Mutation and polymorphism analysis of the human homogentisate 1, 2-dioxygenase gene in alkaptonuria patients.

Alkaptonuria (AKU), a rare hereditary disorder of phenylalanine and tyrosine catabolism, was the first disease to be interpreted as an inborn error of metabolism. AKU patients are deficient for homogentisate 1,2 dioxygenase (HGO); this deficiency causes homogentisic aciduria, ochronosis, and arthritis. We cloned the human HGO gene and characterized two loss-of-function mutations, P230S and V300G, in the HGO gene in AKU patients. Here we report haplotype and mutational analysis of the HGO gene in 29 novel AKU chromosomes. We identified 12 novel mutations: 8 (E42A, W97G, D153G, S189I, I216T, R225H, F227S, and M368V) missense mutations that result in amino acid substitutions at positions conserved in HGO in different species, 1 (F10fs) frameshift mutation, 2 intronic mutations (IVS9-56G-->A, IVS9-17G-->A), and 1 splice-site mutation (IVS5+1G-->T). We also report characterization of five polymorphic sites in HGO and describe the haplotypic associations of alleles at these sites in normal and AKU chromosomes. One of these sites, HGO-3, is a variable dinucleotide repeat; IVS2+35T/A, IVS5+25T/C, and IVS6+46C/A are intronic sites at which single nucleotide substitutions (dimorphisms) have been detected; and c407T/A is a relatively frequent nucleotide substitution in the coding sequence, exon 4, resulting in an amino acid change (H80Q). These data provide insight into the origin and evolution of the various AKU alleles.

Tophus-like cholesterol nodules in 2 patients with rheumatoid disease.

We describe 2 patients, both with rheumatoid disease, with tophus-like nodules that contained cholesterol crystals. A tophus-like cholesterol nodule had developed in a tendon sheath of the left little finger of one. The other presented with multiple tophus-like nodules on his left elbow and both forefeet. We discuss the etiology and pathogenesis of crystalline deposits of cholesterol. Nodules at sites of local pressure in patients with rheumatoid arthritis may be deposits of cholesterol crystals.

Influence of antibiotics on IgA and IgG response and persistence of Yersinia enterocolitica in patients with Yersinia-associated spondylarthropathy.

The IgA and IgG antibody response to plasmid-encoded outer membrane proteins was studied in 59 patients with yersinia-associated spondylarthropathy during 15 months of follow-up. Initially, all patients had specific IgA and IgG antibodies to the 36 and 46 kDa and 30% also to the 26 and 58 kDa released proteins, which correlated with the finding of virulent Yersinia bacilli in intestinal biopsies. IgA disappeared in 69% of untreated patients after nine months and persisted in 31% after one year. IgA disappeared within three to six months in 81% of the patients treated with antibiotics for four to six weeks and persisted in 6% after one year (p less than 0.002). IgG antibodies to the 36 and 46 kDa outer membrane proteins persisted in 80% of all patients. Disappearance of IgA was coupled with disappearance of yersinia from intestinal biopsies.

Gonarthritis as only manifestation of chronic disseminated histoplasmosis.

A native from Surinam (South America), known to have a chronic gonarthritis for 20 years, died from an acute disseminated histoplasmosis. His gonarthritis was retrospectively shown to have been due to histoplasmosis. Although histoplasmosis rarely presents as a monarthritis, unacquaintance with this entity may result in fatal acute dissemination of the histoplasmosis.

Frequency of infections among rheumatoid arthritis patients, before and after disease onset.

The self-reported frequency of genitourinary and bronchopulmonary infections in postmenopausal women with rheumatoid arthritis (RA) and in postmenopausal women with osteoarthritis and/or soft tissue rheumatism was compared. Neither before, nor after the onset of joint disease was a higher frequency reported by the RA patients. The previously established increased mortality from infectious disease among RA patients might be due to a more severe infectious disease course, leading to an increased case-fatality rate.

Noncontraceptive hormones and rheumatoid arthritis in perimenopausal and postmenopausal women.

