K. D. Muirden

Rheumatic disease in a Philippine village II: A WHO-ILAR-APLAR COPCORD study, phases II and III

SummaryMany difficulties were encountered in a population survey of rheumatic complaints in a remote village area in the Philippines affecting the reliability of estimates of population prevalence. In phase I, a simple questionnaire identified 269 adults out of 950 who had rheumatic symptoms. In Phase II, 234 or 87% of positive respondents were requestioned using a more detailed pro forma. There were 196 with peripheral joint pain, 67 with neck pain and 137 with back pain. One third attributed their symptoms to work and 127 subjects had to stop work because of their complaints. Disability, including an inability to carry loads, affected nearly 1.8% of the population. Questions designed to detect rheumatoid arthritis and gout were not satisfactorily answered. Of those with complaints, 82% indicated that they still required help for their symptoms. In phase III, 166 subjects were medically examined. Osteoarthritis of the knee was found in 25 and 17 had Heberdens nodes. There were 16 with epicondylitis; 16 had rotator cuff pain and 35 had levator scapulae insertion pain. Three of these and three others had neck or shoulder swellings related to carrying loads on poles. Definite rheumatoid arthritis was diagnosed in two subjects and gout in five. No case of ankylosing spondylitis was identified. Thus, rheumatic complaints were common in this rural, community and were frequently severe enough to cause disability and loss of time from work. Health worker education is required on how to handle these problems.

Antibodies to type II collagen and HLA disease susceptibility markers in rheumatoid arthritis.

OBJECTIVE To seek associations between antibodies to native and denatured type II collagen (NCII and DCII) and HLA in rheumatoid arthritis (RA). METHODS One hundred fourteen patients with clinically well-defined RA were HLA-DR and DQ typed. Those who were DR4 positive were subtyped for DRB1*0401-*0408 alleles by polymerase chain reaction using allele-specific oligonucleotide probes. Antibodies to human NCII and DCII (heat-denatured) were measured by enzyme-linked immunosorbent assay. The frequency of HLA alleles was compared in patients grouped according to the presence and absence of antibodies to NCII and DCII. RESULTS Twenty-seven patients (24%) were positive for antibodies to NCII. There was a significant increase in the frequency of HLA-DR7 in anti-NCII-positive patients compared with anti-NCII-negative patients (30% versus 9%; P = 0.019) and a significant decrease in HLA-DR3 (7% versus 28%; P = 0.044). Repeating the analyses after excluding the 16 patients who were DR7 positive revealed a significant increase in the frequency of HLA-DR1 in anti-NCII-positive patients compared with anti-NCII-negative patients (63% versus 27%; P = 0.045). Moreover, antibodies to NCII were associated with the third hypervariability region susceptibility sequence QRRAA that is present in DRB1*0101, *0404, *0405, and *0408 (84% versus 47%; P = 0.0085); 24 of 27 anti-NCII-positive patients were positive for either DR7, DR1, or DRB1*0404 or *0408. Thirty patients (26%) were positive for antibodies to DCII. There was a significant increase in the frequency of HLA-DR3 in anti-DCII-positive patients compared with anti-DCII-negative patients (40% versus 18%; P = 0.028). CONCLUSION The genetic associations between HLA-DR alleles and antibodies to CII in RA patients is in keeping with the collagen-induced arthritis model and implicates autoimmunity to CII as a major component in the multifactorial pathogenesis of RA.

Coexistent rheumatoid arthritis and systemic lupus erythematosus: clinical, serological, and phenotypic features.

The clinical and serological features and HLA phenotypes are reported for 11 patients with coexistent features of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). All patients had a symmetrical small joint polyarthritis and features of SLE such as rash, photosensitivity, oral ulceration, serositis, cytopenia, and biopsy proved lupus nephritis. Eight had hypocomplementaemia. Autoantibodies were characteristic of the two diseases: all patients had rheumatoid factor and antibodies to double stranded DNA, eight (73%) had antibodies to collagen, and five (46%) had antibodies to Ro (SS-A). There was also an overlap of HLA phenotypes. Six patients were DR4 and seven were DR2 or DR3 positive, and of the five patients who were DR4 negative, four shared class I alleles often associated with DR4. If RA and SLE share a common autoimmune dysfunction, those patients who have the two diseases do so because they have genetic determinants of both.

