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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.

Targeted biologic therapies have revolutionised treatment of immune-mediated inflammatory diseases (IMIDs) due to their efficacy, speed of onset and tolerability. The discovery that clinically unrelated conditions, such as rheumatoid arthritis and Crohn's disease, share similar immune dysregulation has led to a shift in the management of IMIDs from one of organ-based symptom relief to mechanism-based treatment. The fact that anticytokine therapy has been effective in treating multiple orphan inflammatory conditions confirms the IMID paradigm. In this review we examine the biologic agents currently licensed for use in the US and Europe: infliximab, etanercept, adalimumab, rituximab, abatacept, anakinra, alefacept and efalizumab. We also discuss the rationale behind the management of IMIDs using rheumatoid arthritis, Crohn's disease, psoriasis and psoriatic arthritis as examples. For the medical profession, IMID represents a breakthrough in the way pathology is classified. In this burgeoning era of biologic therapy the prospect of complete disease remission is conceivable.

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.

Background: Extracorporeal shock wave therapy (ESWT) is an increasingly popular therapeutic approach in the management of a number of tendinopathies. Benefit has been shown in calcific tendinitis of the rotator cuff, but evidence for its use in non-calcific disorders is limited. Aims: To perform a double blind randomised controlled trial of moderate dose shock wave therapy in plantar fasciitis. Methods: Adults with plantar fasciitis for at least 3 months were randomised to receive either active treatment (0.12 mJ/mm) or sham therapy, monthly for 3 months. Pain in the day, nocturnal pain and morning start-up pain were assessed at baseline, before each treatment and 1 and 3 months after completion of therapy. Results: Eighty-eight subjects participated and no differences existed between the groups at baseline. At 3 months, 37% of the subjects in the ESWT group and 24% in the sham group showed a positive response (50% improvement from baseline) with respect to pain. Positive responses in night pain occurred in 41% and 31% in the ESWT and sham groups, respectively. Positive responses in start-up pain occurred in 37% and 36% in the ESWT and sham groups, respectively. Both groups showed significant improvement over the course of the study, but no statistically significant difference existed between the groups with respect to the changes were seen in any of the outcome measures over the 6-month period. Conclusions: There appears to be no treatment effect of moderate dose ESWT in subjects with plantar fasciitis. Efficacy may be highly dependent upon machine types and treatment protocols. Further research is needed to develop evidence based recommendation for the use ESWT in musculoskeletal complaints. © 2003 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.

Extracorporeal shock wave therapy (ESWT) is an increasingly popular therapeutic approach to the treatment of a number of soft tissue complaints. Whilst benefit has been demonstrated in calcific tendinitis, evidence is lacking for benefit in the management of non-calcific rotator cuff disorders. Aims: To perform a double-blind placebo controlled trial of moderate dose ESWT in chronic lateral epicondylitis. Methods: Adults with lateral epicondylitis were randomised to receive either active treatment (1500 pulses ESWT at 0.12 mJ/mm2) or sham therapy, monthly for three months. All were assessed before each treatment and one month after completion of therapy. Outcome measures consisted of visual analogue scores for pain in the day and at night. Results: Seventy-five subjects participated and there were no significant differences between the two groups at baseline. The mean duration of symptoms was 15.9 and 12 months in the ESWT and sham groups, respectively. Both groups showed significant improvements from two months. No significant difference existed between the groups with respect to the degrees of change in pain scores over the study period. In the ESWT group the mean (SD, range) pain score was 73.4 (14.5, 38–99) at baseline and 47.9 (31.4, 3–100) at three months. In the sham group the mean (SD, range) pain score was 67.2 (21.7, 12–100) at baseline and 51.5 (32.5, 3–100) at three months. At three months, 50% improvement from baseline was noted in 35% of the ESWT group and 34% of the sham group with respect to pain. Conclusions: There appears to be a significant placebo effect of moderate dose ESWT in subjects with lateral epicondylitis but there is no evidence of added benefit of treatment when compared to sham therapy. © 2002 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.

