HLA and disease manifestations in rheumatoid arthritis--a Canadian experience

Forty-eight Canadian patients with rheumatoid arthritis (RA) were tissue typed for class 1 (HLA-A, B, and C) and class 2 (HLA-DR and DQ) antigens in an attempt to identify HLA associations and to relate them to disease manifestations and drug toxicity. HLA-DR4 was found with a significantly higher frequency among patients with RA than in the control population. DR4 correlated with presence of rheumatoid nodules and pulmonary manifestations, and was more frequent among patients who had vasculitis. All 4 patients who died were DR4 positive. DR2 and DR7 were less frequent in our patients. There was no association between the presence of DR3 or DR4 and drug toxicity.     

The association between rheumatoid arthritis and the HLA antigen DR4.

One hundred and forty-two patients with 'definite' or 'classical' rheumatoid arthritis (RA) were studied for the frequency and possible prognostic significance of HLA DR4. Of these, 122 were seropositive, while 20 were negative for rheumatoid factor (RF) in serum. The HLA antigen DR4 was significantly increased in the seropositive group (65%) as well as in the seronegative group (55%) in comparison with a frequency of 27% in 116 healthy controls. Among seropositive patients a higher frequency of DR4 was found in females (73%) than in males (50%), the difference being statistically significant (p less than 0.01). DR4 was more frequent among patients with a family history of RA (74%) than among patients without affected relatives (57%). DR4 appeared to be associated with an early onset of RA. No significant differences in general disease activity or functional capacity between DR4-positive and DR4-negative RA patients were found. Patients without the HLA antigen DR4 had a significantly (p less than 0.05) higher mean titre of RF than those with the antigen.     

HLA-DR4 and pulmonary dysfunction in rheumatoid arthritis

Rheumatoid arthritis is associated with an increased frequency of the B cell alloantigen HLA-DR4, and preliminary work has suggested an association between HLA-DR4 and obstructive lung disease in subjects with rheumatoid arthritis. To prospectively evaluate the influence of HLA-DR4 on pulmonary involvement in patients with rheumatoid arthritis, pulmonary function was measured in four groups of subjects with rheumatoid arthritis in whom HLA-DR4 and smoking status was known: 16 DR4-positive smokers (six current and 10 exsmokers), 16 DR4-negative smokers (six current and 10 exsmokers), eight DR4-positive nonsmokers, and eight DR4-negative nonsmokers. Significant reductions in one-second forced expiratory volume and forced vital capacity were observed in DR4-positive subjects compared with DR4-negative subjects irrespective of cigarette smoking status. In addition, patients with keratoconjunctivitis sicca (secondary Sj?gren's syndrome) demonstrated significant reductions in one-second forced expiratory volume, forced vital capacity, and ratio of one-second forced expiratory volume to forced vital capacity compared with those patients without evidence of secondary Sj?gren's syndrome. It is concluded that the presence of the HLA-DR4 antigen and secondary Sj?gren's syndrome are associated with abnormal pulmonary function in patients with rheumatoid arthritis.     

HLA antigens in juvenile arthritis. Genetic basis for the different subtypes

Serologic HLA typing was performed in 77 patients with juvenile arthritis (JA). The frequency of the DR4 antigen was significantly increased in the seropositive but decreased in the seronegative patients--53% and 17%, respectively (P less than 0.025)--compared with 27% in healthy Norwegians. An increased frequency of the HLA-DR4 antigens was also found in polyarticular onset JA (50% compared with 27%, P less than 0.05). The frequency of both the HLA-B27 (21%) and the DR5 antigen (21%) was increased in the whole patient group compared with controls (10% and 9%, respectively, P less than 0.01). The DR5 antigen was also increased in the systemic onset patients (40%, P less than 0.05). Both the DR5 and the DR8 antigens were increased in the pauciarticular onset group (P less than 0.05 and P less than 0.01, respectively). The results support the view that seropositive and seronegative JA are different disease entities and also that seropositive JA may be an early form of seropositive rheumatoid arthritis. The association between the DR4 antigen and IgM rheumatoid factor suggests that the HLA-DR4 gene or a closely linked gene may regulate autoimmune responses to self IgG.     

