Serum amyloid P component scintigraphy in familial amyloid polyneuropathy: regression of visceral amyloid following liver transplantation

Familial amyloid polyneuropathy (FAP) associated with transthyretin (TTR) mutations is the commonest type of hereditary amyloidosis. Plasma TTR is produced almost exclusively in the liver and orthotopic liver transplantation is the only available treatment, although the clinical outcome varies. Serum amyloid P component (SAP) scintigraphy is a method for identifying and quantitatively monitoring amyloid deposits in vivo, but it has not previously been used to study the outcome of visceral amyloid deposits in FAP following liver transplantation. Whole body scintigraphy following injection of iodine-123 labelled SAP was performed in 17 patients with FAP associated with TTR Met30 and in five asymptomatic gene carriers. Follow-up studies were performed in ten patients, eight of whom had undergone orthotopic liver transplantation 1-5 years beforehand. There was abnormal uptake of 123I-SAP in all FAP patients, including the kidneys in each case, the spleen in five cases and the adrenal glands in three cases. Renal amyloid deposits were also present in three of the asymptomatic carriers. Follow-up studies 1-5 years after liver transplantation showed that there had been substantial regression of the visceral amyloid deposits in two patients and modest improvement in three cases. The amyloid deposits were unchanged in two patients. In conclusion, 123I-SAP scintigraphy identified unsuspected visceral amyloid in each patient with FAP due to TTR Met30. The universal presence of renal amyloid probably underlies the high frequency of renal failure that occurs in FAP following liver transplantation. The variable capacity of patients to mobilise amyloid deposits following liver transplantation may contribute to their long-term clinical outcome.     

Serum amyloid P component prevents proteolysis of the amyloid fibrils of Alzheimer disease and systemic amyloidosis

Extracellular deposition of amyloid fibrils is responsible for the pathology in the systemic amyloidoses and probably also in Alzheimer disease [Haass, C. & Selkoe, D. J. (1993) Cell 75, 1039-1042] and type II diabetes mellitus [Lorenzo, A., Razzaboni, B., Weir, G. C. & Yankner, B. A. (1994) Nature (London) 368, 756-760]. The fibrils themselves are relatively resistant to proteolysis in vitro but amyloid deposits do regress in vivo, usually with clinical benefit, if new amyloid fibril formation can be halted. Serum amyloid P component (SAP) binds to all types of amyloid fibrils and is a universal constituent of amyloid deposits, including the plaques, amorphous amyloid beta protein deposits and neurofibrillary tangles of Alzheimer disease [Coria, F., Castano, E., Prelli, F., Larrondo-Lillo, M., van Duinen, S., Shelanski, M. L. & Frangione, B. (1988) Lab. Invest. 58, 454-458; Duong, T., Pommier, E. C. & Scheibel, A. B. (1989) Acta Neuropathol. 78, 429-437]. Here we show that SAP prevents proteolysis of the amyloid fibrils of Alzheimer disease, of systemic amyloid A amyloidosis and of systemic monoclonal light chain amyloidosis and may thereby contribute to their persistence in vivo. SAP is not an enzyme inhibitor and is protective only when bound to the fibrils. Interference with binding of SAP to amyloid fibrils in vivo is thus an attractive therapeutic objective, achievement of which should promote regression of the deposits.     