Chondrocyte-derived cells and matrix at the rheumatoid cartilage-pannus junction identified with monoclonal antibodies

SummaryIn the cartilage-pannus junction of 14 patients with rheumatoid arthritis (RA) and seven patients with osteoarthritis (OA), monoclonal antibodies to keratan sulphate (KS) and chondroitin sulphate (CS) stained a transitional fibroblastic zone (TFZ) within the pannus in nine RA patients and one OA patient. In three patients this was clearly localised to the cytoplasm of cells in this zone, but in all remaining cases KS and CS could be demonstrated in the surrounding matrix. This area was distinguished from adjacent pannus which contained many blood vessels and cells positive for MHC Class II antigen. Specific markers for glycosaminoglycans have been employed to demonstrate that chondrocyte-derived cells and matrix contribute to the changes seen at the cartilage-pannus junction in RA-affected joints.

The Effect of HLA-DRB1 Disease Susceptibility Markers on the Expression of RA

The study was designed to examine the effect on clinical expression of rheumatoid arthritis (RA) of HLA alleles, particularly DR4 and DR1 that contain susceptibility sequences for RA in the third hypervariable region (HVR3) of HLA-DRB1. We studied 114 consecutive Australian patients with RA attending a hospital outpatient clinic. The effects on indices of disease severity and activity of HLA DR4 and DR1, the DRB1*04 subtypes, and the polymorphism in the RA susceptibility sequence (QRRAA or QKRAA) were examined. The patients were initially divided into 6 groups, DR4,4; DR4,1; DR1,1; DR4/X; DR1,X, and DRX/X, and then further subdivided according to the actual HVR3 susceptibility sequence. The high risk conferred by the HVR3 susceptibility sequence, present in 76%, was confirmed, but 24% of the patients with long-standing seropositive erosive RA lacked this sequence. Among these those with DR2 had early-onset severe disease, and those with DR3 had late-onset milder disease. Differences in expression correlated with polymorphisms in the susceptibility sequence, in that active RA was associated more with QRRAA than QKRAA. There was no correlation of any HLA allele with disease severity. Our finding that the presence of the HVR3 sequence confers susceptibility and also influences the clinical expression and tempo of progression of RA suggests a role in pathogenesis for antigen presentation, whether of an autoantigenic molecule or a persisting infection.

Correlation of histopathological features of pannus with patterns of damage in different joints in rheumatoid arthritis.

The cartilage-pannus junction has been studied in multiple sections from 23 rheumatoid joints. Changes suggesting a metaplastic reaction of the articular cartilage, termed transitional fibroblastic zone, were commonly found in hips and knees, but were rarely present in metatarsophalangeal joints, in which an invasive pannus with cartilage degradation in close association with inflammatory cells was seen. Thus when multiple sections from rheumatoid joints were examined a transitional fibroblastic zone was found in 1/15 (7%) sections from metatarsophalangeal joints compared with 29/57 (51%) and 15/48 (31%) sections from knee and hip joints respectively. In contrast, an invasive pannus occurred in 11/15 (73%) sections from metatarsophalangeal joints compared with 22/57 (39%) sections from knees and 19/48 (40%) sections from hips. These findings led to the suggestion that this pathological variation between different joints may explain the predominance of erosive change in small joints as compared with joint space narrowing with secondary osteoarthritis found in large joints in rheumatoid arthritis. Inappropriate comparisons between different joints may in part explain the variation in findings of previous histopathological studies.