Population study of the importance of rheumatoid factor isotypes in adults.

Blood samples collected from 13,858 randomly selected subjects participating in a health survey in Iceland from 1974 to 1983 were tested for rheumatoid factor. Samples that were positive in a sensitive RF screening test were analysed further by the Rose-Waaler technique and an isotype specific enzyme linked immunosorbent assay (ELISA). In 1987 the 173 available participants who were RF positive and 156 matched RF negative controls were evaluated clinically for rheumatoid diseases. RF levels and isotype patterns were more persistent in the patients with rheumatoid arthritis (RA) than in RF positive subjects who did not have overt RA. The prevalence of RA was only 19% in the participants who were RF positive in 1987. Forty per cent of the participants who had a persistent (four to 13 years) increase of IgA RF combined with either IgM or IgG RF were diagnosed as having RA. A positive correlation was found between RF levels and various manifestations of RA. This association was stronger for the IgA and IgG RF isotypes than for IgM RF. Excluding RF positivity as a diagnostic parameter, RA was diagnosed in 33 of the participants and 20 (61%) of these patients had increased levels of IgM and IgA RF. Patients with RA with bone erosions in their hands had higher levels of IgA RF than patients without erosions, but an association was not found between bone erosions and other RF isotypes. None of the RF negative participants who were symptom free when the original blood sample was taken developed RA during the four to 13 year follow up period. In contrast, five symptom free RF positive participants developed RA during this period. These five patients had all had increased levels of at least two RF isotypes before the onset of their symptoms. It is concluded that the IgA and IgG RF isotypes have a closer association with the clinical parameters of RA than IgM RF. Furthermore, increases in RF can precede clinical manifestations of RA and this applies in particular to the IgA and IgG RF isotypes.     

HLA-DR and tuberculin tests in rheumatoid arthritis and tuberculosis.

Responses to four new tuberculins were found to be significantly reduced in 46 patients with rheumatoid arthritis in comparison with a control group of 79. Except for tuberculin itself, the same was found in 111 patients with tuberculosis. In common with patients with tuberculosis and leprosy, those with rheumatoid arthritis did not respond to common mycobacterial (group i) antigen. Three DR haplotypes were found to have significant effects on skin test responsiveness of the rheumatoid patients but had little or no effect on that of the patients with tuberculosis and none on that of the healthy control group. Rheumatoid patients with the HLA-DR4 haplotype had significantly greater responses to all four reagents than did non-DR4 patients, but their responses to leprosin A and scrofulin remained significantly lower than those of the control group. Possession of HLA-DR3 haplotype was associated with skin test positivity approaching normal, but the sizes of responses were reduced. Possession of DR7 was associated with an unexpected reduction in skin test positivity, especially in the case of tuberculin. These results support the hypothesis that mycobacteria, or autoantigens cross reactive with mycobacteria, may be involved in the aetiology of rheumatoid arthritis. The results also show that the regulation and specificity of responsiveness to mycobacterial antigens are different in patients with rheumatoid arthritis with different HLA-DR haplotypes.     

Association of HLA-Aw31 and HLA-DR1 with adult rheumatoid arthritis.

Forty-nine Israeli Jewish patients with rheumatoid arthritis (RA) were studied for their HLA A, B, C, DR antigen frequency. A significant increase in HLA Aw31 and HLA DR1 was observed (p less than 5.10(-5) and p less than 5.10(-3) respectively). 45% of Aw31 positive patients were sero-negative for rheumatoid factor, while most HLA DR1 positive individuals were seropositive. DR5 was found to be significantly decreased (p less than 5.10(-4)). Contrary to previous reports, DRw4 was found to be within the range of antigen frequency of the controls (34.7% vs. 32%). It is suggested that in our population of patients Aw31 and DR1 and not DR4 are highly associated with adult onset of RA.     