Autoantibody studies in juvenile rheumatoid arthritis

Early studies showed few immunologic abnormalities in juvenile rheumatoid arthritis (JRA) patients. There were no specific laboratory markers useful for diagnosis and assessment of the course of disease in JRA. Previous work showed an association of antinuclear antibodies (ANA) with early-onset pauciarticular disease and iridocyclitis. Similarly, the presence of 19S immunoglobulin (Ig) M rheumatoid factors (RF) was associated with late-onset polyarticular disease in girls. More recent studies have detected many unique autoantibodies. Newer assays show 19S IgM RF in up to 35% of JRA patients, although still mainly in girls with late-onset polyarticular disease. Hidden 19S IgM RF can be shown in up to 75% of JRA patients using different procedures, primarily in those with active polyarticular-or pauciarticular-onset disease. Immune complexes have been detected in JRA patients by means of different techniques; their presence usually correlates with active disease. Studies on a specific ANA in JRA have shown no common extractable nuclear antigen, but antihistone antibodies have been found in up to 75% of cases, again mainly in those with pauciarticular onset and iritis. Finally, a variety of unusual immunologic proteins have also been detected, including anti-ocular, anti-cellular, anti-cardiolipin, anti-perinuclear factor, and anti-collagen antibodies. This review evaluates the significance of these antibodies that can now be found in JRA.     

Scintigraphy using iodine 123-labeled serum amyloid P component in ten patients with secondary AA type amyloidosis. A descriptive study

Several problems in the management of life-threatening mucormycosis remain unresolved, necessitating new methods of management. Four patients with histopathologically proven rhinocerebral mucormycosis were treated with high cumulative doses of granulocyte colony-stimulating factor (G-CSF). All had multiple predisposing factors for mucormycosis, particularly leukemia and neutropenia. Two patients refractory to fluconazole therapy were treated with liposomal amphotericin B. The improvement in clinical manifestations was closely related to neutrophil recovery, and all patients were alive at the end of therapy. In addition to surgical debridement and antifungal therapy, G-CSF seems to have played a role in their survival.     

Methotrexate in the treatment of juvenile rheumatoid arthritis and other pediatric rheumatoid and nonrheumatic disorders

The goal of treatment for juvenile rheumatoid arthritis (JRA) and other pediatric rheumatic disorders is to minimize joint destruction, pain, and deformity and to maximize all aspects of growth and development. Oral and injectable methotrexate are now often given early in the treatment of JRA, childhood dermatomyositis, difficult-to-control arthritis in the pediatric spondyloarthropathies, SLE, sarcoidosis, several of the vasculopathies, and idiopathic iritis. Weekly low-dose MTX has become a mainstay of long-term improved control of these disorders, and is associated with strikingly few documented long-term side effects. Dosages, pharmacology, side effects, efficacy, and treatment strategies are discussed. Although formal studies are lacking, MTX for the pediatric rheumatic disorders seems to be associated with less frequent physician visits, lower total costs, improved function, and fewer late reconstructive surgeries.     

Bone mineral density and turnover in children with systemic juvenile chronic arthritis

OBJECTIVE: To assess bone mineral status in a group of children with systemic type juvenile chronic arthritis (JCA), which places them at high risk to develop osteoporosis. METHODS: Bone mineral density (BMD) was measured in 17 children aged 6-18 yrs (mean 14.9 +/- 4.5) with systemic JCA and in 18 matched controls by dual energy x-ray absorptiometry. Bone turnover was determined by quantitative bone scintigraphy, using quantitative single photon emission computed tomography based on skeletal uptake of methylene diphosphonates (MDP uptake). Serum concentrations of minerals, osteocalcin, and bone alkaline phosphatase were determined. Nutrient intake was assessed by a 24 hour dietary recall. RESULTS: Patients with systemic JCA who received corticosteroid therapy had significantly reduced BMD in both the lumbar spine (p < 0.05) and the femoral neck (p < 0.05) compared to controls, whereas BMD values of the non-steroid systemic JCA patients were not different from controls. Bone turnover measurement by MDP uptake showed no difference between patients with JCA and controls. Levels of calcium, phosphorus, alkaline phosphatase. and osteocalcin were within normal limits in all patients. CONCLUSION: Patients with systemic JCA receiving longterm steroid treatment may develop a significant decrease in BMD. The normal MDP uptake values together with normal osteocalcin levels that we observed in our patients indicate that their disease is not associated with enhancement of bone turnover rates. These observations might have therapeutic implications for prevention and management of osteoporosis in JCA.     

