Rhinological manifestations of Sjögren's syndrome: a cohort-matched, prospective, cross-sectional, observational study.

OBJECTIVE: To assess the prevalence of abnormal rhinological findings in a Sjögren's syndrome population. METHODS: A cohort-matched, prospective, cross-sectional, observational study was conducted. Sixty-seven subjects (30 patients and 37 controls) were enrolled. Rhinological assessment including smell threshold was evaluated using a standardised, validated clinical test as part of a larger study. RESULTS: Smell thresholds were -4.4 and -5.4 in the Sjögren's syndrome and control groups, respectively (p = 0.001). Hyposmia (threshold values of less than -4.5) was demonstrated in the Sjögren's syndrome group (47 per cent). Smell was negatively correlated with age (p = 0.040). Nasal septal perforation was noted in 3 Sjögren's syndrome patients (10 per cent) and nasal mucosal dryness in 10 patients (33 per cent), but none of the control group were affected. CONCLUSION: Hyposmia in Sjögren's syndrome was demonstrated using the Smell Threshold Test. Nasal septal perforation and nasal mucosa dryness were also noted in patients with Sjögren's syndrome. A diagnosis of Sjögren's syndrome should be considered and investigated in smell deprivation and/or nasal septal perforation patients.

Lupus band test in untreated SLE patients: correlation of immunoglobulin deposition in the skin of the extensor forearm with clinical renal disease and serological abnormalities.

This study demonstrated that 88% of untreated systemic lupus erythematosus patients with clinical renal disease displayed the deposition of immunoglobulin and complement at the dermal epidermal junction of the noninvolved light exposed extensor surface of the upper 1/3 of the forearm (P less than 0.005) (positive lupus band test). Eighty-five percent of these untreated systemic lupus erythematosus patients with anti-deoxyribonucleic acid antibodies (native and/or single stranded) (P less than 0.001) and 96% of systemic lupus erythematosus patients with hypocomplementemia had a positive lupus band test (P less than 0.001). Those systemic lupus erythematosus patients with a negative lupus band test or a positive lupus band test composed of pure IgM had a decreased incidence of renal disease, serum hypocomplementemia and anti-DNA antibodies. Their sera, however, frequently contained antibodies directed against nuclear ribonuclear protein or against the cytoplasmic non-nucleic acid glycoprotein termed Ro. On the contrary, 85% of systemic lupus erythematosus patients with a positive lupus band test composed solely or in part of IgG, had anti-DNA antibodies (P less than 0.001). Their sera also frequently contained anti-Sm antibodies. The lupus band test was found to be dynamic. In general, the appearance as well as the disappearance or the marked decrease in intensity and complexity of a positive lupus band test was found to correlate with disease exacerbation, remission and the appearance and disappearance of DNA antibodies and serum hypocomplementemia.

Unusual cutaneous manifestations of systemic lupus erythematosus: I. Urticaria-like lesions. Correlation with clinical and serological abnormalities.

Ten of 143 systemic lupus erythematosus patients demonstrated urticaria-like lesions. Lesional biopsies in 7 of 9 patients tested revealed a leukocytoclastic angiitis and in 2, a mononuclear perivascular infiltrate. Direct immunofluorescent studies in 2 of 6 patients tested revealed IgM and C3 deposition in and about dermal blood vessels. Nine of the 10 systemic lupus erythematosus, patients displayed active clinical disease (e.g., arthritis, renal disease, etc.), a positive lupus band test, antibodies against deoxyribonucleic acid or Sm macromolecules, serum hypocomplementemia and markedly elevated quantities of serum immune complexes as determined by an immunoradiometric assay employing Raji cells. Similar lesions were not detected in 35 discoid lupus erythematosus patients. These studies strongly suggest: (1) urticaria-like lesions are uncommon cutaneous manifestations of systemic lupus erythematosus. (2) These urticaria-like lesions do not represent a classic IgE mediated urticaria. (3) These urticaria-like lesions generally occur in lupus erythematosus patients demonstrating clinical and/or serological evidence of systemic disease activity. (4) These lesions are probably secondary to immune complex deposition. We, therefore, conclude that all urticarial lesions in lupus erythematosus patients should be biopsied and the patient evaluated for active systemic disease.

Serological findings in patients with "ANA-negative" systemic lupus erythematosus.