Our aim was to correlate the activity of matrix metalloproteinases (MMPs) with denaturation and the turnover of collagen in normal and pathological human tendons. MMPs were extracted from ruptured supraspinatus tendons (n=10), macroscopically normal ("control") supraspinatus tendons (n=29) and normal short head of biceps brachii tendons (n=24). Enzyme activity was measured using fluorogenic substrates selective for MMP-1, MMP-3 and enzymes with gelatinolytic activity (MMP-2, MMP-9 and MMP-13). Collagen denaturation was determined by alpha-chymotrypsin digestion. Protein turnover was determined by measuring the percentage of D-aspartic acid (% D-Asp). Zymography was conducted to identity specific gelatinases. MMP-1 activity was higher in ruptured supraspinatus compared to control supraspinatus and normal biceps brachii tendons (70.9, 26.4 and 11.5 fmol/mg tendon, respectively; P

The purpose of this study was to investigate the effects of some commonly used non-steroidal anti-inflammatory drugs (NSAIDs) on human tendon. Explants of human digital flexor and patella tendons were cultured in medium containing pharmacological concentrations of NSAIDs. Cell proliferation was measured by incorporation of3H-thymidine and glycosaminoglycan synthesis was measured by incorporation of35S-Sulphate. Diclofenac and aceclofenac had no significant effect either on tendon cell proliferation or glycosaminoglycan synthesis. Indomethacin and naproxen inhibited cell proliferation in patella tendons and inhibited glycosaminoglycan synthesis in both digital flexor and patella tendons. If applicable to the in vivo situation, these NSAIDs should be used with caution in the treatment of pain after tendon injury and surgery.

Atlas™ cDNA cell interaction arrays (CLONTECH) were used to examine degenerate tissue from four patients with Achilles tendon disorders, in order to identify changes in expression of genes important in cell–cell and cell–matrix interactions. The greatest difference between normal (post-mortem) and degenerate tissue samples was in the level of MMP-3 (stromelysin) mRNA, which was down-regulated in all the degenerate samples. Quantitative RT-PCR assay of RNA extracted from paired ‘normal’ and degenerate Achilles tendon tissue samples taken from tendons during surgery mirrored the results of the arrays. Levels of MMP-3 mRNA were lower, whereas levels of type-I and type-III collagen mRNAs were significantly higher, in the degenerate compared to the ‘normal’ samples. Immunoblotting of proteins extracted from the same tendon samples showed that three of four normal tissue samples taken from individuals without apparent tendon disorder had much higher levels of MMP-3 protein than ‘normal’ or degenerate samples from patients with tendinosis. We suggest that MMP-3 may play an important role in the regulation of tendon extracellular matrix degradation and tissue remodelling.

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.

The matrix metalloproteinases are a family of enzymes involved in the turnover of the connective tissues. The regulation of these enzymes is complex, involving the control of synthesis, the activation of proenzyme forms and the presence of specific inhibitors. Retinoids have been reported to inhibit the production of metalloproteinases by human and rabbit synovial fibroblasts and by human skin fibroblasts. The production of the highly specific tissue inhibitor of metalloproteinases (TIMP) by connective tissue cells may be crucial in the regulation of connective tissue breakdown and this present study was undertaken to determine if retinoic acid (RA) could modulate TIMP and collagenase production by synovial fibroblasts. The results show that RA at concentrations from 10 −7 to 10 −5 M significantly stimulated the secretion of TIMP by two of three human synovial cell lines. The effect of mononuclear cell factor (MCF) on TIMP and collagenase levels was also investigated. The apparent reduction of collagenase levels in the presence of RA, could result from a failure to accurately measure this enzyme in the presence of increased levels of TIMP.

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.

IL-1 stimulates the secretion of metalloproteinases by a variety of connective tissue cells and is thought to be the primary inducing agent of connective tissue breakdown in rheumatoid arthritis. Transforming growth factor-beta (TGF-beta) is known to be capable of inhibiting the synthesis of metalloproteinases and to be able to partially inhibit interleukin-1 (IL-1) induced cartilage degradation. The present paper examines the ability of TGF-beta to modulate the action of IL-1 on fibroblasts of synovial and skin origin and investigates the secretion of the tissue inhibitor of metalloproteinases (TIMP) by these cells after exposure to TGF-beta and IL-1. The principal findings are that when four out of five fibroblast lines were exposed to TGF-beta and IL-1 in combination they displayed a significant increase in TIMP secretion; furthermore, in two of these cell lines a significant stimulation of TIMP secretion was induced by TGF-beta alone.

