Characteristics of joint involvement and relationships with systemic inflammation in systemic sclerosis: results from the EULAR Scleroderma Trial and Research Group (EUSTAR) database.

OBJECTIVE: To determine the prevalence of and independent factors associated with joint involvement in a large population of patients with systemic sclerosis (SSc). METHODS: This study was cross-sectional, based on data collected on patients included in the European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) registry. We queried this database to extract data regarding global evaluation of patients with SSc and the presence of any clinical articular involvement: synovitis (tender and swollen joints), tendon friction rubs (rubbing sensation detected as the tendon was moved), and joint contracture (stiffness of the joints that decreased their range of motion). Overall joint involvement was defined by the occurrence of synovitis and/or joint contracture and/or tendon friction rubs. RESULTS: We recruited 7286 patients with SSc; their mean age was 56 +/- 14 years, disease duration 10 +/- 9 years, and 4210 (58%) had a limited cutaneous disease subset. Frequencies of synovitis, tendon friction rubs, and joint contractures were 16%, 11%, and 31%, respectively. Synovitis, tendon friction rubs, and joint contracture were more prevalent in patients with the diffuse cutaneous subset and were associated together and with severe vascular, muscular, renal, and interstitial lung involvement. Moreover, synovitis had the highest strength of association with elevated acute-phase reactants taken as the dependent variable. CONCLUSION: Our results highlight the striking level of articular involvement in SSc, as evaluated by systematic examination in a large cohort of patients with SSc. Our data also show that synovitis, joint contracture, and tendon friction rubs are associated with a more severe disease and with systemic inflammation.

Tumorous variant of scleromyxedema. Successful therapy with intravenous immunoglobulins.

We present an unusual tumorous variety of scleromyxedema mimicking facies leonina in lymphoma. In spite of pronounced and widespread cutaneous changes, hypergammaglobulinaemia and paraproteinaemia, the general condition of the patient was satisfactory, there was no internal involvement and no symptoms of any malignancy. Initially, melphalan and corticosteroids were applied but were not effective. High-dose intravenous immunoglobulin (IVIG) therapy had dramatic effect, and after five 5-day monthly courses the tumours almost regressed and the skin became less hard. After a further five courses in the following year there was complete clearance, which was sustained without any therapy for 1 year (until now). IVIG appears to be the therapy of choice for scleromyxedema. We stress, however, that at the start of therapy, IVIG applications should be supplemented with small doses of melphalan and/or corticosteroids.

Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.

Germline mutations of the fumarate hydratase (FH, fumarase) gene are found in the recessive FH deficiency syndrome and in dominantly inherited susceptibility to multiple cutaneous and uterine leiomyomatosis (MCUL). We have previously reported a number of germline FH mutations from MCUL patients. In this study, we report additional FH mutations in MCUL and FH deficiency patients. Mutations can readily be found in about 75% of MCUL cases and most cases of FH deficiency. Some of the more common FH mutations are probably derived from founding individuals. Protein-truncating FH mutations are functionally null alleles. Disease-associated missense FH changes map to highly conserved residues, mostly in or around the enzyme's active site or activation site; we predict that these mutations severely compromise enzyme function. The mutation spectra in FH deficiency and MCUL are similar, although in the latter mutations tend to occur earlier in the gene and, perhaps, are more likely to result in a truncated or absent protein. We have found that not all mutation-carrier parents of FH deficiency children have a strong predisposition to leiomyomata. We have confirmed that renal carcinoma is sometimes part of MCUL, as part of the variant hereditary leiomyomatosis and renal cancer (HLRCC) syndrome, and have shown that these cancers may have either type II papillary or collecting duct morphology. We have found no association between the type or site of FH mutation and any aspect of the MCUL phenotype. Biochemical assay for reduced FH functional activity in the germline of MCUL patients can indicate carriers of FH mutations with high sensitivity and specificity, and can detect reduced FH activity in some patients without detectable FH mutations. We conclude that MCUL is probably a genetically homogeneous tumour predisposition syndrome, primarily resulting from absent or severely reduced fumarase activity, with currently unknown functional consequences for the smooth muscle or kidney cell.

Pemphigus herpetiformis with IgA and IgG antibodies to desmoglein 1 and IgG antibodies to desmocollin 3.

