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Objectives: To investigate change in psychiatric disorder and change in cognitive function in patients with systemic lupus erythematosus (SLE) assessed on two occasions two years apart., Methods: A prospective cohort study of 49 patients with SLE using standardised psychiatric and clinical research methods., Results: The point prevalence of psychiatric disorder (20% and 24%), and of cognitive impairment (23% and 18%), was similar at first and second interview for the whole group. There was, however, considerable change in individual patient's psychiatric status and cognitive function: only 1/9 patients with impairment on two or more cognitive tests at first interview was still impaired at second interview. Change in cognitive function appeared to mirror change in psychiatric status., Conclusions: These findings suggest that the previously reported high prevalence of cognitive impairment in SLE may be explained by coexisting psychiatric disorder, rather than reflecting subclinical central nervous system (CNS) involvement.

Objectives: To determine whether HLA-DP genes are involved in determining susceptibility to systemic lupus erythematosus (SLE)., Methods: HLA-DPA1 and DPB1 genes were amplified by PCR of DNA samples from a panel of patients with SLE and normal controls. Amplified DNA was blotted on to nylon filters and probed with sequence-specific oligonucleotide (SSO) probes., Results: No DPA1 or DPB1 allele was significantly associated with SLE, or with any immunological or clinical subset of SLE. Evidence was found for only limited linkage disequilibrium between HLA-DP and HLA-DQ/DR variants, and none between HLA-DP and the TAP2 gene., Conclusions: These data indicate that HLA-DP genes do not contribute towards determining susceptibility to SLE.

A feature common to all forms of chronic inflammatory arthritis, irrespective of the possible underlying cause, is the persistent exudation of large numbers of polymorphonuclear leucocytes (PMNL) into synovial fluid. These cells possess potent degradative enzymes and proinflammatory mediators, and their removal is vital to normal inflammatory resolution. A major route of disposal of extravasated PMNL appears to be programmed cell death (apoptosis), followed by their rapid recognition, and intact phagocytosis, by mature tissue macrophages. Such macrophages, containing PMNL (cytophagocytic mononuclear cells (CPM)), long recognised in synovial fluid as Reiter cells, are commonly found in reactive arthritis, spondyloarthritis, and crystal arthritides, but only rarely in rheumatoid disease. In a retrospective analysis of 187 knee synovial fluid cytospins, the relation between the formation of CPM and the presence of apoptotic (pyknotic) PMNL was investigated. As long as the synovial fluid examined was fresh there was a high correlation between numbers of CPM (as a percentage of macrophages) and pyknotic numbers of PMNL in fluids containing CPM. This suggests that the formation of CPM occurs in vivo and is involved in the disposal of PMNL. Numbers of pyknotic PMNL increased rapidly in stored synovial fluid without a significant change in numbers of CPM, and were highest in synovial fluid which did not contain CPM. The presence or absence of CPM, or their disease associations, could not be explained simply by limiting numbers of macrophages, or apoptotic PMNL in synovial fluid. These findings are consistent with a regulatory role for CPM in synovial fluid, where they may be important in preventing autolysis of PMNL, and thus local tissue damage.

Two patients with pachydermoperiostosis were studied in whom the predominant features at presentation were severe and disabling knee and ankle joint pain in association with distal long bone pain. Analysis of synovial fluid from the knee joints showed non-inflammatory changes. In one patient a bicortical iliac crest bone biopsy specimen, taken after labelling with demeclocycline, showed appositional rates which were increased in cortical bone but reduced in trabecular bone. This mismatching resulted in trabecular osteoporosis, which occurred in association with increased numbers of osteoclasts, findings which suggest differential functional changes affecting the two bony envelopes.

This study is in two parts. In the first synovial fluid from 1892 patients with 14 different arthropathies was examined microscopically. Crystals of different types were identified and the disease distribution of these and various cell types, including several not previously reported in synovial fluid, have been described. These features have been used to derive a series of microscopic diagnostic criteria for each arthropathy. The criteria have been used in the second part of the study to examine synovial fluids from 200 patients without knowledge of any clinical diagnosis. Cytological and clinical diagnoses were compared at the end of the study. Matching diagnoses were made in 71 (35.5%) and a short list of differential diagnoses (based on cytological criteria), which included the clinical diagnosis, was made in a further 43 (21.5%). Of the rest, 63 (31.5%) were correctly described as inflammatory or non-inflammatory and in five (2.5%) no diagnosis could be made. Only in seven cases (3.5%) was an inaccurate (false positive) cytological diagnosis made. The results indicate that synovial fluid microscopy is a potentially more important diagnostic screening test in rheumatological and orthopaedic practice than it would at first appear from published reports.

