Gary Wright

Mutations in ANKH Cause Chondrocalcinosis

Chondrocalcinosis (CC) is a common cause of joint pain and arthritis that is caused by the deposition of calcium-containing crystals within articular cartilage. Although most cases are sporadic, rare familial forms have been linked to human chromosomes 8 (CCAL1) or 5p (CCAL2) (Baldwin et al. 1995; Hughes et al. 1995; Andrew et al. 1999). Here, we show that two previously described families with CCAL2 have mutations in the human homolog of the mouse progressive ankylosis gene (ANKH). One of the human mutations results in the substitution of a highly conserved amino acid residue within a predicted transmembrane segment. The other creates a new ATG start site that adds four additional residues to the ANKH protein. Both mutations segregate completely with disease status and are not found in control subjects. In addition, 1 of 95 U.K. patients with sporadic CC showed a deletion of a single codon in the ANKH gene. The same change was found in a sister who had bilateral knee replacement for osteoarthritis. Each of the three human mutations was reconstructed in a full-length ANK expression construct previously shown to regulate pyrophosphate levels in cultured cells in vitro. All three of the human mutations showed significantly more activity than a previously described nonsense mutation that causes severe hydroxyapatite mineral deposition and widespread joint ankylosis in mice. These results suggest that small sequence changes in ANKH are one cause of CC and joint disease in humans. Increased ANK activity may explain the different types of crystals commonly deposited in human CCAL2 families and mutant mice and may provide a useful pharmacological target for treating some forms of human CC.

High-resolution ultrasonography of the first metatarsal phalangeal joint in gout: a controlled study

Objective: To compare high-resolution ultrasound (HRUS) with conventional radiography in the detection of erosions in the first metatarsophalangeal joints (1st MTPJs) of patients with gout and to identify the characteristic sonographic features of gout. Methods: HRUS examination of the 1st MTPJs of both feet was performed by two independent sonographers. The presence of joint and soft-tissue pathology was recorded. x Ray examination of the feet was performed on the same day and reported by the same radiologist. Results: 39 male patients with gout and 22 age-matched control subjects (14 with an inflammatory arthropathy and 8 disease free) were studied. The agreement on erosion between HRUS and x ray was poor, κ = 0.229 (non-weighted), with McNemar’s test being significant (p<0.001) indicating a large number of false negative x rays. 22 MTPJs in patients with gout had never been subjected to a clinical attack of acute gout. In these MTPJs, there were 10 erosions detected by HRUS and 3 erosions on x ray. HRUS features significantly more prevalent in the patients with gout were hard and soft tophus-like lesions (p<0.01) and the double contour sign (p<0.01). Conclusions: These data show that HRUS may assist in the management of gout in two ways: first, by aiding in the diagnosis by identifying the sonographic features that may be representative of the disease, and, second, by allowing the early detection of erosive joint damage and/or tophaceous deposits even in clinically silent joints.

Association of two loci on chromosome 2q with nodal osteoarthritis.

OBJECTIVE: To search for genetic association between microsatellite marker loci and sibling pairs with nodal osteoarthritis (NOA). METHODS: Using the affected sibling pair method of analysis, genomic DNA from 66 sib pairs with NOA was analysed for association with highly polymorphic microsatellite marker loci. The microsatellite markers were amplified using polymerase chain reaction and typed on polyacrylamide gels. RESULTS: A significant association (p < 0.05) was identified between NOA and two loci on the short arm of chromosome 2 (2q 23-35). Candidate genes for osteoarthritis in this region include: fibronectin, a glycoprotein present in the extracellular matrix of normal cartilage; the alpha 2 chain of collagen type V, a major constituent of bone; and the interleukin-8 receptor, important in the regulation of neutrophil activation and chemotaxis. CONCLUSIONS: The chromosomal region 2q 23-35 requires further detailed study in NOA. Confirmation of these findings in large independent data sets and further analysis of candidate genes in this region will be important in unravelling the molecular basis for this common disease.

Steroid injection for inferior heel pain: a randomised controlled trial

Background Plantar fasciitis is a common cause of heel pain. The aim of this study was twofold: to compare steroid injection with placebo injection and to compare ultrasound guided with unguided steroid injection in the management of this condition. Methods 65 patients with inferior heel pain were recruited between November 2008 and June 2011. Heel pain was measured using a visual analogue scale (VAS) at baseline and follow-up 6 and 12 weeks after injection. Results 22 patients were randomised to ultrasound guided steroid injection, 21 patients to palpation guided steroid injection and 22 to ultrasound guided placebo injection. There was a significant difference in VAS scores between the groups at 6 and 12 weeks (p=0.018 and p=0.004, respectively). There was a 19.7 (95% CI 2.5 to 37.0) difference in mean VAS scores at 6 weeks between the ultrasound guided steroid group and the placebo group and a 24.0 (95% CI 6.6 to 41.3) difference between the unguided steroid group and the placebo group at 6 weeks. At 12 weeks, the mean difference was 25.1 (95% CI 6.5 to 43.6) and 28.4 (95% CI 11.1 to 45.7) respectively between both steroid injection groups and the placebo group. There was no difference in VAS scores following steroid injection between the ultrasound guided and the unguided groups at either time point. Plantar fascia thickness was significantly reduced after injection in both active treatment groups (p=0.00). Conclusions In this study, steroid injection showed a clear benefit over placebo at 6 weeks and this difference was maintained at 12 weeks. Trial Registration No ISRCTN79628180 (www.controlled-trials.com).