Methotrexate in juvenile rheumatoid arthritis. Evidence of age dependent pharmacokinetics

Children with juvenile rheumatoid arthritis (JRA) have been reported to require higher doses (per kg body weight) of methotrexate (MTX) than adults with rheumatoid arthritis to control their disease. The purpose of the present study was to characterise the plasma pharmacokinetics of MTX and its major metabolite, 7-hydroxymethotrexate (7-OHMTX) in children, and to compare the results with those previously obtained in adults. Thirteen patients (age 5-16 y) with JRA (median disease duration 5.5 y) were studied after once weekly oral administration of MTX (median 0.21 mg.kg-1). The analytical method was sufficiently sensitive to permit determination of plasma and urinary concentrations of MTX and 7-OHMTX during the entire dose interval in most of the patients. The dose normalized area under the plasma concentration versus time-curve (AUC) of MTX increased with the age of the children and was lower than previously found in adults. The dose normalized AUC of 7-OHMTX was not dependent on age. No correlation was found between the AUCs of MTX and 7-OHMTX. The results suggest that the age-dependence of the pharmacokinetics of MTX might explain the observation that at least some children require higher doses of MTX than adults to obtain a sufficient therapeutic effect.     

Serum immunoglobulins, rheumatoid factor, and pneumoconiosis in coal miners with rheumatoid arthritis

The occurrence and severity of pneumoconiosis were studied in 100 coal miners with rheumatoid arthritis (RA) and compared to findings in a geographically relevant survey of coal workers' pneumoconiosis. Contrary to European reports, miners with RA were not found to have an excessive frequency or severity of pneumoconiosis. In 55 of these men, serum immunoglobulin levels and rheumatoid factor were compared with data from matched RA patients with no history of silica exposure. The immunochemical results were unrelated to the stage of pneumoconiosis, nor did they differ from those in the control group.     

Is bone turnover a determinant of bone mass in rheumatoid arthritis?

OBJECTIVE: The aim of this study was to measure ultrasound (US) densitometric parameters [Broadband Ultrasound Attenuation (BUA), Speed of Sound (SOS), and stiffness of the os calcis] in patients with inflammatory bowel disease (IBD) and to compare the results with those obtained with conventional x-ray absorptiometry (DXA) of the lumbar spine. METHODS: Twenty-two patients with Crohn's disease (13 with ileal and nine with ileocolonic disease), 11 patients with ulcerative colitis (eight with left-sided and three with pancolitis), and 18 healthy controls. US densitometry of the right heel and DXA of the lumbar spine were performed within the same day. RESULTS: Compared to controls, IBD patients had significantly lower values with both methods, US and DXA. Forty-nine percent of patients had a lumbar T score below -1. Calcaneal SOS and stiffness of these patients were significantly reduced (p < 0.03 and p < 0.05, respectively). Positive significant correlations were found between lumbar DXA and calcaneal US parameters. Lumbar bone density and calcaneal US stiffness correlated inversely with the lifetime prednisone intake (p < 0.03 andp < 0.05, respectively), but not with age or duration of disease. A cut-off level of 80 dB/MHz for calcaneal BUA predicted axial osteopenia correctly in 74%, but some underestimation of spinal BMD was observed, especially in female patients with Crohn's disease. CONCLUSION: US evaluation of the os calcis gives results similar to those of conventional DXA and therefore may be used for screening IBD patients for axial osteoporosis. Because US does not expose patients to radiation, repeated measurements are possible and may be used to assess short term variations and the effect of treatment of IBD-associated bone disease.     

A case of malignant rheumatoid arthritis complicated by secondary amyloidosis and membranous nephropathy

A 30-year-old man had been treated for malignant rheumatoid arthritis from 1989 with a non-steroidal anti-inflammatory drug, then bucillamine for six months and prednisolone. Mild proteinuria appeared in May 1994, 4 years after bucillamine therapy was conducted. The patient was admitted to our hospital for a renal biopsy in July 1994. The specimen revealed secondary amyloidosis and membranous nephropathy (MGN). These findings suggest that MGN unrelated to bucillamine therapy might have occurred with secondary amyloidosis in rheumatoid arthritis.     

