First case report of pre-mortem biopsy-proven kidney involvement by necrobiotic xanthogranuloma with monoclonal gammopathy.

Necrobiotic xanthogranuloma (NXG) is a rare non-Langerhans cell histiocytosis with characteristic cutaneous features and rare visceral involvement. More than 80% of individuals with this disease have a detectable paraprotein but the precise pathogenesis remains obscure. A 68-year-old man with known cutaneous necrobiotic xanthogranuloma presented with acute kidney injury and imaging suggestive of bilateral perinephric infiltration. Renal biopsy showed a prominent histiocytic infiltration of renal capsule and cortex with necrobiosis and characteristic 'Touton-type' giant cells suggestive of necrobiotic xanthogranuloma involvement. Kidney function returned to normal and cutaneous lesions improved with a combination of corticosteroid, chlorambucil and rituximab. This case represents only the second reported incidence of kidney involvement by necrobiotic xanthogranuloma and the first with acute kidney injury and pre-mortem histopathology. This report adds to a small body of literature on the diagnosis and management of visceral involvement by this rare disease.

Body mass index and noninfectious comorbidity in HIV-positive patients commencing antiretroviral therapy in Zimbabwe.

OBJECTIVES: The aim of the study was to describe the prevalence of elevated body mass index (BMI) in a cohort of treatment-naïve people living with HIV (PLWH) and to investigate the association of BMI with CD4 count and noninfectious comorbidities including hypertension and renal impairment. METHODS: A retrospective cohort study of 1598 PLWH at the Newlands Clinic in Harare, Zimbabwe was carried out. Data were extracted from the medical records at baseline and 6 months after initiation of treatment. The univariate association between BMI and CD4 count was assessed and multiple regression models were used to predict factors associated with loss of renal function and change in CD4 count at 6 months. RESULTS: Overweight and obesity (BMI ≥ 25 kg/m2 ) were prevalent in this cohort (34%), as was the presence of hypertension (18%). Higher BMI was associated with a higher CD4 count at baseline and 6 months (B = 0.28 and 0.24, respectively; P < 0.001 for both), adjusted for age and sex. The presence of hypertension independently predicted loss of renal function at 6 months (B = -15.31; P < 0.001), adjusted for BMI, CD4 count and sex. High BMI itself was also independently associated with a decline in renal function (B = -0.41; P = 0.003), adjusted for other significant variables. CONCLUSIONS: We demonstrate a high prevalence of overweight/obesity and hypertension in an urban cohort of PLWH in Zimbabwe. Higher BMI was associated with a higher CD4 count, both before and 6 months after commencing antiretroviral therapy; it was also associated with loss of renal function in this cohort.

A Year of Fractures: a snapshot analysis of the logistics, problems and outcomes of a hospital-based fracture liaison service.

SUMMARY: Our fracture liaison service identifies patients with low trauma fractures, determines the need for osteoporosis therapy and instigates therapy if necessary. We describe the tracking and outcome of 768 patients attending our emergency department over 1 year and discuss the problems we encountered and potential solutions. INTRODUCTION: Osteoporotic fractures result in substantial morbidity, mortality and economic cost, and patients sustaining a first fracture are known to be at higher risk of sustaining future fracture. Treatment of at-risk patients has been shown to assist in prevention of future fracture including hip fracture. We established a "First Fracture Project" to identify and treat these patients in 2003. METHODS: We assessed "A Year of Fractures": the logistics, outcome and problems in tracking patients presenting to our emergency department with a low trauma fracture by our fracture liaison service, over 1 year from July 2008 to June 2009. Patients were tracked by our osteoporosis nurse and offered assessment, and treatment where necessary. RESULTS: In 1 year, 768 patients aged 50 or over were identified from emergency department records as attending with a low trauma fracture. About 84 % of patients eventually received assessment. Of the162 patients progressing through the entire process, 74 % had osteoporosis treatment planned and/or commenced. CONCLUSIONS: Our fracture liaison service was effective at identifying most low trauma fracture patients at risk of further fracture and providing access to osteoporosis assessment. There were many difficulties: we outline logistic and practical issues in delivering our service and suggest potential improvements.