Hypertrophic pulmonary osteoarthropathy (HPOA) (Pierre Marie-Bamberger syndrome): two cases presenting as acute inflammatory arthritis. Description and review of the literature.

We report the cases of two middle-aged male smokers who presented to the early synovitis clinic with an acute phase response, synovitis of the wrists and ankles and clubbing of the fingers, but no respiratory symptoms. Both proved to have primary lung tumours with hypertrophic pulmonary osteoarthropathy, in one case resolving promptly with treatment of the carcinoma. We review the literature, including theories on pathogenesis.

Calcium pyrophosphate crystal deposition is not always ‘wear and tear’ or aging

A 54 year old man gave a two year history of a painful right hip, fingers, and wrists. There was no past medical history of note. On examination there were bilateral, bony, metacarpophalangeal (MCP) joint swellings and painful restriction of movement in his right hip. The remainder of the examination was unremarkable. It was thought, at the initial presentation, that the clinical and radiographic features (fig1) were consistent with osteoarthritis and he was treated symptomatically. A further rheumatology opinion was sought two years later as his symptoms were progressive. Because of the history and radiographic features further investigations were requested. Radiographs of his knees confirmed chondrocalcinosis and calcium pyrophosphate dihydrate (CPPD) crystals were identified in synovial fluid aspirate by compensated polarised light microscopy. The serum ferritin concentration was found to be increased at 1200 μg/l. The γ-glutamyltransferase was 65 (10–50 U/l) and the alanine aminotransferase 65 (5–40 U/l), the remainder of the liver function tests were normal. A liver biopsy confirmed haemochromatosis. Regular phlebotomy was instituted. Eight months later his serum ferritin and liver function tests had returned to normal. The arthropathy, however, remained symptomatic, requiring regular topical agents, analgesics, and education in pain management. He eventually required a right hip arthroplasty. Screening of family members identified an asymptomatic affected sister who subsequently underwent phlebotomy. Figure 1 (A) Hand radiograph showing pronounced eccentric loss of joint space at the MCP joints, with sclerosis, osteopenia, and radial ‘hook’ osteophytes. (B) Hip radiograph showing attrition of the femoral head with …

Evidence for genetic anticipation in nodal osteoarthritis

OBJECTIVE Evidence was sought for genetic anticipation (disease occurring at an earlier age in subsequent generations, with increasing severity) in nodal osteoarthritis (NOA). METHODS Age at symptom onset and disease severity was compared within 30 parent/offspring pairs with NOA. Correlation between the offspring age of disease onset and the parental age at conception was also assessed. RESULTS The age at onset of nodal symptoms was earlier in the offspring (43 years (95% confidence intervals (CI) 38 to 47) v 61 (CI 58 to 65); mean difference 18 years (CI 13 to 22): p< 0.001) as was large joint symptom onset (48 years (CI 41 to 55) v 67 (CI 61 to 73); mean difference 20 years (CI 13 to 27): p< 0.01). A negative correlation existed between age of offspring symptom onset and parental age at conception. Fifteen (50%) offspring had similar or more extensive disease than their parents. CONCLUSIONS These results suggest genetic anticipation occurs in NOA and if confirmed a search for trinucleotide repeats is warranted.

A randomised study of two training programmes for general practitioners in the techniques of shoulder injection

Objectives: To evaluate the impact of two different modes of shoulder injection training on the level of confidence and number of injections performed by general practitioners (GPs) Methods: Demographic details, and information on referrals for shoulder problems, shoulder joint injection activity, and confidence in the six months before training were obtained for 40 GP principals at baseline. Standardised training in the techniques of shoulder joint injection using rubber mannequins was given to all GPs. Twenty of these GPs were randomly allocated to receive additional training on patients in hospital joint injection clinics. Six months after both forms of training the shoulder injection and referral activities of all GPs were reassessed. Results: Both training groups had comparable demographic characteristics and baseline clinical activity. GPs who had additional training with patients reported a marked increase in their level of confidence in performing shoulder injections and the number performed. The number of shoulder referrals did not differ between the groups Conclusion: Training on patients in addition to conventional training on mannequins increased GPs’ shoulder injection activity and their level of confidence. Hospital injection clinics may provide a suitable setting in which to train GPs interested in developing their shoulder joint injection skills.

Can rheumatologists agree on a diagnosis of inflammatory arthritis in an early synovitis clinic

Irreversible joint damage can occur within months rather than years of the onset of rheumatoid arthritis.1 It is therefore important that these patients are diagnosed and treated as early as possible. To facilitate the early introduction of effective treatment, a rapid referral system is important. Throughout Europe, a number of centres have developed early synovitis clinics (ESCs) for this purpose. However, the diagnosis of early inflammatory arthritis (IA) is often difficult and confusing for the primary care doctor and experience suggests that the efficiency of ESCs is impaired by inappropriate referrals.2 Is this criticism justified? If general practitioners find it difficult to diagnose early IA, what about hospital …

Case number 8

A 57 year old woman with metastatic ovarian carcinoma presented with painful, swollen, stiff, hands. Examination showed pronounced thickened palmar fascia and flexor tendons, with fixed flexion deformities of her fingers. Mild sclerodactly …