Young adults with juvenile arthritis in remission attain normal peak bone mass at the lumbar spine and forearm.

OBJECTIVE: To assess the impact of disease activity on acquired peak bone mass and bone turnover in young adult patients with either persistent juvenile arthritis (JA) or a history of JA (JA in remission). METHODS: Two hundred twenty-nine patients with JA were studied after a mean +/- SD of 15.6 +/- 2.4 years in women and 14.9 +/- 2.1 years in men since disease onset. One hundred forty-five women and 84 men were over the age of 20 at the time of examination (mean +/- SD age 24.9 +/- 2.9 years for women and 25.2 +/- 3.1 years for men). Forty-one healthy women (mean +/- SD age 27.4 +/- 3.1 years) and 55 healthy men (mean +/- SD age 25.7 +/- 3.1 years) served as a reference group. Bone mineral density (BMD) was analyzed by dual x-ray absorptiometry. Serum osteocalcin concentrations and urinary concentrations of deoxypyridium (D-Pyd) were measured. Linear regression analyses were performed to evaluate the impact of disease on BMD. RESULTS: Patients with persistent disease had significantly lower BMD compared with healthy subjects (P < 0.001 for women at all measured sites and for men at the femoral neck and total body; P < 0.05 for men at the radius and lumbar spine). Of the patients with a history of JA, only women had significantly lower BMD at the femoral neck and total body (P < 0.05). Patients with persistent JA had significantly more osteopenia and osteoporosis than healthy subjects, while patients with a history of JA had more frequent osteopenia only in the total body. Weight, urinary concentration of D-Pyd, and belonging to the patient group significantly affected BMD at all measured sites in the entire study population, while analysis of all patients found that only the number of months taking corticosteroids significantly affected BMD at all measured sites. However, the impact of the variables differed from site to site. CONCLUSION: Our findings imply that most young adults with JA attain the same BMD as healthy subjects if the disease goes into remission, while young adults with active disease have increased risk for osteopenia and osteoporosis.

Measuring disability in early juvenile rheumatoid arthritis: evaluation of a Norwegian version of the childhood Health Assessment Questionnaire.

OBJECTIVE: To assess the reliability, validity, and sensitivity to change of the Norwegian version of the childhood Health Assessment Questionnaire (CHAQ) and to examine the relationship between disability, disease severity, and psychosocial factors in patients with early juvenile rheumatoid arthritis (JRA). METHODS: Physical functioning was assessed by the CHAQ in 109 patients (median age 6.6 years, range 1.0-16.6) with JRA and a median of 4 months' (range 2-23) disease duration. Eighty-three patients were reassessed after a median of 6 months (range 3-21). Psychosocial functioning was assessed by the Child Behavior Checklist (n=39). RESULTS: The internal consistency of the CHAQ was good (Cronbach's alpha=0.83). The test-retest and parent-patient correlations were high [intraclass correlation coefficients 0.85 (n=18) and 0.75 (n=20), respectively, p < 0.001]. The CHAQ correlated moderately with number of tender, swollen and mobility restricted joints, morning stiffness, C-reactive protein, pain, and patients' and physicians' global assessments [correlation coefficients (r) ranging from 0.55 to 0.30, p < 0.01], but weakly with erythrocyte sedimentation rate (r=0.17, NS). The CHAQ also correlated with low levels of social competence (r=-0.49, p < 0.05) and high levels of internalizing behavior problems in the patients (r=0.43, p < 0.01) and low education levels of the mothers (r=-0.31, p < 0.01). Pain (beta 0.45, p < 0.001), number of swollen joints (beta 0.31, p < 0.001), and internalizing behavior problems (beta 0.45, p < 0.01) were predictors of disability. The median CHAQ changed from 0.25 to 0.00 (p < 0.05) in the 41 patients who improved, from 0.31 to 0.85 (p < 0.05) in the 18 patients whose condition was worse, and from 0.50 to 0.59 (NS) in the 24 patients whose condition was unchanged after 6 months. The effect size of the change was small (0.28) in those who improved and moderate (0.54) in those who became worse. CONCLUSION: The Norwegian version of the CHAQ is a reliable and valid instrument for measuring disability in children with early JRA. Pain, joint inflammation, and psychosocial factors are the most important correlates of disability and the CHAQ is sensitive to clinical change.