HLA antigens in juvenile arthritis

Serologic HLA typing was performed in 77 patients with juvenile arthritis (JA). The frequency of the DR4 antigen was significantly increased in the seropositive but decreased in the seronegative patients—53% and 17%, respectively (P < 0.025)—compared with 27% in healthy Norwegians. An increased frequency of the HLA-DR4 antigens was also found in polyarticular onset JA (50% compared with 27%, P < 0.05). The frequency of both the HLA-B27 (21%) and the DR5 antigen (21%) was increased in the whole patient group compared with controls (10% and 9%, respectively, P < 0.01). The DR5 antigen was also increased in the systemic onset patients (40%, P < 0.05). Both the DR5 and the DR8 antigens were increased in the pauciarticular onset group (P < 0.05 and P < 0.01, respectively). The results support the view that seropositive and seronegative JA are different disease entities and also that seropositive JA may be an early form of seropositive rheumatoid arthritis. The association between the DR4 antigen and IgM rheumatoid factor suggests that the HLA-DR4 gene or a closely linked gene may regulate autoimmune responses to self IgG.     

Association of HLA-DR with susceptibility to and clinical expression of rheumatoid arthritis: re-evaluation by means of genomic tissue typing

The clinical expression of rheumatoid arthritis (RA) varies considerably among individual patients. Genetic variations in human leucocyte antigen (HLA) may influence clinical expression. We re- examined the association of HLA-DR with susceptibility to and clinical expression of RA using genomic tissue typing, since most studies were based on (less reliable) serological techniques. Seventy-eight patients with recent-onset RA, all participating in a clinical trial on therapeutic strategies, were HLA-DR typed by means of low-resolution genomic typing. Cumulative disease activity within the first 3 yr of disease was measured. Of the RA patients, 54% expressed DR4 (DR4+) vs 26% of healthy controls. Rheumatoid factor (RF)-positive patients had a higher cumulative disease activity than RF-negative patients. Patients who were either DR1+ or DR4+ had a higher cumulative disease activity than those who expressed neither DR1 nor DR4. This association was less obvious after correction for RF status. The association of DR52+ (DR3, 5, 6) and a lower cumulative disease activity could also not be demonstrated after correction for RF status. Among RF-negative patients, DR51+ (or DR2+) was associated with a higher cumulative disease activity. Other HLA-DR types (including DR1 and DR4 separately) were not associated with the severity of RA. DR4 was associated with susceptibility to RA in our patients; HLA-DR low-resolution genomic tissue typing did not yield additional information to RF status for the clinical identification of individual patients with a poor prognosis.      

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.     

Examination of HLA-DR4 as a severity marker for rheumatoid arthritis in Greek patients.

OBJECTIVES--Previous reports have shown that HLA-DR4 may be a severity marker for rheumatoid arthritis (RA) in patients of northern European origin. The aim of the present study was to investigate this relation in Greek patients with RA, as RA in Greece differs from the RA described previously on clinical, serological, and immunological grounds. METHODS--Eighty four patients were studied in whom HLA-DR typing was performed by restriction fragment length polymorphism and the subtypes of HLA-DR4 were determined by the polymerase chain reaction. The absence or presence of HLA-DR4 and its subtypes was correlated with the clinical and serological characteristics of the patients and with the side effects due to disease modifying drugs. RESULTS--Twenty one of the 84 (25%) patients with RA were DR4+. There was no difference between the DR4+ and DR4-patients with respect to duration of disease, severity of arthritis, functional grade, and joint erosion score. The DR4+ group were more likely to have side effects due to disease modifying drugs (43%) than DR4- patients (36%), but this difference was not statistically significant. DR4-patients had more extra-articular manifestations, including Sjögren's syndrome (47 v 19%). Analysis of the DR4 subtypes showed that Dw15 was the most common variant (9/21 patients; 43%). There was no statistical difference in the clinical manifestations among patients with different DR4 subtypes. The same was also true when the clinical picture was correlated with the 'shared RA epitope' (QKRAA/QRRAA/RRRAA), which is common to all HLA-DRB1 alleles positively associated with RA. CONCLUSIONS--These results suggest that HLA-DR4 is not a severity marker in Greek patients with RA and further indicate differences in the clinical expression of RA in Greece.     