Cells and Matrix Expressing Cartilage Components in Fibroblastic Tissue in Rheumatoid Pannus

Our studies of the cartilage-pannus junction in rheumatoid joints have demonstrated the frequent presence of a transitional fibroblastic zone (TFZ) overlying articular cartilage. Using immunohistochemical techniques this zone has been shown to contain cells and matrix expressing specific cartilage components but not antigens present on cells in invasive vascular pannus. These findings support the concept that fibroblastic pannus is derived from the underlying articular cartilage rather than adjacent tissues. This type of reaction involving a metaplastic change in the chondrocyte is particularly common in large weight-bearing joints and may represent a different mechanism of cartilage degeneration to the classically described direct invasion of cartilage by hypertrophic synovial tissue.

Arthritis community education by leather puppet (wayang kulit) shadow play in rural Indonesia (Java)

SummaryAs part of the WHO/International League Against Rheumatism (ILAR) sponsored community organized programme for the control of rheumatic disease (COPCORD), an arthritis community education programme (ACE) was undertaken utilizing the traditional form of entertainment in a rural area in Central Java-the wayang. The point prevalence rate of musculoskeletal complaints was estimated in 4683 men & women aged 15 years and over by house-to-house interviews. From 1105 respondents recording recent musculoskeletal pain, 844 were randomly selected and half the latter attended a puppet shadow play (wayang) incorporating the ACE. The other half, matched for age, sex and educational level who did not see the play, served as controls. A questionnaire containing biphasic choices of correct or incorrect ways of performing activities of daily living (ADL) to minimize musculoskeletal problems was administered to the whole group before, 1 month and 6 months after the wayang. Increased knowledge of correct ways of performing ADL (correct ADL) in the intervention group compared with the control group at 1 and 6 months after wayang was significant (P<0.05). Comprehension of correct ADL following the wayang could be demonstrated even in subjects who were illiterate and those who had attended primary school only. Retention of knowledge at the 6 month assessment declined more markedly in the illiterate group. ACE by wayang was shown to be feasible and effective in transferring knowledge on ADL to people with musculoskeletal problems in the sample population in Java. This effect could be shown even in the poorly educated section of the community. In the absence of adequate numbers of skilled primary health care professionals, public education programmes utilizing traditional forms of entertainment should be considered, especially in rural communities in developing countries.

Study of enzyme inhibitors in the rheumatoid pannus-cartilage area

SummaryImmunoperoxidase studies were carried out on the pannus-cartilage junction (PCJ) of patients with rheumatoid arthritis (RA) and psoriatic arthritis to investigate the distribution of the enzyme inhibitors α2 macroglobulin (α2 M) and α1 antitrypsin (α1 AT). Comparisons were made with the equivalent synovial cartilage junctional area in osteoarthritis (OA). In all 12 patients with RA, prominent deposits of α2 M and α1 AT were found within the PCJ whereas in OA patients and the case of psoriatic arthritis fewer or no deposits were seen. Inhibitors were localised in pannus synovial lining cells, perivascular inflammatory cells, macrophage and fibroblast-like cells invading the cartilage as well as along the junctional cartilage matrix and in the adjacent pannus-free cartilage. Deposits of immunoglobulins were found in similar areas to enzyme inhibitors. The presence of enzyme inhibitors at the PCJ suggests that this area is not unprotected against enzymatic attack. Thus the concept that pannus is a prime area for cartilage damage because aggressive, invasive cells release destructive enzymes in an environment free from inhibitors should be reviewed.

Immuno-electron microscopy of chondrocyte-derived cells in the rheumatoid cartilage-pannus junction

SummaryImmuno-electron microscopy has been utilised to examine the cartilage-pannus junction in seven patients with rheumatoid arthritis. Using a monoclonal antibody, keratan sulphate was localised to cells with the ultra-structural appearance of fibroblasts within a transitional fibroblastic zone in the pannus in two cases. This confirms previous light microscopy evidence that this area (which is clearly separate from articular cartilage) contains cells which produce keratan sulphate, and strengthens the hypothesis that these cells are derived from cartilage rather than from the adjacent synovial membrane.