HLA class II alleles and heterogeneity of juvenile rheumatoid arthritis. DRB1*0101 may define a novel subset of the disease.

OBJECTIVE: To examine the distribution of HLA class II alleles in clinically distinct juvenile rheumatoid arthritis (JRA) subsets. METHODS: We typed 298 patients and 181 controls for HLA-DRB1, DQA1, DQB1, and DPB1 alleles using polymerase chain reaction and oligonucleotide probe techniques. RESULTS: Each JRA subset was characterized by a distinct distribution of HLA class II alleles. For the persistently pauciarticular and rheumatoid factor-negative polyarticular JRA subsets, certain combinations of DRB1 and DPB1 alleles were characteristic. In patients without antinuclear antibodies and chronic iridocyclitis, there was an increase of DRB1*0101/02 and DQA1*0101. CONCLUSION: Findings of HLA typing support clinical subdivisions of the disease and suggest the existence of a novel DRB1*0101/02 and DQA1*0101 associated disease subset.

Immune responses to 18.6 and 30-kDa mycobacterial antigens in rheumatoid patients, and V beta usage by specific synovial T-cell lines and fresh T cells.

We have investigated both the humoral and the cellular immune responses of patients with juvenile rheumatoid arthritis (JRA) and rheumatoid arthritis (RA) to mycobacterial antigens. The JRA group was not Bacillus Calmette Guerin (BCG) vaccinated whilst the majority of the RA group was. As determined by immunoblotting, 79% of sera from patients with JRA reacted mainly with a 18.6-kDa protein (P18.6), whilst 70% of sera from patients with RA reacted mainly with a 30-kDa protein (P30) of BCG, M. tuberculosis and M. kansasii. In contrast, only a moderate proportion of the control sera (25% of adult and 20% of children) showed reactivity to P30, and none of the samples had significant reactivity with the P18.6 antigen. Furthermore, T-cell proliferation to the P18.6 and P30 antigens was detected in the majority of JRA and RA patients, and was nearly always higher in synovial fluid (SF) than in the peripheral blood (PB). We also investigated the usage of V beta family genes in P18.6 and P30 antigen-specific T-cell lines established from the SF of one patient with active RA. We showed that V beta 2, -4, -5, -6, -7, -14, -17, -18 and V beta 19 were over-represented compared with other known V beta families. We also noted that the proportion of V beta 14 was higher in freshly isolated SF mononuclear cells compared with the blood in this patient and in 2 out of 4 other RA patients examined. Other V beta families such as V beta 6, V beta 8, V beta 16, V beta 18 and V beta 19 were also over-represented in the SF compared with the blood in some patients. Taken together our results provide more information concerning the role of mycobacterial antigens in RA and suggest that there may be an in vivo clonal expansion of T lymphocytes in the synovium.

T gamma delta cells in juvenile rheumatoid arthritis and rheumatoid arthritis. In the juvenile rheumatoid arthritis synovium the T gamma delta cells express activation antigens and are predominantly V delta 1+, and a significant proportion of these patients have elevated percentages of T gamma delta cells.

Using the anti-TcR gamma/delta-1 monoclonal antibody and flow cytometry, we examined the number of T gamma delta cells in paired samples of peripheral blood and synovial fluid or tissue from 24 children with juvenile rheumatoid arthritis (JRA), five adult patients with JRA, and 14 patients with rheumatoid arthritis (RA). No significant difference was found in the synovial compartment T gamma delta values compared with the blood in JRA, adult JRA, or RA patients. Nor was any significant difference found in the peripheral blood or synovial compartment T gamma delta values in any of the three patient groups compared with the peripheral blood of normal controls. However, seven of the children with JRA had very high T gamma delta values in the synovial compartment while none of the normal children had high T gamma delta values in the blood (P = 0.02, Fisher's exact test). This may indicate a possible separate JRA patient group with high T gamma delta levels in the synovial compartment. In six JRA patients further analysed for T gamma delta subpopulations, a significant predominance of V delta 1+ cells was found in the synovial compartment compared with the corresponding peripheral blood samples (P less than 0.05, Wilcoxon's signed test) and with peripheral blood of child controls (P less than 0.05, Mann-Whitney U test). In these six patients, the T gamma delta-cell expression of the very early activation antigen CD69 were significantly higher (P less than 0.05, Wilcoxon's signed test) in the synovial compartment compared with the peripheral blood. Synovial T gamma delta cells expressing HLA-DR and interleukin 2 receptors could also be detected, in contrast to the peripheral blood in which no T gamma delta cells expressing these antigens could be found. These data suggest that the synovial T gamma delta cells had been activated in vivo.