Models of care for the secondary prevention of osteoporotic fractures: a systematic review and meta-analysis.

Most people presenting with incident osteoporotic fractures are neither assessed nor treated for osteoporosis to reduce their risk of further fractures, despite the availability of effective treatments. We evaluated the effectiveness of published models of care for the secondary prevention of osteoporotic fractures. We searched eight medical literature databases to identify reports published between 1996 and 2011, describing models of care for secondary fracture prevention. Information extracted from each publication included study design, patient characteristics, identification strategies, assessment and treatment initiation strategies, as well as outcome measures (rates of bone mineral density (BMD) testing, osteoporosis treatment initiation, adherence, re-fractures and cost-effectiveness). Meta-analyses of studies with valid control groups were conducted for two outcome measures: BMD testing and osteoporosis treatment initiation. Out of 574 references, 42 articles were identified as analysable. These studies were grouped into four general models of care-type A: identification, assessment and treatment of patients as part of the service; type B: similar to A, without treatment initiation; type C: alerting patients plus primary care physicians; and type D: patient education only. Meta-regressions revealed a trend towards increased BMD testing (p = 0.06) and treatment initiation (p = 0.03) with increasing intensity of intervention. One type A service with a valid control group showed a significant decrease in re-fractures. Types A and B services were cost-effective, although definition of cost-effectiveness varied between studies. Fully coordinated, intensive models of care for secondary fracture prevention are more effective in improving patient outcomes than approaches involving alerts and/or education only.

Intravenous zoledronic acid and oral alendronate in patients with a low trauma fracture: experience from an osteoporosis clinic.

BACKGROUND/AIMS: Oral bisphosphonates have been shown to be effective in treating osteoporosis. However, there has been a significant problem with compliance. Newer intravenous bisphosphonates are available for osteoporosis management, but have not been compared with oral bisphosphonates in a clinical setting. The aim of this study was to compare the safety and effectiveness of intravenous zoledronic acid (ZOL) and oral alendronate (ALN) in osteoporotic patients following a low trauma fracture. METHODS: A non-randomized, retrospective cohort study was conducted of 169 patients with a low trauma fracture and reduced bone mineral density (BMD). Patients were treated with either an infusion of 4 mg ZOL or ALN 70 mg weekly. The outcomes measured were change in BMD after 12 months of treatment with either bisphosphonate, and new osteoporotic fractures. All adverse events were documented. RESULTS: Lumbar spine BMD (L2-L4) improved 5.6% in the ZOL group (P < 0.001) and 5.5% in the ALN group (P < 0.001). Total hip BMD improved 2% in the ZOL group (P < 0.01) and 2.5% in the ALN group (P < 0.001). There was no significant difference in BMD change between the groups. There were significantly more new fractures (P < 0.001) in the ZOL group (7.2%) than the ALN group (1%). The ZOL group were significantly older (P < 0.01) and had a significantly higher proportion of males (P < 0.05) at baseline. There were no serious adverse reactions in either group. CONCLUSION: ZOL and ALN both produce a significant increase in BMD and are well tolerated in patients with osteoporotic, low trauma fractures. Yearly ZOL provides a safe, convenient alternative to weekly oral bisphosphonates.

First Fracture Project: addressing the osteoporosis care gap.

Patients sustaining a low-trauma fracture are at greater risk of subsequent fracture, but as a group are poorly managed. We report the development of our 'First Fracture Project', in which we attempt to assess all patients over 50 years of age with a low-trauma fracture attending orthopaedic fracture clinics and treat osteopenia and osteoporosis. We found that the First Fracture Project has greatly increased our success in improving delivery of osteoporosis care to appropriate at-risk patients.

Effect of leflunomide on the peripheral nerves in rheumatoid arthritis.