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.

Calcific tendinitis of the shoulder is a self-limiting calcification of the rotator cuff (Figure 1). Radiologically evident calcification has been reported in 7.5 to 20 percent of adults with no symptoms1,2 and in 6.8 percent of those with shoulder pain.2 The disorder is most common among people between 30 and 60 years of age. Women are slightly more likely to be affected than men, and workers in sedentary jobs appear to be at higher risk than those in manual work. Bilateral involvement is not uncommon. The reason for the deposition of calcium hydroxyapatite crystals in the tendon is unclear. . . .

Connective-tissue cells produce a family of metalloproteinases which, once activated, can degrade all the components of the extracellular matrix. These potent enzymes are all inhibited by the tissue inhibitor of metalloproteinases (TIMP), and it was thought that the levels of this inhibitor controlled the extracellular activity of these enzymes. We recently detected a new metalloproteinase inhibitor present in culture media of WI-38 fibroblasts. The inhibitor, named ‘large inhibitor of metalloproteinases’ (LIMP), can be separated from TIMP by gel filtration on Ultrogel AcA 44, where it is eluted with an apparent Mr of 76,000. A portion of this inhibitor-containing peak binds to concanavalin A-Sepharose, indicating that at least some of the inhibitor contains carbohydrate. LIMP inhibits collagenase (MMP-1), stromelysin (MMP-3) and gelatinase (MMP-2) in a dose-dependent fashion. Collagenase forms tight-binding complexes with LIMP, which can be separated from free collagenase on gel-filtration columns. The complex is eluted with Mr 81,600 (AcA 44) or Mr 60,000 (Superose 12). This complex is larger than that formed between collagenase and TIMP, which has Mr 52,800 (Aca 44) or 41,000 (Superose 12). Polyclonal antibody to TIMP does not recognize LIMP by immunoblotting, and will not block the inhibition of collagenase by LIMP, showing that LIMP is not a multimeric form of TIMP. The role of this new inhibitor in connective-tissue breakdown studies and its relationship to previously described inhibitors of metalloproteinases is discussed.

Rheumatoid synovial fibroblasts were treated with purified porcine interleukin 1 α and recombinant human interleukin 1B, and the production of secreted and cell-associated plasminogen activator activity was measured. No stimulation of plasminogen activator activity was seen in response to either preparation of interleukin 1, and in more than half of the cell cultures interleukin 1 caused a significant decrease in the secreted levels of PA activity. Increased levels of prostaglandin E were produced in the same experiments, indicating that the cells were responsive to the interleukin 1 preparations. Both retinoic acid and unfractionated monocyte conditioned medium were able to stimulate the production of PA activity by the rheumatoid synovial fibroblast cultures. The rheumatoid synovial fibroblasts produced two species of plasminogen activator as indicated by SDS polyacrylamide gel electrophoresis, with apparent M r of approx. 50 000 and 100 000. The M r = 50 000 species co-migrates with urokinase-type plasminogen activator. No species is produced which co-migrates with tissue type plasminogen activator. Studies with antibodies also indicate that the activity produced is urokinase-type plasminogen activator. The M r = 100 000 species may be an enzyme-inhibitor complex. Two non-rheumatoid synovial fibroblast cultures and two out of six human skin fibroblast cultures did produce elevated levels of plasminogen activator activity in response to recombinant human interleukin 1B. The results suggest that fibroblast populations may differ in their response to interleukin 1, in terms of production of plasminogen activator activity.

Since their development and licencing no class of drug has received as much attention both in the scientific and lay press as the cyclo-oxygenase 2 (COX-2) inhibitors. These compounds, also known as coxibs, were developed as a safer alternative to traditional non-steroidal anti-inflammatory drugs (NSAIDs) due to their reduced propensity to cause gastrointestinal (GI) irritation. However, an unforeseen complication was identified of increased cardiovascular (CV) morbidity and mortality. This observation threw into question the true 'safety' of the class and their subsequent role, if any, in patient management. The amount of information and misinformation regarding the coxibs is vast and as this field is in a state of flux much more will be forthcoming. This article will attempt to review the data regarding coxibs and make some recommendations regarding their ongoing use.

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.