A selective polyclonal increase in IgG1 has been described previously in a group of patients with connective tissue disease; nine of the 16 patients had a prior diagnosis of systemic lupus erythematosus (SLE). A detailed clinical and serological study of 32 patients with this immunoglobulin abnormality has now been made. Most cases showed a characteristic autoantibody profile of antinuclear antibody, rheumatoid factor, and antibodies to Ro and La. Sjögren's syndrome was diagnosed as 'definite' in 16 cases and 'possible' in seven cases by Fox's criteria. The remainder had unclassified connective tissue disease (three), rheumatoid arthritis with dry eyes (two), SLE (one), scleroderma (two), and Raynaud's disease (one). Extraglandular features were invariably present in patients with primary Sjögren's syndrome. The highest concentrations of IgG1 were found in patients with the shortest disease duration. Selective polyclonal increase of IgG1 should alert the doctor to the development of Sjögren's syndrome, usually with extraglandular disease and antibodies to Ro and La.

Seventy-five patients aged 7 to 17 with juvenile chronic arthritis were interviewed to identify their beliefs about the physical nature of their illness and the relevance and modes of action of their clinical treatment. Children in the 7-11 age group were found to perceive their arthritis largely in terms of its immediately manifestations, to have little conception of internal pathology, and to be less aware of the value of their medical therapy. Children in the 12-17 age group showed a greater tendency to recognize arthritis as a condition of internal pathology, to experience distressing fantasies about the internal appearance of their affected joints, and to appreciate the purpose of their therapy.

Using a new solid-phase double-antibody radioimmunoassay we have determined the incidence of serum IgG antibodies to native bovine type I and type II collagens in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis. Raised serum IgG antibody levels to native type I collagen were present in 49% of patients with RA, 30% with AS, and none of the patients with psoriatic arthritis. Raised serum IgG antibody levels to native type II collagen were present in 42% of patients with RA, 30% with AS, and none of the patients with psoriatic arthritis. In rheumatoid arthritis there was a lack of correlation between IgG antibody levels to collagen and the erythrocyte sedimentation rate, IgG rheumatoid factor, and circulating immune complexes measured by the Clq-binding activity. In ankylosing spondylitis IgG antibody levels to native type II collagen were raised only in patients with peripheral joint involvement. The significance of IgG anticollagen antibodies is not certain, but parallels with rheumatoid factor are discussed.

Native 1 alpha 2 alpha 3 alpha collagen (500 micrograms per rat) was both immunogenic and arthritogenic in Alderley Park rats (46% developed arthritis) but only immunogenic in Sprague-Dawley rats. Conversely, native type II collagen (500 micrograms per rat) was immunogenic and arthritogenic in both strains (64% arthritic in Alderley Park strain, 57% arthritic in Sprague-Dawley strain). The inflammatory polyarthritis induced by 1 alpha 2 alpha 3 alpha collagen was similar to that produced by native type II collagen in clinical appearance, time of onset, and histology. Antibodies raised to native bovine type II collagen cross-reacted with native 1 alpha 2 alpha 3 alpha collagen and vice versa. Thus the minor collagen component of cartilage, the 1 alpha 2 alpha 3 alpha collagen, as well as the major collagen component, type II collagen, are immunogenic and arthritogenic in the rat, with strain differences.

An acute inflammatory arthritis has been induced in 76% of rats injected intradermally with native bovine type II collagen emulsified in Freund's complete (CFA) or incomplete (ICFA) adjuvant. The arthritis became chronic in 14 out of 31 rats, and ear and tail lesions were noted in some rats. No arthritis was induced by native type I collagen, denatured type II collagen, rabbit IgG, or buffer alone injected intradermally with adjuvant. Using a solid-phase radioimmunoassay for serum antibodies we have shown that IgM and IgG levels to native bovine type II collagen were significantly higher in arthritic than nonarthritic rats. Antiglobulin antibody levels were not raised in arthritic rats. Equivalent antibody levels to native type II collgen were obtained whether this antigen was emulsified in ICFA or CFA. However, native type I collagen produced high antibody levels only when emulsified in CFA, indicating a difference in the immunogenicity of these collagens. These studies suggest that native type II collagen possesses arthritogenic properties in the rat and that humoral immunity may play a role in the induction of this arthritis.