BACKGROUND: The objective of this study was to determine the neurophysiological effects of leflunomide on peripheral nerves in rheumatoid arthritis. METHODS: We conducted a prospective cohort trial of 32 patients with rheumatoid arthritis with 16 patients receiving leflunomide treatment and 16 receiving other disease-modifying anti-rheumatic drug therapies. Clinical, laboratory and neurophysiological measurements were used to determine the presence of a peripheral neuropathy in these patients at study entry and then after a further 3 and 6 months. RESULTS: Fifty-four per cent of the leflunomide group and 8% of the control group had an increase in their neuropathy symptom score 6 months into the study (P = 0.01). No correlation was found between the electrophysiological findings and the clinical symptoms. There was no significant difference between the two groups in upper and lower limb sensory and motor amplitudes and conduction velocities recorded at 3 and 6 months. One patient developed both clinical and neurophysiological evidence of a peripheral neuropathy 5 months into the study that improved after cessation of leflunomide therapy and cholestyramine washout. CONCLUSION: After 6 months of exposure we found that leflunomide was associated with an apparent increase in the clinical symptoms of peripheral neuropathy in patients with rheumatoid arthritis. These symptoms did not correlate with neurophysiological studies.

Telopeptides as markers of bone turnover in rheumatoid arthritis and osteoarthritis.

AIMS: The aim of the present study was to determine if urinary excretion of type I collagen N-terminal telopeptides (UrNTx) and deoxypyridinoline (UrDPD) and serum levels of type I collagen C-terminal telopeptides (SeCTx) differed in patients with rheumatoid arthritis (RA) compared with populations matched for age and gender with and without osteoarthritis (OA). The correlation of markers of bone turnover with disease activity in patients with RA or radiographic severity in patients with OA was also examined. METHODS: Patients with RA aged >50 years (men) and >60 years (women) were identified from computer databases at two tertiary referral centres for rheumatology. Strict exclusion criteria were applied to avoid the effects of factors known to influence markers of bone turnover. Patients with RA and OA were matched for age and sex with a control population free of known arthritic disease and a population with OA. Bone markers were assayed in serum and urine. Urine markers were measured on three consecutive days and mean values used to minimize day-to-day variability of these analytes. RESULTS: The level of UrNTx was elevated in patients with RA compared with normal controls and patients with OA. UrNTx and UrDPD correlated with markers of disease activity in patients with RA (erythrocyte -sedimentation rate and C-reactive protein), but not with -clinical signs of inflammation (swollen and tender joint counts). Patients with OA failed to show any correlation between markers of bone turnover and radiographic severity. CONCLUSIONS: These data support a role for the use of UrNTx and UrDPD in further studies of the patho-physiology of RA and in longitudinal studies designed to modify the course of clinical disease.

Osteoporosis: A possible aetiological factor in the development of Scheuermann's disease.

The aim of this study was to test the hypothesis that spinal osteoporosis is an aetiological factor in the development of Scheuermann's disease in adolescents. Clinical and radiological data was collected on 12 individuals with Scheuermann's disease (SD). Lumbar spine bone mineral density (L2-4) was measured using dual energy X-ray absorptiometry. Age and sex-matched adolescents were used as controls. The number of standard deviations from the mean of age and sex-matched controls were calculated. In regards to results, SD patients demonstrated high bone densities of between 1 and 1.5 standard deviations above the mean of age-matched controls. These results suggest that osteoporosis is not an aetiological factor in Scheuermann's disease and that bone density measurements may indeed be higher than aged-matched controls in the general population.

Androgen deficiency and bone mineral density in men with rheumatoid arthritis.

OBJECTIVE: To investigate the prevalence of osteopenia/osteoporosis in a group of men with rheumatoid arthritis (RA); and to analyze the relationship between sex hormone status and bone mineral density (BMD), taking into account disease activity, disease duration, and corticosteroid intake. METHODS: Clinical and demographic details were collected on 50 consecutive men with RA. BMD at the lumbar spine and femoral neck were measured, together with plasma concentrations of testosterone, sex hormone binding globulin, and luteinizing hormone. RESULTS: The median age of patients was 67 years, with median disease duration 20 years. Fourteen patients had never been treated with oral corticosteroids, the remaining 36 received a range of prednisone doses over prolonged periods. Plasma testosterone concentration was moderately reduced in 40% (< 10 nmol/l) and severely reduced in 6% of men (< 8 nmol/l), but androgen deficiency was not related to bone density or fractures. Spinal and femoral neck BMD was reduced in 38 and 71% of the men, respectively. Femoral neck BMD was related to age, weight, disability status, and specific disease activity scores. The only predictors of spinal BMD were pack-years of smoking and physician global assessment. CONCLUSION: Reduced BMD is common among men with RA. The predictors for spine and femoral neck BMD bear little direct relationship to blood testosterone concentrations despite the relatively high prevalence of low testosterone concentrations in this population. These findings are more consistent with the possibility that low testosterone concentrations in men with RA are a bystander effect of systemic inflammatory disease.