IgM rheumatoid factor (RF), IgA RF, IgE RF, and IgG RF detected by ELISA in rheumatoid arthritis.

One hundred patients with rheumatoid arthritis (RA), of whom 73 were seropositive by latex or Waaler-Rose (WR) assays, or both, 100 healthy subjects, and 102 diseased controls (22 patients with systemic lupus erythematosus (SLE) and 80 with bronchial asthma) were evaluated for the presence of IgM rheumatoid factor (RF), IgA RF, IgE RF, and IgG RF by an enzyme linked immunosorbent assay (ELISA). Ninety two per cent, 65%, 68%, and 66% of the patients with RA were found to be positive for IgM, IgA, IgE, and IgG respectively. A positive correlation existed between the levels of IgM RF and IgA RF on the one hand and disease activity on the other, and the levels of IgM RF and IgA RF correlated with the levels of circulating immune complexes as measured by a C1q binding assay. The presence of extra-articular features also correlated positively with the levels of IgA RF and IgE RF. Five out of six patients with Sjögren''s syndrome had very high levels of IgA RF. Of 47 patients typed for HLA-DR, DR1 and DR2 were significantly more frequent in those with the highest levels of IgM RF. Conversely, DR3 was associated with low levels or absence of IgA RF and IgE RF. These results suggest that immune response genes may regulate the level of different RF isotypes. The frequencies of IgM, IgA, IgE, and IgG RF were 59%, 36%, 9%, and 27% respectively in SLE and 25%, 2.5%, 70%, and 59% in bronchial asthma.     

HLA antigens and toxic reactions to sodium aurothiopropanol sulphonate and D-penicillamine in patients with rheumatoid arthritis.

One hundred and forty-one patients with rheumatoid arthritis treated with aurothiopropanol sulphonate or D-penicillamine, or both were examined for HLA antigens to investigate the genetic influence on the occurrence of different adverse reactions during therapy. All 13 patients possessing HLA-DR3 had toxic reactions. The relative risk for DR3 positives of developing skin eruptions or proteinuria was calculated to be 10.5 times and seven times respectively that of DR3 negatives. The incidence of DR7 antigen in 94 patients with toxic reactions was significantly decreased (11% compared with 28% in controls) suggesting a protective role for this antigen.     

Trypanosoma cruzi: a carbohydrate epitope defined by a monoclonal antibody as a possible marker of the acute phase of human Chagas' disease.

An IgM monoclonal antibody (MAb) against a carbohydrate epitope present in Trypanosoma cruzi trypomastigote excretory-secretory antigens and expressed by different developmental stages of the parasite (epimastigote, trypomastigote and intracellular amastigote) was linked to a solid phase matrix and used as an antigen-capture antibody. Human serum complexes containing the epitope were then detected by using specific secondary antibodies against human immunoglobulin isotypes. Results of detection of IgM, IgG, and IgA serum complexes (SC) containing a T. cruzi polypeptide epitope showed that SC could be detected in 69% of the 13 Chagasic acute phase sera studied with IgG, in 84% with IgM, and in 75% with IgA. Only 16% (IgG-SC), 8% (IgM-SC), and 10% (IgA-SC) of chronic sera from 50 patients were positive. No patients with toxoplasmosis or rheumatoid factor were positive. Of the 11 leishmaniasis sera studied, four had IgG-SC, two had IgA-SC, and five had IgM-SC. Of the eight Yanomamo Indians infected by Onchocerca volvulus, three were found to have IgG-SC, two had IgM-SC, and two had IgA-SC. Thirteen sera from healthy individuals living in an endemic area were also studied. One subject had IgG IgM and IgA-SC. The results presented in this study show for the first time, the specific detection of IgM, IgG, and IgA immune complexes using a MAb against T. cruzi. The presence of the epitope in association with IgM antibodies in sera from patients with the acute phase of the disease suggests that this antigen(s) carrying the epitope that reacts with the MAb could be a marker(s) of active infection. In addition, the specificity of the serum complex capture assay allowed the detection of Chagas' disease in two different endemic areas (Argentina and Venezuela).     