Increased natural killer cell activity and numbers of Leu-7 and Leu-11b (CD 16)-positive cells in bone marrow of children in remission from acute lymphoblastic leukaemia.

Natural killer (NK) cell activity and related markers were analysed in childhood acute lymphoblastic leukaemia (ALL). Children with untreated ALL, children with active disease, and children in remission for less than 1 month and undergoing induction therapy had significantly lower NK cell activity in peripheral blood than the control group (P less than 0.05, P = 0.0005, and P less than 0.0025). Patients in remission for 1-3 months and undergoing consolidation chemotherapy had normal NK activity (P greater than 0.05). Children in complete remission for more than 3 months and undergoing maintenance therapy also had a normal NK activity in their peripheral blood (P greater than 0.05). However, their bone marrow cells showed an increased NK cell activity (P less than 0.0005). Cells positive for the Leu-7 marker were reduced in the peripheral blood from untreated children (P less than 0.025) and children in remission for less than 1 month (P = 0.025). The percentage of cells from peripheral blood expressing the marker Leu-11b (CD 16) did not differ significantly from that of the controls (P greater than 0.05). However, children in complete remission for more than 3 months had a higher number of bone marrow cells expressing the Leu-7 (P = 0.005) and the Leu-11b (CD 16) markers (P = 0.05) than controls. Stimulation of mononuclear cell suspensions with recombinant alpha interferon and recombinant interleukin 2 were shown to cause a normalization of the NK cell activity in peripheral blood and bone marrow.

Altered natural killer cell activity in childhood acute non-lymphoid leukaemia. Augmented natural killer cell activity and cells expressing the Leu 7 and Leu 11b (CD 16) markers in the bone marrow of children in remission.

Peripheral blood and bone marrow mononuclear cells from 25 children with acute non-lymphoid leukaemia were analysed for natural killer cell activity and for cells with the Leu-7 and Leu-11b (CD 16) markers. Significantly reduced spontaneous cytotoxicity was detected in peripheral blood from children with untreated and active acute non-lymphoid leukaemia compared with that of the controls (P = 0.01 and P less than 0.05). Patients in remission, however, had normal natural cytotoxicity and normal numbers of Leu-7 and Leu-11b (CD 16)-positive cells. The natural killer cell activity in bone marrow from patients with untreated acute non-lymphoid leukaemia was also significantly reduced (P = 0.025). On the other hand, patients in remission had both an increased percentage of Leu-7 and Leu-11b (CD 16)-positive cells (P less than 0.05) and an increased natural killer cell activity (P less than 0.0005) in their bone marrow cells in comparison with the control group. This augmented natural killer cell activity is most probably a result of anti-leukaemic treatment. Stimulation with recombinant alpha interferon and recombinant interleukin 2 caused an increase in natural killer cell activity that was both significant and normal in both peripheral blood and bone marrow from children with acute non-lymphoid leukaemia.

Natural cytotoxicity in adult acute leukemia.