Changes in serum cartilage marker levels indicate altered cartilage metabolism in families with the osteoarthritis-related type II collagen gene COL2A1 mutation.

OBJECTIVE: The Arg5l9-Cys mutation in type II collagen results in severe, precocious familial osteoarthritis (OA) in 100% of carriers within the first 3 decades of life. The carrier population provided a well-defined patient population for the study of serum markers of familial OA with respect to pathogenesis, diagnosis, and prognosis. METHODS: Serum was obtained from 31 mutation-positive individuals and 16 mutation-negative individuals. OA severity was determined by clinical and radiologic assessments. Levels of serum cartilage oligomeric matrix protein (COMP), keratan sulfate (KS) epitope, the 846 epitope of aggrecan, and the C propeptide of type II collagen (CPII) were measured and were correlated with the radiologic findings. RESULTS: COMP and KS levels, both of which have been suggested to be indicative of disturbed cartilage turnover, were significantly elevated in mutation-positive individuals and in the individuals with OA regardless of mutation status. There was no statistically significant difference between mutation-positive, mutation-negative, OA-positive, and OA-negative individuals with respect to serum concentrations of epitope 846 or CPII, both of which are putative markers of cartilage repair. CONCLUSION: Study of the macromolecular constituents of cartilage released into serum in subjects with familial OA revealed altered metabolism in OA, as demonstrated by elevated COMP and KS levels. Other constituents, the 846 epitope and CPII, were not altered, indicating dissociation of cartilage anabolism and breakdown. Future sequential studies will provide an opportunity to define biochemical changes as familial OA develops and to monitor therapeutic responses.

Five families with arginine 519-cysteine mutation in COL2A1: evidence for three distinct founders.

Arginine519-cysteine mutation in the type II procollagen gene (COL2A1) is known to be associated with mild spondyloepiphyseal dysplasia (SED) and precocious generalized osteoarthritis (OA). Five families have now been identified with this mutation. To determine whether a common founder was responsible for the mutation in these five families, we defined the haplotype of the mutation-bearing chromosome using four restriction fragment length polymorphisms (RFLPs) and the 3'-untranslated region VNTR. Haplotype frequencies were estimated for 69 control samples. Three distinct mutation-bearing haplotypes were identified, with three families sharing a common haplotype. For three distinct haplotypes to have derived from a single founder, three independent recombination events would have had to occur. Thus the arg519 codon appears to represent a possible site of recurrent mutations in COL2A1, an uncommon phenomenon in collagen genes.

Hereditary osteoarthritis with mild spondyloepiphyseal dysplasia--are there "hot spots" on COL2A1?

OBJECTIVE: To define the genetic basis of a family with an autosomal, dominantly inherited form of spondyloepiphyseal dysplasia (SED) associated with tall stature. METHODS: A 6 generation family with early onset osteoarthritis (OA) associated with mild SED was studied. 14 individuals were examined clinically and radiologically, and DNA analysis was performed on 5. As the clinical pattern of joint involvement and tall stature of affected individuals resembled a family recently reported with an exon 11 mutation in COL2A1, this same mutation was specifically sought. In 2 clinically affected and 3 unaffected family members, exon 11 was amplified by polymerase chain reaction (PCR) followed by restriction enzyme digestion with Asp H1, the enzyme recognition sequence of which is altered by the mutation. The PCR product containing exon 11 was then directly sequenced. RESULTS: OA with widespread involvement of peripheral joints, in addition to spondylodysplasia, was seen in 14 members of the kindred. Affected family members had brachydactyly and were of average to above average height. Asp H1 digestion of the PCR product containing exon 11 in those with clinical disease was consistent with the presence of a mutation. Direct sequencing of this PCR product conclusively showed that a single base substitution was present in those with clinical disease, resulting in an arginine 75-cysteine (Arg75-Cys) mutation. CONCLUSION: We describe a 3rd family with an Arg75-Cys mutation with precocious generalized OA and mild SED. This finding supports the concept of mutational hot spots on COL2A1 related to the hypermutability of the cytosine-guanine doublet.

