a section on the revascularisation of tendon during its use as a tendon graft in both ligament reconstruction and tendon–tendon grafting.

The diagnostic criteria and nomenclature used to describe the painful stiff shoulder remain confused. Arthrographic features of capsulitis have come to be accepted as characteristic of the frozen shoulder. Increased technetium uptake has also been noted. Both features have been considered to have possible prognostic and therapeutic importance. During a therapeutic study of strictly defined clinical frozen shoulder 35 of 38 patients showed increased technetium diphosphonate uptake in the affected shoulder in comparison with the opposite side. Of 36 patients who had arthrography 15 showed evidence of capsulitis, 11 rupture of the rotator cuff, and five no abnormality. Five tests failed owing to technical difficulty. There was no association between the technetium uptake and the arthrographic features, and neither was useful in predicting the rate or extent of recovery. Frozen shoulder of traumatic onset behaved no differently from that which arose spontaneously. We do not therefore consider that arthrography or technetium diphosphonate scanning performed at presentation contributes to the assessment of the painful stiff shoulder.

There are many difficulties associated with the assessment of disease activity in rheumatoid arthritis. Infrared thermography has been used to quantify joint inflammation. The heat distribution index (HDI) is reproducible, sensitive, quantifiable, and not subject to circadian variation or interobserver error. In this study the HDIs for both elbows, wrists, knees, and ankles were summated and compared with other parameters of disease activity. There were 167 sets of observations in 20 patients with classical, seropositive, rheumatoid arthritis followed up over 12 months. There was a significant correlation (p less than 0.001) for thermography with the Ritchie articular index, Mallya score, grip strength, morning stiffness, erythrocyte sedimentation rate, and pain score. Significant correlations (p less than 0.05) for thermography with these parameters were found in individual patients. The summated HDI is a suitable, objective method for the assessment of response to therapy in patients with rheumatoid arthritis.

Twenty-eight knees with chronic arthritis and effusion were treated with intra-articular 90Y. Synovial activity was assessed by measuring 99mTc pertechnetate uptake. There was a significant difference in uptake between controls and patients. Those who had a good response to 90Y (15 patients) showed a significant decrease in uptake, not seen in those who failed to respond. The pattern of 90Y distribution was examined and appeared to correspond to areas of increased synovial activity; these patterns and their significance have not been previously reported. Factors which could help to predict response to 90Y are discussed.

A quantitative mouse calvarial bone resorption assay was employed to investigate the effects of the mast cell products, heparin and histamine, and of salmon calcitonin. 'Amorphous' heparin, containing a range of molecular weight fractions, inhibited resorption by 15-20% at concentrations of 0.75-5.0 mg/ml. A 'defined' heparin species of mol.wt 13 500 inhibited resorption by 14-28% at 10(-5)-10(-4) mol/l. Histamine inhibited resorption by 19-55% at 10(-3)-10(-2) mol/l. It is proposed that heparin and histamine depress coupled bone resorption and formation and may lead to net loss of bone. Salmon calcitonin inhibited resorption at concentrations as low as 10 pg/ml. 'Amorphous' (but not 'defined') heparin blunted calcitonin induced inhibition of bone resorption and may derepress osteoclasts.

Serial samples of synovial fluid aspirated from two patients with septic arthritis were assayed for proteinases and proteinase inhibitors. Active metalloproteinases but no proteinase inhibitors were present in all samples taken prior to treatment. The levels of active metalloproteinases fell with time although proenzyme forms were still present in the fluids. Both alpha 2-macroglobulin and the tissue inhibitor of metalloproteinases were found in the septic synovial fluids after treatment commenced. It is proposed that the lack of inhibitors and the presence of active proteinases capable of digesting collagen, gelatin and proteoglycan accounts for the rapid loss of cartilage found in septic arthritis.

We have identified regular thermal patterns over normal knee, ankle, and elbow joints and demonstrate how synovitis affecting these joints may be identified by alteration or loss of the thermal pattern. Sixty healthy volunteers were thermographed on a total of 190 occasions, and 614 out of 618 joints conformed to the normal thermal pattern. Eighty-five patients with synovitis of at least one of the specified joints were thermographed on a total of 339 occasions, and 322 out of 1362 thermograms were abnormal. No joint with clinical evidence of synovitis had a normal thermal pattern. As temperature-based parameters have been found to show marked diurnal variation and relative frequency distributions do not have this drawback, we suggest that quantification of synovitis by thermography should in future be based on abnormalities of thermal pattern rather than absolute skin temperature values.

Polymyalgia rheumatica (PMR) is considered to be a benign disease by some, while others think it is a more serious illness which required similar treatment to giant cell arteritis (GCA). The progress of 85 patients with PMR who presented to a district general hospital has been studied in an attempt to study this relationship. Thirty-eight patients had PMR alone, and 14 developed PMR and GCA within 1 month. Five patients presented with GCA and then developed PMR, and 28 patients developed symptoms of GCA after presenting with PMR (PMR leads to GCA). Arteritis and complications developed up to 9 years after the onset of PMR (mean 1 year). Twenty-two patients (26%) developed some cerebral or visual complication. Fifteen of these patients were in the PMR leads to GCA group. All 6 patients with permanent loss of vision were in this group. Seven patients developed complications while on corticosteroids. 97% of patients required corticosteroids for at least 1 year; 32% of patients still required 10 mg of prednisone or more after 1 year. PMR is not a benign disease.