The autonomic nervous system and the immune system in juvenile rheumatoid arthritis

CD16, the low affinity receptor for monomeric IgG (Fc gamma RIIIA), is a well characterized activation molecule on NK cells. In this study we investigated the role of CD16 in NK cell-mediated regulation of immunoglobulin production. Cocultures of the CD16+ human NK clone CNK6 and highly purified SAC/IL-2-activated B lymphocytes with various CD16 antibodies showed significantly diminished NK-enhanced immunoglobulin production in a dose-dependent manner, indicating that CD16 is relevant in NK-B cell interaction. Similarly, recombinant soluble CD16 incubated with B cells before cultures, suppressed the NK cell-stimulated B cell antibody response. Enhanced immunoglobulin production was also inhibited by Fc-specific F(ab')2 anti-body fragments. Coculture of NK cells with B lymphocytes resulted in induction of mRNA for IFN-gamma and TNF-alpha. The accumulation of mRNA for these cytokines was prevented by addition of CD16 and Fc-specific antibodies. It is proposed that interaction of CD16 on NK cells with B cell bound immunoglobulin leads to induction of cytokines in NK cells which stimulate immunoglobulin production by B cells.     

The Juvenile Arthritis Quality of Life Questionnaire--development of a new responsive index for juvenile rheumatoid arthritis and juvenile spondyloarthritides

OBJECTIVE: To develop a disease specific measure of quality of life for application in children with juvenile rheumatoid arthritis and juvenile spondyloarthritides-the Juvenile Arthritis Quality of Life Questionnaire (JAQQ). METHODS: Patients and their parents were interviewed by a trained interviewer using a questionnaire focusing on physical function, psychosocial function, and general symptoms to determine the most appropriate items to include in the JAQQ. Respondents volunteered items and scored them for frequency of occurrence and importance. Items so generated were scored by a panel of experts for potential responsiveness and categorized into dimensions. Item number was reduced using this scoring system. The product was then pretested to confirm its construct validity and responsiveness. Thereafter, it was distributed to clinical experts to establish face and content validity. RESULTS: 91 patients, mean age 10.35 years (range 1.25-18.0), mean disease duration 3.99 years, and their parents were included in the interview process. 220 items generated were ultimately reduced to 85. Pretesting this version of the instrument in a further 30 patients showed it to have construct validity and responsiveness and led to a further reduction in items to 74, distributed in 4 dimensions: gross motor function (17 items), fine motor function (16 items), psychosocial function (22 items), and general symptoms (19 items). Face and content validity were established in 20 clinicians. Scaling was by 7 point Likert scale to enhance responsiveness. English and French versions were developed. CONCLUSION: The JAQQ measures physical and psychosocial function and an array of general symptoms. Preliminary data suggest it is valid and responsive and thus might have potential in clinical trials.     

Serum homocysteine and methylmalonic acid in patients with rheumatoid arthritis and cobalaminopenia

This paper describes the synthesis of 14C-labeled glycosphingolipids using the reverse hydrolysis reaction (condensation) of sphingolipid ceramide N-deacylase. It was found that 50-70% of 14C-fatty acids were incorporated into various lyso-glycosphingolipids when a mixture of lyso-glycosphingolipids and fatty acids was incubated at 37 degrees C with 1 mU of the enzyme for 20 h in 1 ml of 25 mM phosphate buffer, pH 6.0-7.0, containing 0-0.1% Triton X-100. The optimum concentration of lyso-glycosphingolipids was 100-400 microM depending on the species of lyso-form when [14C]stearic acid was used at the concentration of 100 microM. Free 14C-fatty acids and lyso-glycosphingolipids were separated from the synthesized 14C-glycosphingolipids by using a Sep-Pak Plus Silica and a Sep-Pak CM or a QMA cartridge, respectively. After treatment of 14C-glycosphingolipids with endoglycoceramidase or sphingolipid ceramide N-deacylase, digestion products were clearly separated from the parent glycosphingolipids on TLC and determined using an image analyzer with a sensitivity 100 times higher than that using non-radiolabeled substrates. Using this method, we found endoglycoceramidase activity in a seaflower, Condylactis sp., for the first time.     