Serological studies were performed on sera from 66 patients with the clinical picture of systemic lupus erythematosus (SLE). These sera failed to give a positive antinuclear antibody test when tested on cryostat sections of mouse liver and thus these patients' sera appear to be ANA negative. Precipitating antibodies to the cytoplasmic antigen Ro were found in 41 cases and of the remaining 25 sera, 18 were found to have antibodies to single stranded DNA detectable by radioimmunoassay. Thus, 50 of the 66 patients exhibited serological findings which are commonly found in ANA positive SLE patients. Studies with KB cells as immunofluorescent substrate revealed that 66% of these sera were positive for nuclear staining demonstrating that at least part of the failure of these sera to stain mouse liver is due to antigenic deficiency of this substrate. The clinical picture of these patients was dominated by a severe photosensitive dermatitis but more than half of the patients had widespread multisystem disease. As a group these patients had a low frequency of nephritis and neuropsychiatric disease. Detection of these antibodies relates these patients serologically to other SLE patients and suggests that they are best perceived as part of the clinical spectrum of SLE.

The Felty syndrome: a case-matched study of clinical manifestations and outcome, serologic features, and immunogenetic associations.

Thirty-two patients with the Felty syndrome, defined by the presence of rheumatoid arthritis, splenomegaly, and neutropenia, have been studied in comparison with 32 patients with rheumatoid arthritis matched for age, sex, and disease duration, and 9 patients with rheumatoid arthritis and idiopathic neutropenia. Patients with the Felty syndrome had severe destructive arthritis, which progressed during follow-up despite little evidence of objective synovitis, and a higher frequency of extra-articular manifestations, including vasculitis. Bacterial infection tended to occur in patients with the lowest neutrophil count but continued to occur in some despite normalization of the WBC. Prognosis was poor and 8 deaths occurred, predominantly from sepsis. Serologic features were prominent. High titers of IgG rheumatoid factor and circulating immune complexes characterized patients with persistent neutropenia. A family history of rheumatoid arthritis was more common in patients with the Felty syndrome. The association with HLA DR4 was very strong; in addition there was an increased frequency of the DQw3 variant, 3b, suggesting that HLA Class II genes in linkage with DR4 may contribute to disease expression.

Connective tissue disease and autoantibodies in the kindreds of 63 patients with systemic sclerosis. The United Kingdom Systemic Sclerosis Study Group.

Systemic sclerosis (SSc) tends to occur in a sporadic fashion and familial occurrence of the disease is unusual. Nevertheless, reports of related connective tissue diseases (CTD), autoantibodies, or both in family members together with associations of certain HLA class II phenotypes with SSc suggest that genetic factors might play a part in susceptibility to the disease. Because of the relative rarity of SSc only a small number of family pedigrees have been studied previously. This report represents the largest study to date, to our knowledge, of family members of patients with scleroderma, and provides the opportunity to investigate the relative importance of genetic and environmental factors operating in the disease. The family pedigrees of 63 patients with systemic sclerosis were examined with respect to clinical, serologic, and immunogenetic features. Multiple cases of SSc were seen only in 1 family, in which the disease affected a father and daughter. Disease expression in these 2 individuals was very similar both clinically and serologically; relatives with other connective tissue diseases were found in 9 families, and nonspecific features of CTD such as Raynaud phenomenon, and arthralgia or arthritis, occurred commonly, especially in female relatives. Antinuclear antibodies (ANA) were also detected more frequently in relatives than in controls. However, antibodies previously demonstrated to have a high degree of specificity for SSc were confined to patients with this disease. Probands had an increase in the frequency of HLA-DR3, DR5, and C4AQO. Patients with diffuse scleroderma had an increased frequency of HLA-DR3, while those with the limited form of the disease had an increased frequency of HLA-DR5.(ABSTRACT TRUNCATED AT 250 WORDS)

The efficient production of stable, human monoclonal antibody-secreting hybridomas from EBV-transformed lymphocytes using the mouse myeloma X63-Ag8.653 as a fusion partner.