The levels of metalloproteinases and metalloproteinase inhibitors were measured in rheumatoid synovial fluid. Reliable estimates of total enzyme and inhibitor levels in the synovial fluids were obtained only after hyaluronidase treatment and gel filtration. Three latent metalloproteinases were found which, after activation, degraded collagen, proteoglycan, and gelatin. These enzymes closely resembled the metalloproteinases secreted into connective tissue culture medium. In addition to alpha 2 macroglobulin, an Mr 30,000 collagenase inhibitor was detected which closely resembled the tissue inhibitor of metalloproteinase found in tissue culture medium.

The diagnosis and management of many soft-tissue lesions remains difficult largely as a result of a lack of objective assessment. It is considered that thermography may fulfil this role. During a therapeutic study of 56 tennis-elbow lesions, detailed clinical assessment was supplemented by serial thermography of the lateral elbow. A characteristic localized thermographic abnormality was found in 53 of the 56 affected elbows and only 3 of 60 (120 elbows) normal age- and sex-matched controls. Microcomputer analysis of the thermal gradient slope across the abnormal area showed a correlation with clinical state, reflecting recovery, and revealing a much smaller diurnal variation than was seen in the solely temperature-based parameters. Clinical features do show some variability both with regard to the site of tenderness and degree of involvement of supination and pronation. While these differences may have pathological significance they do not appear to have prognostic importance. Thermography is a useful objective method for assessment of tennis elbow and may aid the investigation and understanding of other soft-tissue lesions.

In the investigation of six patients with giant cell arteritis and abnormal liver function radionuclide liver scans were found to be abnormal in all. The abnormality may be due to arteritis of hepatic vessels. It is important to recognise that giant cell arteritis may cause liver scan abnormalities. If other pathology is suspected and corticosteroid treatment delayed while further investigations are carried out, patients are at risk of complications such as blindness.

This is the first study to show a quantitative thermographic difference between patients with Raynaud's syndrome and normal controls after cold stress testing. An improved thermographic response to cold stress testing after treatment of Raynaud's syndrome with PGE1 has also been shown for the first time. Discriminant analysis of the change in temperature of a finger after cold stress, and the mean thermal gradient along the finger during rewarming, clearly separated patients from controls. After treatment with PGE1 the patients' discriminant values moved into the normal range. Symptomatic improvement after PGE1 correlated well with thermographic improvement, and both persisted for up to 12 weeks.

The erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) were measured in 74 patients with polymyalgia rheumatica (PMR)/giant cell arteritis (GCA) on presentation, in the first month of treatment, and at long term follow up (up to 177 weeks). Before treatment the ESR was raised (greater than 30 mm/h) in all cases and the CRP was raised (greater than 6 mg/l) in 49/55 cases. The ESR was a better indicator of clinical disease activity except in patients who felt completely well at week 1. 9False positive9 increases of ESR or CRP were rare. During relapses ESR was normal in 37/77 (48%) of cases and CRP in 41/73 (56%). It is suggested that ESR is the most useful laboratory parameter in assessing PMR/GCA.

Serum samples were obtained from patients with polymyalgia rheumatica (PMR: n = 10) or giant cell arteritis (GCA; n = 7), or both. Samples were taken either before treatment or within one week of starting prednisolone. Immune complexes (IC) were concentrated by polyethylene glycol (PEG) precipitation then purified with either IgG anti-C1q-Sepharose or IgG anti-C3c-Sepharose. Complex components were separated by sodium dodecyl sulphate (SDS) gradient polyacrylamide gel electrophoresis then transferred to nitrocellulose by Western blotting. Identification of proteins was carried out using specific antisera. All the IC contained IgM (mu chain), some contained IgA (alpha chain), and IgG (gamma chain). C1r, C1s, C1q, C3, C4, and C reactive protein (CRP), where tested, were found in most but not all IC. The occurrence of properdin, factor B, alpha 2 macroglobulin (alpha 2M), factor H (beta 1H), C1 esterase inhibitor, and C4 binding protein was also investigated. Immune complexes in PMR and GCA differed from those previously characterized in rheumatoid arthritis (RA)1 purified by anti-C1q-Sepharose which contained immunoglobulins and C1q only. No properdin or factor B were detected in RA IC purified with either anti-C1q-Sepharose or anti-C3c-Sepharose.

In a prospective study of 74 patients and a retrospective study of 35 patients with polymyalgia rheumatica/giant cell arteritis steroid related side effects occurred in at least one third of patients, and in two thirds if weight gain was included. Side effects were significantly related to an initial prednisolone dose of more than 30 mg and to the cumulative prednisolone dose. Patients taking a mean daily dose of 5 mg prednisolone or less were significantly less likely to develop side effects.

An explant method for the isolation of fibroblasts from adult human tendon is described. Cells were successfully isolated from 22 out of 27 common biceps tendons obtained from cadaveric donors (age range 11-83 years). The fibroblasts could be maintained in culture using standard methods and morphologically resembled those of synovial rather than dermal origin. Growth characteristics of 12 cell lines were assessed by deoxyribose nucleic acid (DNA) synthesis using [3H]thymidine incorporation in response to stimulation by fetal calf serum. Cells obtained separately from superficial and deep parts of the tendons produced almost identical responses. No significant reduction in growth response with increasing age was found when related to the age of the donor. Therefore this study did not show any age related defect in the short term tendon fibroblast replicative responses to serum.

Forty-one patients with rheumatoid arthritis (RA) maintained on low dose prednisolone (mean 5.8 mg) participated in a double-blind cross-over study to determine the effect of timing (morning or night) of prednisolone dosage on morning stiffness. Prednisolone given at night resulted in a significantly shorter duration of morning stiffness (p = 0.0001) than did an equivalent dose given in the morning.