We describe a case with clinical and histologic features of pemphigus herpetiformis associated with IgG and IgA anti-keratinocyte cell surface antibodies to desmoglein 1 (Dsg1) and exclusively IgG antibodies to desmocollin 3 (Dsc3). The clinical presentation was somewhat similar to IgA pemphigus; the main difference was the prevailing association with IgG antibodies to Dsg1. The presence of IgA anti-Dsg1 antibodies was confirmed by IgA enzyme-linked immunosorbent assay and IgG anti-Dsc3 antibodies were detected by a novel enzyme-linked immunosorbent assay with the use of baculovirus expressing recombinant Dscs for IgG and IgA. The reactivity of IgG antibodies with Dsc3 was confirmed by COS-7 cell cDNA transfection method using cDNA of human Dsc1 to Dsc3. We discuss the differentiation of pemphigus herpetiformis, associated with both IgG and IgA antibodies, from IgA pemphigus, particularly in regard to the autoimmune reaction with Dsgs and Dscs.

Celiac disease and immunoglobulin a deficiency: how effective are the serological methods of diagnosis?

Immunoglobulin A (IgA) deficiency is 10 to 15 times more common in patients with celiac disease (CD) than in healthy subjects. Serological tests have become the preferred methods of diagnosing CD in both symptomatic and asymptomatic patients. However, commercially available serological methods are limited in that they detect only the IgA isotype of antibodies (with the exception of IgG gliadin assays); hence, IgA-deficient patients with CD may yield false-negative serology. Fifteen pediatric patients with CD and 10 IgA-deficient pediatric patients without CD were examined for IgA and IgG antibodies to endomysium, gliadin, and tissue transglutaminase. Twenty-five specimens from patients with IgA deficiency were examined. Fifteen were from patients with CD, and 10 were patients without CD. All 15 IgA-deficient patients with CD were positive for endomysium antibodies of the IgG isotype and for IgG gliadin antibodies. All but one of the IgA-deficient patients with CD were also positive for IgG tissue transglutaminase antibodies. None of the IgA-deficient patients without CD were positive for any of the antibody markers. All the specimens examined were also negative for IgA-specific antibodies to endomysium, gliadin, and tissue transglutaminase. IgG-specific antibody tests for endomysium, gliadin, and tissue transglutaminase are useful for the identification of IgA-deficient patients with CD. IgG antibody tests along with tests routinely being used in clinical laboratories can reliably detect all active patients with CD. In addition, the levels of these CD-specific IgG antibodies could be used to monitor patient dietary compliance.

Intravenous immunoglobulins control scleromyxoedema.

BACKGROUND: Scleromyxoedema is a variant of papular mucinosis affecting the skin and internal organs. The different therapeutic approaches proposed for scleromyxoedema are still unsatisfactory. Intravenous immunoglobulin (IVIg) has been successfully employed in the treatment of connective tissue diseases and vasculitides. PATIENTS: The successful treatment of three cases of scleromyxoedema with IVIg is reported here. CONCLUSIONS: The relatively low risk of the drug and the high effectiveness seen in three patients suggest that IVIg is a new treatment potentially useful in scleromyxoedema.

Mutation and abnormal expression of the p53 gene in the viral skin carcinogenesis of epidermodysplasia verruciformis.

Patients suffering from epidermodysplasia verruciformis are prone to nonmelanoma skin cancers, due to an inherited abnormal susceptibility to the oncogenic human papillomavirus type 5. Genotoxic sunlight ultraviolet B radiations are likely to be a cofactor. Lesions of two human-papillomavirus-type-5-infected epidermodysplasia verruciformis patients collected during an 8 y period were retrospectively studied for p53 mutations in exons 5 through 8 by a polymerase chain reaction single-strand conformation polymorphism technique and/or by DNA sequencing of amplified exons. Mutations were detected in 11 of 26 (42.3%) specimens, including five (62.5%) squamous cell carcinomas, three (33.3%) Bowen's carcinomas in situ, two (40%) actinic keratoses, and one (33%) benign lesion. The nine mutations characterized by sequencing were shown to be missense and to affect mutational hotspots in human cancers. Five were C-->T transitions at dicytidine sites considered as ultraviolet signature mutations. Two were transversions (C-->G and C-->A) at dicytidine sites and two were C-->T transitions at nondipyrimidine sites. A marked p53 immunoreactivity was disclosed in 72.7% of 11 invasive carcinomas, 55.6% of nine carcinomas in situ, 37.5% of eight actinic keratoses, and one of three benign lesions. This includes 81.8% of 11 specimens with a p53 mutation but also 50% of 14 specimens with no mutation detected. A dysfunction of the p53 gene is thus likely to play a part in epidermodysplasia verruciformis carcinogenesis, either due to ultraviolet-B-induced p53 mutations, as in nonmelanoma skin cancers in the general population, or involving other mutagens or mechanisms. The part played by human papillomavirus type 5 proteins expressed in epidermodysplasia verruciformis keratinocytes remains to be determined.