Increased frequency of Gm(1,2;21) phenotype in HLA-DR4 positive seropositive rheumatoid arthritis

Ninety-four patients with seropositive rheumatoid arthritis (RA) were typed for HLA-A, B, C and DR antigens and for immunoglobulin G (Gm) allotypes. Isolated IgG from patient serum was used to avoid interference of IgM rheumatoid factor (RF) with Gm typing in sera with high IgM-RF titer. Besides the association of seropositive RA with the antigen DR4 and an earlier disease onset in DR3/DR4 heterozygotes, we found the uncommon Gm phenotype Gm(1,2;21) significantly more often in our patient group than in healthy controls. Combination of HLA-DR and Gm data shows that individuals with both DR4 and Gm(1,2;21) are at a particularly high disease risk.     

Anti-agalactosyl IgG antibodies in sera from patients with systemic sclerosis

OBJECTIVE: To determine the prevalence and clinical correlations of anti-agalactosyl IgG antibodies (anti-AG IgG) in patients with systemic sclerosis (SSc). METHODS: Serum samples from patients with limited cutaneous SSc (lSSc; n = 49), diffuse cutaneous SSc (dSSc; n = 21), rheumatoid arthritis (RA; n = 10), systemic lupus erythematosus (SLE; n = 20), and healthy individuals (n = 20) were examined by lectin-enzyme immunoassay using human agalactosyl IgG as antigen. RESULTS: Anti-AG IgG were detected in 52 (74%) of 70 patients with SSc, which was much higher than the frequency of rheumatoid factor positivity in SSc (16%). Levels of anti-agalactosyl IgG antibodies were significantly higher than in healthy controls or patients with SLE, but lower than patients with RA. Levels of anti-AG IgG in patients with dSSc were significantly higher than in lSSc. SSc patients with anti-topoisomerase I antibodies had significantly higher levels of anti-AG IgG than SSc patients with anticentromere antibodies. Concerning clinical correlation, patients with pulmonary fibrosis showed elevated levels of anti-AG IgG compared to those without pulmonary fibrosis. Patients with decreased %VC or %DLCO showed increased levels of anti-AG IgG. Elevated levels of anti-AG IgG were associated with the presence of contracture of phalanges or cutaneous calcinosis, but not the presence of arthritis/arthralgia. CONCLUSION: The results suggest that anti-agalactosyl IgG antibody is frequently detected in SSc and is a serological indicator for more severe SSc.     

Immunogenetic heterogeneity of rheumatoid arthritis.

Association of HLA-DR4/Dw4 with rheumatoid arthritis (RA) is well established, but conflicting data exist on a possible association with the severity of the disease, including its extra-articular manifestations. In order to investigate whether a subgroup of RA is preferentially associated with DR4, HLA typing was performed in two groups of patients with severe extra-articular manifestations (Felty's syndrome and histologically proved leucocytoclastic vasculitis), patients with severe joint destruction (seropositive and seronegative), a group with only mild joint destruction, and in healthy controls. The frequency of HLA-DR4 was significantly raised in all patient groups compared with that in healthy controls. The two groups with severe extra-articular manifestations, however, both had a DR4 frequency of 92%, which was significantly (p = 0.002) higher than the 62.7% found in the remaining patients. No significant differences were observed between severe or mild joint destruction and seropositivity or seronegativity in the groups without the above-mentioned extra-articular manifestations. From these data we concluded that DR4 is preferentially associated with severe extra-articular disease manifestations of RA. This observation provides an immunogenetic basis for the disease heterogeneity and for the immunological analogy between RA and leprosy.     