The medicinal benefits of green tea (Camellia sinensis) consumption have been attributed to bioavailable polyphenols, notably epigallocatechin gallate (EGCG). We have assessed the effects of EGCG and its non-esterified counterpart EGC on the expression of the collagenases, matrix metalloproteinases (MMP)-1 and -13, and the stromelysin, MMP-3, in human tendon-derived fibroblasts. Interleukin (IL)-1beta increased MMP-1, -3 and -13 mRNA and output at least 30-fold. EGCG reduced this stimulation, by 20-30% at 2.5 microM and more than 80% at 25 microM, and had a smaller effect on MMP-2 mRNA expression, which was not stimulated by IL-1beta. In all experiments EGCG was at least 10-fold more potent than EGC. EGCG reduced the stimulation of p54 JNK/SAPK phosphorylation by IL-1beta but did not affect p38 MAPK phosphorylation, the degradation of IkappaB or the activating phosphorylation of NFkappaB. We conclude that EGCG reduces the IL-1-stimulated expression of both collagenase and stromelysin mRNA species, an effect which may be mediated by inhibition of the JNK/SAPK pathway. Taken together with previous reports of EGCG effects on the expression and/or activity of gelatinases and aggrecanases, our results underline the importance of extracellular matrix breakdown as a potential target for the actions of green tea polyphenols.

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.

110 consecutive patients were asked about their degree of anxiety (SAI scores), pain (VAS scores) and preferences at various stages before and after imaging in order to determine whether patients with shoulder problems prefer MRI or shoulder arthrography. 88 patients underwent MRI, 42 arthrography and 19 both. Mean levels of anxiety were slightly higher for patients undergoing MRI than those having arthrography, but this difference was not statistically significant. There was a statistically significant (p0.03) reduction in anxiety after arthrography, but not following MRI. Pain scores fell for both patient groups while at rest during the imaging procedure compared with their pre-imaging baseline measurement. This was statistically significant (p0.03) for MRI, but not for arthrography. A significantly higher proportion (p0.001) of patients found MRI unpleasant or extremely unpleasant (20/77) compared with arthrography (3/41). Of the 25 patients who expressed a preference on the basis of past or current experience, 11 preferred MRI and 14 arthrography (NS). There was no significant difference in the proportion of patients who would not allow the test to be repeated (29/73 for MRI, 15/39 for arthrography): Although there were minor differences in both the anxiety and pain experienced by patients undergoing MRI and arthrography, this study did not reveal any firm preference for either investigation.

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

The aim of the study was to immunolocalise interstitial collagenase (MMP-1) and the tissue inhibitor of metalloproteinases (TIMP-1) in ulcerating corneas from patients with rheumatoid arthritis, to determine whether changes in expression are associated with destructive corneal disease. Collagenase was expressed by stromal cells in 8 of 8 ulcerating corneas but was not seen in normal tissue (n = 3). TIMP-1 was abundant throughout the normal stroma, but was much reduced or absent from diseased corneas. Collagenase staining was frequently more intense near the epithelial surface and associated with a cellular infiltrate consisting of activated antigen-presenting cells (HLA-DR+), many of which were macrophages (CD68+) and derived from the epithelium or limbus (S100+). Interstitial collagenase produced by infiltrating macrophages and/or stimulated corneal fibrocytes is probably a major mediator of collagen degradation in rheumatoid corneal ulceration. In addition, reduced levels of TIMP-1 expression are consistent with collagenase activity and tissue destruction. Epithelial-stromal cell interactions and the production of local inflammatory mediators are of major importance in the pathogenesis of corneal destruction, although the precise nature of the antigenic stimulation and/or cellular interactions remains to be elucidated.

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.

Samples of synovial fluids aspirated from patients with septic arthritis prior to the commencement of any treatment contained active metalloproteinases but proteinase no inhibitory activity. We therefore assayed these samples for proteinase-inhibitor complexes. Although no biologically active α 2 -macroglobulin or tissue inhibitor of metalloproteinase (TIMP) was present in the fluids, immunoassay of the samples clearly showed that high molecular weight proteinase-TIMP complexes were present. It is proposed that high levels of active metalloproteinases are released from neutrophils into septic synovial fluids and that these proteinases complex all the available TIMP, forming metalloproteinase-TIMP complexes.

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.