Clinical correlations of osteoarthritis associated with single base mutations in the type II procollagen gene.

There are increasing numbers of mutations described in the gene for type II collagen (COL2A1). Recently, COL2A1 mutations were shown to be associated with milder forms of chondrodysplasia, which may present with precocious generalized osteoarthritis (OA). The arginine519-cysteine and the arginine75-cysteine mutations are 2 such sites on COL2A1 where multiple unrelated families have been reported presenting with early onset, generalized OA and chondrodysplasia. The observation of multiple sites where recurrent mutations occur suggests that certain areas of COL2A1 are more prone to mutational events.

Type II procollagen gene (COL2A1) mutation in exon 11 associated with spondyloepiphyseal dysplasia, tall stature and precocious osteoarthritis.

OBJECTIVE: To define the clinical, pathological and molecular genetic characteristics of a family with mild spondyloepiphyseal dysplasia (SED) and precocious osteoarthritis. METHODS: The proband was a 46-year-old man with precocious generalized OA, tall stature, mild chondrodysplasia and moderate deafness. His daughter, aged 21, showed similar clinical features. Electron microscopic (EM) analysis of collagen from an affected joint of the proband was performed. DNA was extracted from whole blood on the proband, his affected daughter, unaffected wife and second daughter, to look for a mutation in exons 31 or 11, sites where point mutations have been previously described in mild forms of SED. After finding no mutation in exon 31, exon 11 of COL2A1 was further analyzed. Exon 11 was amplified using polymerase chain reaction (PCR), and screening for the mutation was undertaken using a restriction enzyme digestion, the recognition sequence of which is altered by this point mutation. Sequence analysis was then performed. RESULTS: Electron microscopic (EM) analysis of cartilage from the proband showed thin appearing collagen fibrils organized into parallel lamellar structures. DNA studies revealed a single base change in one allele of exon 11 which produced an arginine to cysteine mutation at position 75 of the triple helix of type II collagen in the proband and his affected daughter. CONCLUSION: This is the 2nd example of an Arginine75-Cysteine mutation associated with SED; in our case, however, contrasting clinical features were present. Recurrent mutations at a few specific sites of COL2A1 suggest the possibility of susceptibility "hot spots" for mutational events.

Total hip arthroplasty in the young arthritic patient.

BACKGROUND: Hip disease is a major cause of immobility and pain in children and young adults with inflammatory arthritides. Total hip arthroplasty (THA) has previously been avoided in young patients because of the concern about durability of the prosthesis and the need for multiple revisions. There are now, however, growing reports of the success of such procedures in improving mobility and relieving pain in the young patient with severe hip disease. In this study we aimed to determine the clinical and radiological results in patients with inflammatory arthritides who had undergone THA before the age of 35 years. METHODS: Twenty-one patients who had undergone a total of 38 hip arthroplasties were identified. Patients' hips were scored both pre-operatively and at follow-up using the scoring system of the Hospital for Special Surgery, which allots a score for pain, walking, motion and muscle power, and function. Complications were noted and follow-up X-rays were compared to postoperative films to assess radiological loosening. RESULTS: The mean age at operation was 24 years, and the mean follow-up was 8.6 years. The results in terms of pain relief, mobility, movement and functional capacity were good. Revision was required in 13 hips (34%). This was mostly due to the failure of resurfacing prostheses. Radiological loosening was evident in a further six hips, five of which were asymptomatic. CONCLUSIONS: THA can dramatically improve the quality of life of the young patient with arthritis. The main concern is the likely need for multiple revisions, with progressive loss of bone stock.