Beta2 glycoprotein 1 in Indian patients with SLE.

Forty-five patients with systemic lupus erythematosus (SLE) were investigated to evaluate the role of antiphospholipid antibodies in causation of thrombosis in Indians. The antiphospholipid antibodies studied included lupus anticoagulant (LAC), anticardiolipin antibodies (aCL), and anti-beta(2)-glycoprotein 1 (a beta(2)-GP1). Twenty-seven patients (60%) had clinical manifestations of antiphospholipid antibody syndrome. Nineteen patients (42.2%) had a history of thrombosis, and eight (17.7%) had a history of recurrent fetal loss. aBeta(2)-GP1 was (IgG) was positive in 23 (51.1%), aCL in 13 (28.8%), and LAC in four (8.8%). Of 19 patients with thrombosis, 14 (73.6%) were positive for abeta(2)-GP1, eight (42.1%) for aCL, and none of them was positive for LAC. Of the eight patients with recurrent fetal loss, two (25%) patients were positive for beta(2)-GP1, five (62.5%) for aCL, and one (12.5%) for LAC. Of 18 patients without any manifestations of antiphospholipid syndrome (APS), seven patients (38.8%) were positive for abeta(2)-GP1, and three (16.6%) for aCL and LAC each. It is concluded that presence of abeta(2)-GP1 increases the risk of thrombosis and therefore should be looked for in all cases of SLE to consider prophylactic antithrombotic therapy in these patients.     

Clinical manifestations of co-infection with malaria and leptospirosis

Though both malaria and leptospirosis are frequent in the tropics, co-infections are under-recognized due to overlapping of clinical features. Here, we reviewed clinical manifestations of published co-infection along with our three cases. Out of a total of 18 patients, nine patients (50%) required ICU admission. Almost all patients had prodromal symptoms in the form of fever, headache and myalgia. Seven patients (37%) had altered sensorium, three patients (17%) had hypotension at admission, and 11 patients (61%) had acute kidney injury (AKI). Pulmonary manifestations in the form of pulmonary bleeding were present in four cases (22%). Three (17%) patients had acute lung injury/ acute respiratory distress syndrome. Almost 55% patients had DIC in the form of altered prothrombin time, activated partial thromboplastin time and low fibrinogen level. Four patients (22%) had subconjuctival suffusion, two of them had haematuria, while one presented with nasal bleeding. All patients had altered liver function tests. Of all the 18 patients, 17 (94%) survived, while one died.     

Relationship between high-resolution computed tomography findings and the Stoke index in patients with rheumatoid arthritis

The aim of this study was to evaluate the relationship between high-resolution computed tomography (HRCT) findings and the Stoke index (SI) in patients with rheumatoid arthritis (RA). Forty RA patients (31 women, 9 men) were evaluated. All patients fulfilled the criteria proposed by the American College of Rheumatology. Clinical evaluation, haematological data, chest radiography, pulmonary function tests (PFTs) and HRCT were obtained in all patients. The SI was used to assess disease activity. In 17 (42.5%) patients, there were no signs of pulmonary involvement on HRCT; 23 (57.5%) of 40 patients had abnormal HRCT findings. Of 23 patients with HRCT abnormalities, six (two male, four female) had respiratory symptoms, four (one male, three female) had abnormalities on chest radiography and five (all female) had abnormalities on PFTs. There was no relationship between pulmonary changes observed on HRCT, clinical and laboratory disease activity parameters, chest X-ray and PFTs. There was no difference in the mean SI between patients included in the HRCT (+) and those included in the HRCT (-) groups. No significant correlations between the HRCT and the SI were seen. The main findings of this study are that HRCT can give useful information on RA-associated lung changes and that there was no relationship between the SI and the HRCT findings of patients with RA.