The relationship between cell mediated immunity to collagen and arthritis was studied with lymphocytes from arthritic and nonarthritic rats after immunisation with native bovine type II collagen. With the in-vivo radiometric ear assay arthritic rats gave a significantly higher response to native type II collagen than did nonarthritic rats. However, there was an overlap of values, and some arthritic rats gave no response to collagen even on the day of onset of arthritis. There was no difference in the response of lymphocytes from arthritic and nonarthritic rats with in-vitro transformation to native type II collagen, responses being found in both groups. All rats which developed arthritis had serum antibodies to native type II collagen, but not all responded to the tests for cell mediated immunity. These findings suggest that antibodies to collagen are more associated with the development of arthritis than is cell mediated immunity to collagen.

The frequencies of antibodies to the cartilage type IX and XI collagens and to type I collagen were determined in 188 patients with rheumatoid arthritis, of whom 76 were positive for antibodies to native type II collagen. A higher proportion of patients with antibodies to native type II collagen had antibodies to these other collagens, but about one third of patients without antibodies to native type II collagen had antibodies to one or more denatured collagens. The patterns of antibodies present in individual sera suggested that there was a selective response to the collagens in an individual patient. The incidence of patients having antibodies to these native and denatured collagens in a random group of patients with rheumatoid arthritis was calculated.

Antigen specific and cross reacting antibodies to native and denatured types II and XI collagen were detected in the sera of rats immunised with either of these antigens. The antibodies from rats immunised with type XI collagen initially showed the strongest binding to the alpha 2(XI) chain of type XI collagen but later binding to the alpha 3(XI) chain was seen. Sera from patients with rheumatoid arthritis had antibodies that bound to both type II and XI collagens. Immunoblotting studies showed that most patients had antibodies which bound to the alpha 1(II) chain of type II collagen and to the alpha 3(XI) chain of type XI collagen. Some patients also had antibodies which bound to the alpha 1(XI) and to the alpha 2(XI) chains of type XI collagen. Thus antibodies to unique as well as to common epitopes on each of the two types of collagen molecule occur in some patients with rheumatoid arthritis.

In rheumatoid arthritis the mean platelet volume does not alter with the institution of parenteral gold therapy and with long term gold therapy. It appears to have no value in predicting the onset of thrombocytopenia. It may, however, predict a haemorrhagic diathesis once gold induced thrombocytopenia is established.

Collagens type I, II, III, IV, and V and the minor cartilage collagens, 1 alpha 2 alpha 3 alpha, C-PS 1, and C-PS 2, were purified, antibodies raised, and then used in immunofluorescence studies on bovine nasal cartilage (BNC). Punctate localisation was seen with the type II antibody. However, pretreatment of sections with hyaluronidase to remove the proteoglycan resulted in diffuse staining over all the section with this antibody. Antibodies to 1 alpha 2 alpha 3 alpha, C-PS 1, and C-PS 2 collagens gave no staining on untreated BNC sections, but after treatment with hyaluronidase all 3 antibodies showed as a diffuse 'halo' round each chondrocyte lacuna. Anti-type I, anti-type III, and anti-type IV collagen antibodies did not stain untreated or enzyme treated BNC. Type V collagen antibodies gave a bright ring in the pericellular region of the lacunae of hyaluronidase-treated BNC. This was unexpected, as we could not detect type V collagen biochemically in the same cartilage. Anti-fibronectin antibodies stained areas distant from the chondrocytes, these areas being distinct from those stained by 1 alpha 2 alpha 3 alpha and C-PS antibodies, suggesting that fibronectin is not associated with these collagens in BNC. These results suggest that different collagen types may have different locations within the cartilage matrix, that proteoglycans may inhibit antibody association with collagen, and that fibronectin is normally not associated with all types of collagen.

Doses of 600 mg and 1200 mg of D(-)penicillamine daily were superior to a standard regimen of therapy in rheumatoid arthritis. The higher dose did not produce significantly greater therapeutic benefit in the group of patients so treated, although individual patients sometimes improved more. The frequency of rashes, blood dyscrasias, and withdrawals from the trial increased withe dosage. It is concluded that D(-)penicillamine is a useful treatment that the daily dose should be as low as possible, and that it should be increased at infrequent intervals only, with due regard to the likelihood of further improvement in relation to an increased risk of adverse reactions.