The mouse myeloma X63-Ag8.653 was fused to peripheral blood lymphocytes (PBL) from apparently healthy individuals, autoimmune patients and volunteers immunised with Rhesus (D) positive erythrocytes. Fusions were performed with or without prior transformation of PBL with Epstein-Barr virus (EBV). Using untransformed PBL, under the best conditions a mean fusion frequency of 8.4 X 10(-6) was obtained, with 22% of the resulting hybridomas secreting human immunoglobulin. Fusions with EBV-transformed cells gave fusion frequencies of 1.0 X 10(-4), with 85-90% of hybridomas secreting human immunoglobulin. The heterohybridomas formed in both cases cloned efficiently and had doubling times of 24-30 h. The heterohybridomas secreted human IgM, IgG and IgA of both kappa and lambda isotypes and culture supernatants contained up to 50 micrograms ml-1 of human immunoglobulin. Mouse immunoglobulin was not detected in the culture supernatants. 28 hybrids were selected for vigorous growth and antibody production by repeated cloning. Immunoglobulin synthesis was stabilised in 26 of these hybridomas after two or three cloning steps. The heterohybridomas have been successfully grown in large volumes for periods up to 15 months. It is concluded that the mouse myeloma X63-Ag8.653 is a suitable fusion partner with EBV-transformed B cells in the efficient production of human monoclonal antibodies.

Effects of antinuclear autoantibodies on RNA polymerase.

DNA-dependent RNA polymerase was partially purified from wheat germ extract and tested for inhibition by antinuclear autoantibodies from the sera of patients with connective tissue diseases. The enzyme was inhibited by anti-DNA and by autoantibodies to the nuclear ribonucleoprotein nRNP. Autoantibodies to other ribonucleoproteins (Sm, Ro, La) did not cause inhibition. The enzyme preparation was shown to contain material with Ro and La antigenic activity but there was no nRNP or Sm detectable by immune precipitation. Previous work [3] has shown inhibition of prokaryotic (E. coli) RNA polymerase by anti-DNA, and our results show that the eukaryotic enzyme, in this case from wheat germ, is also inhibited. The results are consistent with the suggestion that inhibition by anti-DNA is due to template masking. Inhibition of RNA polymerase by antibodies to cellular ribonucleoprotein suggests that the antigen is in some way associated with the activity of the enzyme.

HLA DQ alpha and DQ beta restriction fragment length polymorphisms associated with Felty's syndrome and DR4-positive rheumatoid arthritis.

HLA DQ alpha and DQ beta cDNA probes were used to study TaqI generated restriction fragment length polymorphisms (RFLPs) in DR4-positive patients with Felty's syndrome (FS), seropositive rheumatoid arthritis (RA), and in HLA-DR4 positive controls. The results of this analysis revealed two DQ beta RFLP patterns (DQ beta 3a and DQ beta 3b) associated with DR4, of which DQ beta 3b was found at significantly higher frequency in patients with FS (73%) or with RA (52%) than in DR4 controls (29%). Hind III generated RFLPs provide evidence that DQ beta 3b is in strong linkage disequilibrium with the gene encoding the serologically recognized epitope TA10. Results obtained using a DQ alpha chain probe revealed polymorphic differences between DQ alpha chain genes associated with different DR types, thereby providing a possible explanation for the lack of association between RA and other DR haplotypes in linkage disequilibrium with TA10. We conclude that both DQ alpha and DQ beta genes may be important in determining HLA-linked susceptibility to severe forms of RA.

A possible haplotype association in Felty's syndrome.

The HLA-B7/DR association was examined in a normal British population and in seven HLA-B7-positive patients with Felty's syndrome. After the exclusion of the most frequent A3-B7-DR2 association, a significant A2-B7-DR4 association was evident. This was present in six of the seven HLA-B7-positive Felty's patients and might indicate that the A2-B7-DR4 haplotype is prevalent in some forms of rheumatoid arthritis.

Restriction fragment length polymorphism in Felty's syndrome.

Southern blot analysis with DR beta and DQ beta cDNA probes was used to compare genomic DNA from Felty's syndrome patients with HLA-DR-matched normal controls. We describe two restriction fragment length polymorphisms putatively associated with Felty's syndrome.

A randomized and controlled trial of hydrotherapy in rheumatoid arthritis.

OBJECTIVE: The aim of this study was to evaluate the therapeutic effects of hydrotherapy which combines elements of warm water immersion and exercise. It was predicted that hydrotherapy would result in a greater therapeutic benefit than either of these components separately. METHODS: One hundred thirty-nine patients with chronic rheumatoid arthritis were randomly assigned to hydrotherapy, seated immersion, land exercise, or progressive relaxation. Patients attended 30-minute sessions twice weekly for 4 weeks. Physical and psychological measures were completed before and after intervention, and at a 3-month followup. RESULTS: All patients improved physically and emotionally, as assessed by the Arthritis Impact Measurement Scales 2 questionnaire. Belief that pain was controlled by chance happenings decreased, signifying improvement. In addition, hydrotherapy patients showed significantly greater improvement in joint tenderness and in knee range of movement (women only). At followup, hydrotherapy patients maintained the improvement in emotional and psychological state. CONCLUSIONS: Although all patients experienced some benefit, hydrotherapy produced the greatest improvements. This study, therefore, provides some justification for the continued use of hydrotherapy.