Clinical and radiographic evaluation of juvenile rheumatoid arthritis: report of a case

Rheumatoid arthritis (RA) is an inflammatory disease of the synovium which may lead to proliferative and degenerative changes in the body's joints, including the temporomandibular joint (TM Joint). Although the exact etiology of rheumatoid arthritis remains unknown, it is suspected that the disease is often initiated by an infectious organism, or by genetic and/or environmental factors. Juvenile rheumatoid arthritis (JRA) is a chronic disease of childhood with a spectrum of joint involvement and associated systemic and other organ involvement. Five percent of all rheumatoid arthritis patients are children. In the United States, approximately 150,000 children are affected by JRA. With upper limb involvement, routine oral hygiene procedures become difficult. Dental evaluations/screenings may not be included in the initial team assessment of these patients until the TM Joint is affected; however, prior to this time, the patient may have had years of poor oral hygiene which could contribute to severe decay and early tooth loss. This case report describes the oral health status of a child with polyarticular juvenile rheumatoid arthritis and the specific recommendations for dental management.     

Radionuclide diagnosis of local inflammation in patients with rheumatoid arthritis

Radionuclide scintigraphy with osteotropic radiopharmaceuticals labelled 99Tc proved highly sensitive in assessment of local inflammation. Osteoscintigraphy allows detection of preclinical and pre-x-ray lesions in the joints in RA and assessment of the treatment efficacy. Characteristic signs of the radionuclide distribution and accumulation can serve as a prompt in differential diagnosis of RA, DOA, reactive and gouty arthritis.     

Perturbations of hypothalamic-pituitary-gonadal (HPG) axis and adrenal androgen (AA) functions in rheumatoid arthritis

The available evidence reviewed does not allow definitive response to the question of a primary versus secondary role of sex hormone perturbations in RA. However, this conclusion should not be discouraging in view of the relatively recent focus upon this facet of the physiopathogenesis of RA and the enormous complexities of sex hormone biology and this disease. Specifically, data on the incidence of RA as well as life cycle changes in serum androgenic-anabolic (A-A) and sex hormone levels suggest important risk correlations. Furthermore, HLA-susceptibility markers for RA, gender, menopause and older age are all factors which significantly relate to the risk of developing RA and each has been shown to associate with sex hormone status. Whether or not HPG-AA hormonal status may modulate RA risk (or its course) primarily and independently or merely be predictive markers of other biological mechanisms was critically considered and requires further study. Sex hormone influences on cellular and humoral immunological reactivity and vascular pathogenetic mechanisms in RA were summarized. Androgens generally suppress immunoreactivity and cartilage responses to inflammation-mediated injury processes and may enhance synovial macrophage-like lining cell apoptosis. Oestrogens generally enhance immunoreactivity, offer some protection to inflammation-mediated cartilage damage (but less than androgens) and may inhibit apoptosis in certain in vitro cell models. Scant information is available on the balance of sex hormones (and glucocorticoids) in RA or its presumed pathogenetic mechanisms. Data were reviewed which support the concept of a spectrum of androgenicity in the normal population, particularly among women. A simplified schema of trophic and tropic steroidogenic mechanisms was proposed which could influence androgenic-anabolic (A-A) status and might relate to RA. Serum concentrations of DHAS (mumol/l), T (nmol/l) and O2 (pmol/l) span several orders of magnitude in normal physiology. The effects of alterations in the individual levels of these sex hormones and deviations from their normal physiological balance are not well understood. Critical attention to their biological functions is needed in RA as well as in health and disease generally. Such focused clinical and experimental investigations of HPG-AA functions promise to clarify the complex physiopathology of RA and contribute to its improved long-term management.