A 15-year-old male developed features of Still's disease. He was treated, with incomplete response, with aspirin and corticosteroids. Some 10 months after the onset he contracted chickenpox and became gravely ill. A diagnosis of histiocytic medullary reticulosis was made because erythrophagocytic histiocytes were detected in marrow aspirate films. Necropsy studies showed systemic infiltration by benign-appearing histiocytes and led to the final diagnosis of the virus-associated haemophagocytic syndrome due to varicella-zoster infection in an immunocompromised patient.

A collaborative study of 75 selected patients with rheumatoid arthritis (RA) employing 6 different methods for the detection of antibodies to type II collagen showed highly significant correlations between all the assays. The radioimmunoassays showed a greater sensitivity than either the passive haemagglutination or immunofluorescent techniques, and when the native collagen molecule was heat-denatured a higher number of patients showed increased antibody levels. In 33 patients the measurement of serum antibody levels to human, bovine, and rat native type II collagen showed a lack of species specificity, indicating that heterologous collagens can be employed in these assays. A retrospective analysis of the clinical, laboratory, and radiological features in the 41 patients with raised antibody levels and the 34 patients with normal antibody levels showed very few differences, but there was a significantly lower incidence of subcutaneous nodules (24% versus 56%) in patients with raised antibody levels. This study emphasizes the need to standardize assays for the measurement of serum antibody levels to native type II collagen. More extensive studies will be required before the clinical significance of these antibodies can be fully established.

Serial synovial fluid samples were obtained from patients with rheumatoid arthritis and analysed cytologically. Positive correlations in the serial samples between proportions of polymorphs and ragocytes were found. Based upon the serial synovial fluid cytology, distinct subgroups of rheumatoid joints emerged. Comparison of clinical findings in these subgroups showed that the joints with high ragocyte proportion had a significantly poorer outcome. This study therefore identifies two distinct subgroups of rheumatoid joints on the basis of the nature of the cellular reaction within the joint fluid, which usually holds true during subsequent clinical relapse. Identification of these groups may have prognostic significance.

The patient presented with progressive joint deformity, a hoarse voice, subsequent cachexia, and myoclonic seizures. She was first seen aged 22 months and died aged 6 years. A diagnosis of Farber's disease was made by demonstrating a deficiency of acid ceramidase both in leucocytes and fibroblasts.

Raised serum IgG and IgM antibody levels to native type II collagen were found in patients with rheumatoid arthritis and in patients with juvenile chronic arthritis. There was a good correlation between the serum IgG and the IgM antibody levels in rheumatoid arthritis and a weaker correlation in juvenile chronic arthritis. Raised serum IgM antibody levels to native type II collagen were found in only 1 patient each with ankylosing spondylitis and psoriatic arthritis, and in these groups here was no correlation between the serum IgG and the IgM antibody levels. The highest serum IgG and IgM antibody levels to native type II collagen were found in rheumatoid arthritis. These results, together with the results on serum antiglobulin levels, indicate that patients with rheumatoid arthritis produce antibodies of both IgG and IgM immunoglobulin class which may have pathogenetic significance in the more severe arthritis found in this condition.

A group of 16 patients with a disproportionate polyclonal increase in their serum IgG1, resulting in raised concentrations of total IgG immunoglobulin, has been discovered. The other IgG subclasses in these patients are either normal or slightly reduced, resulting in an IgG1:IgG2 ratio of at least 10:1. Most cases are marked by the presence of anti-extractable nuclear antigen (anti-ENA) antibodies and high titres of rheumatoid factor and antinuclear antibody. All but one patient has a connective tissue disease, nearly twice the prevalence found in similarly hypergammaglobulinaemic patients without this IgG subclass imbalance. Among patients with systemic lupus erythematosus (SLE), those with the IgG1 disorder have a higher prevalence of high titre rheumatoid factor and antinuclear antibody, but a lower prevalence of anti-double-stranded DNA (anti-dsDNA) antibodies above 30 U/ml. It is suggested that this immunoglobulin abnormality may reflect a unique immunoregulatory dysfunction in these patients.