The use of noncontraceptive hormones before onset of joint disease was compared between 490 perimenopausal and postmenopausal women with rheumatoid arthritis and a control group of 659 women with soft-tissue rheumatologic disorders and/or osteoarthritis. Both groups were sampled randomly from the attendees of five rheumatologic clinics. A negative association was found between the onset of rheumatoid arthritis and the previous use of noncontraceptive hormones (odds ratio, 0.32; 95% confidence interval, 0.16 to 0.64). This association persisted on univariate and multivariate control of potentially confounding variables and on subgroup analysis. The protective effect of oral contraceptives on the development of rheumatoid arthritis was confirmed.

Multifocal recurrent periostitis responsive to colchicine.

A brother and sister with multifocal recurrent periostitis are presented. Their disease started at an early age and manifested itself as an episodic migrating arthropathy. At roentgenography, reversible solid periosteal reactions were visible along large tubular bones. Scintigraphic and histological investigations revealed a sterile osteitis and thickened periosteum, but there was no indication of a viral infection. The girl experienced spontaneous amelioration after puberty; the boy improved markedly on colchicine.

Oral contraceptives and rheumatoid arthritis: further evidence for a preventive effect.

To investigate a reported negative association between the use of oral contraceptives (OC) and the development of rheumatoid arthritis, a case-control study was undertaken to compare the histories of OC use between 228 women with a diagnosis of probable or definite rheumatoid arthritis and 302 women with the diagnosis of soft-tissue rheumatism and/or osteoarthritis. The use of OCs before the onset of joint complaints was acknowledged by 31.1% of the rheumatoid arthritis patients and by 55.6% of the controls. After adjustment for possible confounding variables, the rate ratio for ever use became 0.42 (95% confidence interval 0.27--0.65), while it was 0.40 (0.22-0.72) for ex-users and 0.45 (0.28-0.75) for current users. These findings confirm the finding from the Royal College of General Practitioners Oral Contraceptive Study that the incidence rate of rheumatoid arthritis among OC users was halved.

PIP: In order to study a reported negative association between the use of oral contraceptives (OCs) and the development of rheumatoid arthritis, a case-control study was undertaken to compare the histories of OC use between 228 women with a diagnosis of probable or definite rheumatoid arthritis and 302 women with the diagnosis of soft-tissue rheumatism and/or osteoarthritis. 31.1% of the rheumatoid arthritis patients and 55.6% of the controls used OCs before the onset of joint complaints. The adjusted rate ratio for ever use is 0.42 while it was 0.40 for ex-users and 0.45 for current users. The results confirm the theory that OC use is associated with a halving of the incidence rate for rheumatoid arthritis in both current and ex-users. It was also found that OC use effects seropositive more than seronegative rheumatoid arthritis. These results call for further elaboration of biological models of hormonal influences on autoimmune phenomena.

High immune responsiveness in a family with multiple paraproteinaemia and autoimmune thyroid disease.

Immune responsiveness was investigated in a family comprising 12 first- and second-degree relatives, one of whom had kappa-myelomatosis, one IgA-lambda paraproteinaemia, two Graves' disease and a further two thyroid antibodies without disease. Relatives by marriage served as controls. Parameters of immune capacity studied were the humoral and cellular immune response to haemocyanin of Helix pomatia (HPH), dinitrochlorobenzene (DNCB) skin reactivity and in vitro lymphocyte proliferation capacity to phytohaemagglutinin (PHA). Mean antibody titres to HPH were higher in the family than in the control group in all main Ig classes and IgG subclasses after primary and secondary immunization, and the difference was statistically significant for IgG, IgG2 and IgG4 titres. This could not have been predicted from the (normal) serum Ig levels in this family. In vitro lymphocyte proliferation capacity to HPH after primary and secondary immunization was also significantly increased. DNCB skin reactivity also tended to be high in the family, whereas PHA-induced lymphocyte proliferation was normal. These findings support the idea that myelomatosis clusters in families with immune dysregulation.

Immunoglobulins in families of myeloma patients.

The serum immunoglobulin levels of 200 first-degree relatives and 23 spouses of 32 patients with myelomatosis were compared with those of age- and sex-matched control persons. First-degree relatives of myeloma patients appeared to have higher serum levels of IgG (P less than 0.05), IgA (P less than 0.05), and IgM (P less than 0.01) than their age- and sex-matched controls. The spouses as a group did not differ from their controls in this respect. No statistically significant difference in the incidence of M-components among family members (0.6%) and spouses (4.3%) was found compared with the incidence in the general population (0.9%). Myelomatosis as such appeared to be more frequent than in the general population (P less than 0.05).