The neonatal lupus syndrome.

The neonatal lupus syndrome and congenital heart block are strongly associated with the presence of antibodies to the ribonucleoprotein antigen Ro. The study of these conditions has given insight into possible pathogenetic mechanisms operating in connective tissue diseases.

Analysis of polyethylene glycol precipitates from SLE sera: antibody enrichment in association with disease activity.

Twenty two systemic lupus erythematosus patients were assessed clinically for periods of up to six years. Polyethylene glycol precipitates of serial serum samples were analysed for the presence of autoantibodies by specific enzyme-linked immunoabsorbent assays. Increased enrichment of anti-Ro(SSA) was found to correlate with disease activity. Longitudinal studies of individual patients showed an association between disease exacerbation and enrichment of anti-Ro(SSA), anti-La(SSB) and anti-ssDNA. Circulating immune complexes isolated by anti-C3 affinity chromatography were also found to contain anti-Ro(SSA), anti-La(SSB) and anti-ss DNA and fixation of complement by complexes could be demonstrated. Enrichment of these autoantibodies in renal eluates of two patients with diffuse proliferative glomerulonephritis provided further evidence for a pathogenic role of these immune complexes.

The arthropathy of systemic sclerosis (scleroderma); comparison with mixed connective tissue disease.

Arthritis in systemic sclerosis (PSS) can be prominent and an overlap with rheumatoid arthritis (RA) has sometimes been queried. We therefore analysed the pattern of joint involvement of hands and wrists in 34 patients (1 male) with PSS and compared it with that of 9 patients with mixed connective tissue disease (MCTD), a condition with distinct overlap features. Although MCTD patients were younger, disease duration was similar in both groups. Extra-articular radiological findings such as calcinosis, pulp atrophy and tuft resorption were present in over half the patients with PSS but were less frequent in MCTD. Marginal erosions occurred in over 50% and ulnar styloid erosions in 35% of the PSS patients. Erosions of the 1st CMC joint were seen in one-third of them and were unrelated to age. Erosions did not correlate with clinical synovitis, the presence of rheumatoid factor which was present in 26% of PSS patients or the presence of anti-centromere or anti-Scl-70 antibodies. Erosions in MCTD patients occurred frequently and were more destructive and rapidly progressive. Correlation between erosions, rheumatoid factor and clinical arthritis was high. We conclude that erosions in PSS are frequent. Their pattern is varied but usually discrete and seldom destructive. They are not related to arthritis or serological abnormalities and may be due to several mechanisms aside from synovitis. In contrast, erosions in MCTD are more frequently destructive and related to arthritis and rheumatoid factor, suggesting a true overlap.

In vitro autoantibody synthesis by anti-La(SSB) positive SLE patients and healthy controls.

In vitro production of anti-La(SSB) and anti-DNA antibodies by mononuclear cells (mnc) from systemic lupus erythematosus (SLE) patients and healthy controls was measured using ELISA techniques. The SLE patients were divided into anti-La(SSB) positive and negative groups depending on Ouchterlony analysis of the serum. Both patient groups spontaneously produced raised levels of total IgG but not IgM compared to controls. Pokeweed mitogen (PWM) stimulated mnc from anti-La(SSB) positive SLE patients and controls gave good total IgM and IgG responses. In contrast the anti-La(SSB) negative group gave no IgG but did make an IgM response. Kinetic studies showed that 14 day cultures were essential to produce detectable amounts of specific autoantibodies which, with a few exceptions, were of IgM isotype. Low levels of anti-La(SSB) and anti-DNA were spontaneously produced by anti-La(SSB) positive SLE patients and controls. PWM stimulation at least doubled autoantibody synthesis in these two groups. The anti-La(SSB) negative SLE group gave similar responses although PWM induced autoantibody levels were reduced. ConA-induced suppressor cell assay showed that anti-La(SSB) positive SLE patients could form suppressor cells but not as effectively as controls. This group of SLE patients were more successful at suppressing IgG than IgM responses.

Joint symptoms in relapsing polychondritis.