Natural cytotoxic activity was studied in 32 adult patients with acute non-lymphoid leukemia (ANLL) and 27 adult patients with acute lymphoblastic leukemia (ALL). Thirteen patients with active ANLL had a significantly reduced natural cytotoxicity in peripheral blood compared with that of healthy controls, 5.0 +/- 3.4 versus 27.1 +/- 11.5 (p less than 0.0005). Patients with ANLL in remission had a normal natural cytotoxicity (p greater than 0.05). Patients with active ANLL had a significantly reduced number of Leu-7-positive cells (p less than 0.001), while patients in remission had normal proportions of these cells (p greater than 0.05). Peripheral blood from patients with ALL showed reduced natural killer (NK) cell activity, both in active disease and in remission (p less than 0.0005). The percentage of Leu-11b (CD 16)-positive cells was increased in patients in remission from ALL (p less than 0.05). Bone marrow cells from patients with ALL in remission had a reduced natural cytotoxicity, 2.8 +/- 4.0 versus 16.3 +/- 9.0 in bone marrow controls (p = 0.01). In contrast, patients with ANLL in remission showed a normal bone marrow cytotoxicity (p greater than 0.05) while patients with active ANLL had a reduced NK cell activity (p less than 0.03). The low NK activity observed in leukemic patients may be of importance for the pathogenesis of the diseases. Acute non-lymphoid leukemia (ANLL) is a malignant disease of the multipotential hemapoietic stem cell. The stem cell is capable of differentiating into various cell lineages, i.e. erythroid, granulocytic, monocytic and megacariocytic cell lineages.(ABSTRACT TRUNCATED AT 250 WORDS)

Natural killer cells in chronic leukemia. Function and markers.

Twenty-two patients with chronic lymphocytic leukemia (CLL) and 14 patients with chronic myelogenous leukemia (CML) were studied with respect to natural killer (NK) cell activity and related cell markers (Leu 7 and Leu 11b). Significantly reduced NK cell activity was detected in peripheral blood from the patients with CLL. Similarly, a reduced number of cells with the markers Leu 7 and Leu 11b (CD 16) were detected in the same patients. Removal of the leukemic cells by centrifugation of cells forming rosettes with mouse erythrocytes led to an augmented, but not fully normalized, NK activity. This indicates that the low NK activity in CLL partly may be due to overgrowth of leukemic cells. However, in spite of the lymphocytic infiltration, the NK cell activity in the bone marrow of CLL patients did not differ significantly from that of normal controls. The patients with CML in the chronic phase as well as patients in the accelerated or blast phase also had a reduced NK activity. The finding that patients in the chronic phase had a reduced NK activity and normal numbers of Leu 11b (CD 16) positive cells, together with no detectable blasts in the peripheral blood, indicates that patients with CML may have an inherent NK cell defect. The highly reduced activity found in patients with the accelerated/blast form may in addition partly be due to overgrowth of leukemic cells. This low NK activity may be of importance in the development of chronic leukemia.

Decreased natural killer cell activity versus normal natural killer cell markers in mononuclear cells from patients with smouldering leukemia.

Peripheral blood (PB) and bone marrow mononuclear cells from 23 patients with smouldering leukemia were analyzed for natural killer (NK) cell activity and various surface cell markers. Significantly reduced NK activity was detected in the patients' PB compared with the activity in the healthy controls (p less than 0.0005). A similar difference in NK cell activity between the 2 groups was also observed in bone marrow mononuclear cells (p = 0.005). In contrast, no significant differences in cells positive for the NK cell markers Leu-7 and Leu-11b were found between patients and controls, either in PB or in bone marrow. The patients' PB and bone marrow mononuclear cells had, however, a reduced percentage and absolute number of Leu 3a+ and T8+ cells. Patients with smouldering leukemia have immunological derangements which may make them predisposed for the later development of florid leukemia.

Natural killer cell activity of peripheral blood and bone marrow mononuclear cells from patients with childhood acute lymphoblastic leukemia.

Patients with untreated acute lymphoblastic leukemia had highly significantly reduced natural killer cell activity in peripheral blood (p less than 0.01) and bone marrow (p less than 0.001) mononuclear cells compared with that in peripheral blood mononuclear cells in normal healthy controls. Patients in remission had normal killer cell activity (p greater than 0.5) both in peripheral blood and bone marrow mononuclear cells. Thus, the natural killer cell activity correlated well with the disease activity in the patients.