OBJECTIVE: To study articular symptoms in relapsing polychondritis (RP) and their relationship to other clinical manifestations and prognosis. METHODS: Fourteen patients who met the diagnostic criteria proposed by Damiani and Levine for RP were studied. Clinical symptoms were recorded and laboratory and radiologic examinations were carried out. In one patient a synovial histology was obtained. RESULTS: Twelve patients had joint symptoms affecting the peripheral joints (9), the chondrocostal junctions (5), or both sites together (2). Peripheral arthritis was the most frequent finding, affecting 6 patients, while peripheral arthralgia was the only articular manifestation in 3 patients. The development of joint symptoms (arthralgia, arthritis and costochondritis) was unrelated to the appearance of chondritis at other sites and no correlation was found between articular involvement and age at onset, duration of the disease, number of flares, or severity of the disease, either in terms of the number of organs involved or fatal outcome (p > 0.05). However, when articular symptoms were analysed separately arthritis was associated with a longer duration (50 months vs 30), more affected organs (4.5 vs 3.3) and a poorer prognosis compared with patients with arthralgias alone or chondrocostal symptoms. CONCLUSION: Articular symptoms are common in RP but the presence of peripheral arthritis is associated with widespread disease and a poorer prognosis.

Is there a relationship between subclinical myocardial abnormalities, conduction defects and Ro/La antibodies in adults with systemic lupus erythematosus?

Thirty-three adult patients with systemic lupus erythematosus (SLE) were studied to determine whether there was an association between subclinical abnormalities of left ventricular function, conduction defects, and the presence of antibodies to Ro and/or La. Twelve patients had one or both of these antibodies. Conduction defects were present in 2, neither being currently positive for Ro or La antibody. There was no difference in abnormalities of left ventricular function between those with or without antibody. Valvular abnormalities were present in 11, 6 of whom had focal or diffuse thickening of one or more valves. Adults with SLE and anti-Ro and/or La antibody do not appear to be at particular risk of conduction defects. Subclinical left ventricular functional abnormalities were not associated with the presence of these antibodies.

Elevated serum interleukin-6 levels associated with active disease in systemic connective tissue disorders.

OBJECTIVE: It is well established that connective tissue diseases such as systemic lupus erythematosus (SLE) are associated with a weak or absent acute phase response, although elevated serum interleukin 6 levels have been described. In this study, we have sought to correlate serum levels of IL-6 with standard laboratory and clinical assessments of disease activity in two connective tissue diseases, namely SLE and systemic sclerosis (SSc), and, for comparative purposes, rheumatoid arthritis (RA). METHODS: Serum IL-6 levels were determined by bioassay and also, in some sera, by immunoradiometric assay. They were compared with two inflammatory parameters, serum C-reactive protein (CRP) and plasma viscosity (PV), and with appropriate clinical measurements in the various patient groups, including BILAG in SLE, the skin score in SSc, and the Ritchie index in RA. RESULTS: Serum IL-6 (SeIL-6) levels were elevated in active SLE, SSc, and RA. This was poorly correlated with the acute phase response in SLE and SSc, but there was a strong relationship of SeIL-6 to disease activity in these conditions. In SLE, the BILAG disease activity index correlated best with SeIL-6 levels while there was only a weak relationship between CRP and IL-6, and no relationship between CRP and disease activity. In SSc there was a relationship of disease activity to SeIL-6 but not between SeIL-6 and either CRP or PV. In a small RA group there was a much stronger relationship of SeIL-6 to CRP and PV, as has been previously described. CONCLUSION: The determination of SeIL-6 may be a useful indicator of disease activity in those patients groups, including SLE and SSc, in which a normal acute phase response by the liver is often lacking. The mechanism underlying this hepatic impairment requires further investigation, but is clearly not due to a failure to generate the appropriate cytokine signal. Excessive local or systemic production of IL-6 in connective tissue diseases could play an important pathogenic role in these conditions, for example through stimulating autoantibody synthesis.

Mitral stenosis in systemic lupus erythematosus. Successful management by mitral valve replacement.

A female Caucasian with a history of 18 years of systemic lupus erythematosus (SLE) developed symptoms and signs of mitral stenosis, but had no history of rheumatic fever. Investigations confirmed severe stenosis, and the diseased valve was replaced by a pericardial xenograft. Histological examination was compatible with steroid-modified Libman-Sacks endocarditis. She remains well 24 months postoperatively.