Natural cell mediated cytotoxicity in systemic lupus erythematosus

The significantly reduced natural killer (NK) cell activity was demonstrated in the peripheral blood lymphocytes (PBL) from 20 female patients with systemic lupus erythematosus (SLE) when compared with NK activity in the age and sex-matched controls. The reduced NK activity did not correlate with clinical parameters including daily prednisolone doses, serum CH50, antinuclear antibody titers, antiDNA activities, circulating immune complex levels, and cytotoxic activities of antilymphocyte antibodies (ALA). The effects of prednisolone and aggregated human IgG on NK activity were only slightly suppressive in the in vitro studies. When normal PBL were pretreated with rabbit complement and SLE sera containing ALA, the NK activity of the surviving cells was markedly decreased. The decrease was specific and did not seem to be due to the physical hindrance of the dead cells. Other heterologous ALA of rabbit origin did not exert a suppressive effect on NK activity. These results suggest that the suppressed NK activity in SLE can be ascribed to an antiNK cell specific antibody in lupus sera, although the participation of circulating immune complexes was not completely excluded.     

Familial juvenile systemic lupus erythematosus in Arab children

Aim of this study is to analyze the demographic, clinical, and biochemical features, and survival of familial juvenile systemic lupus erythematosus (FJSLE) in Arab children. The medical records of children with FJSLE seen at three pediatric rheumatology clinics in Saudi Arabia and Oman were retrospectively reviewed. All included children have met the following criteria: Arab ethnicity, definite diagnosis of SLE using the revised 1982 American College of Rheumatology classification criteria and family history of more than one affected sibling with SLE. The collected data included: gender, age at diagnosis, clinical and laboratory features at diagnosis. Unusual co-morbidity and mortality associated with the disease were studied. There were 50 children with FJSLE belonging to 18 families; the frequency of FJSLE in our cohort was 20.8%. The mean age at onset of SLE was 86?months (range, 18–168?months), while the mean age at diagnosis was 95?months (range, 24–192?months), and the mean duration of follow-up was 60.9?months (range, 7–132?months). The proportion of girls was predominant (78%). Autosomal recessive mode of inheritance was strongly suggested in number of our families. Mucocutaneous manifestations, arthritis, and nephritis were the most frequent features. Thirty-five patients had renal lesions, 18 of them had class IV nephritis according WHO classification. All patients were treated with different doses of steroid and immunosuppressive drugs; 37 (74%) patients received cyclophosphamide, and 6 patients treated with Rituximab. There were 5 patients required dialysis due to ESRD and 8 deaths related to SLE during the period of follow-up. FJSLE is not uncommon in our society. These findings may be helpful in identifying SLE patients with a stronger genetic predisposition; hopefully, one or more additional risk loci can be identified in multiplex Arab families that are different from what has been reported in other ethnic populations.     

Lymphocyte destruction by antibody-dependent cellular cytotoxicity mediated in vitro by antibodies in serum from patients with systemic lupus erythematosus.

Sera from patients with systemic lupus erythematosus (SLE) were tested for the presence of IgG antilymphocyte antibodies that are capable of mediating antibody-dependent cellular cytotoxicity (ADCC) of peripheral blood lymphocytes (PBL) from normal donors. The effector cells employed were PBL autologous with the target PBL. Positive ADCC responses were obtained with serum from 5 SLE patients with severe active diseases. It is possible that ADCC is a mechanism by which IgG antilymphocyte antibodies in patients with SLE may mediate in-vivo lymphocytolysis.     

Natural killer-cell-mediated and antibody-dependent cellular cytotoxicity in leprosy

We have assessed the natural killer (NK) cell-mediated cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) in the peripheral blood lymphocytes (PBL) from untreated lepromatous leprosy (LL) patients, LL patients on multidrug therapy (MDT) with favorable responses (MDT-R), LL patients clinically classified as nonresponders to MDT (MDT-NR), treated tuberculoid leprosy (TT) patients, and healthy donors. NK cytotoxicity was modulated by treating the PBL with recombinant interferon-alpha (IFN-alpha) and recombinant interleukin-2 (IL-2). The mean percent NK cytotoxicity of untreated LL patients (15 +/- 3), treated MDT-R patients (20 +/- 4), and treated MDT-NR patients (12 +/- 4) was significantly lower than that of TT patients (39 +/- 6) and healthy donors (37 +/- 5). Treatment of effectors with IL-2 or IFN-alpha enhanced NK cytotoxicity in 5 of 6 untreated LL patients, 6 of 6 treated MDT-R LL patients, 4 of 5 and 3 of 5 treated MDT-NR LL patients, respectively, and 5 of 8 and 3 of 8 treated TT patients, respectively. Although PBL from TT patients showed initial NK activity comparable to that of healthy donors, fewer TT patients showed modulation of NK activity by IL-2, and IFN-alpha to a lesser extent. The ADCC activity was lower in untreated LL patients compared to treated patients, while TT patients had normal ADCC activity. The results indicate that although LL patients show lowered spontaneous cytotoxicity, it can be modulated favorably by lymphokines.     

Macrophage activation syndrome in children with systemic juvenile idiopathic arthritis and systemic lupus erythematosus

Macrophage activation syndrome (MAS) is a hyper-inflammatory disorder secondary to a rheumatic disease such as systemic juvenile idiopathic arthritis (SJIA) and systemic lupus erythematosus (SLE). We aimed to present the characteristics of our pediatric MAS patients. Clinical features, laboratory parameters, treatment, and outcome of 34 patients (28 SJIA; six SLE; 37 MAS episodes) followed at a tertiary health center between 2009 and 2015 were retrospectively reviewed. The median age at MAS onset was 11 years. More SJIA patients had MAS at disease onset than SLE patients (53.6 vs. 16.7 %). Fever, high C-reactive protein and hyperferritinemia were present in all MAS episodes. Rash was less (p = 0.03), and fatigue was more frequent (p = 0.042) in SLE than SJIA patients. All received corticosteroids. Cyclosporine was given in 74.2 % of SJIA-MAS; 66.7 % of SLE-MAS episodes. Intravenous immunoglobulin, anakinra, or etoposide was administered during 67.7; 41.9; 32.3 % of SJIA-MAS and 33.3; 33.3; 50 % of SLE-MAS episodes, respectively. Plasmapheresis was performed during 41.9 % of SJIA-MAS and 33.3 % of SLE-MAS episodes. The mortality rate was 11.8 % (n = 4;3 SJIA, 1 SLE). Hepatosplenomegaly was more frequent (p = 0.005), and plasmapheresis was performed more frequently (p = 0.021) in the patients who died compared to the cured patients. The median duration between symptom onset and admission to our hospital was longer among the patients who died (16.5 vs. 7 days; p = 0.049). Our patients’ characteristics were similar to the reported cases, but our mortality rate is slightly higher probably due to late referral to our center. Early diagnosis and effective treatment are crucial to prevent mortality.     

Poor agreement of objectively measured and self-reported physical activity in juvenile dermatomyositis and juvenile systemic lupus erythematosus

To examine the agreement and association between objectively measured and indirectly assessed physical activity levels in patients with juvenile dermatomyositis (JDM) and juvenile systemic lupus erythematosus (JSLE) patients. The sample consisted of 19 JDM patients (age 8 to 22 years) and 20 JSLE patients (age 9 to 18 years). Physical activity level was objectively measured using Actigraph® accelerometers and indirectly assessed by the short-form International Physical Activity Questionnaire (IPAQ). Spearman’s correlation coefficients were calculated to test possible associations between physical activity levels across the two instruments. The Bland–Altman technique was used to calculate bias and limits of agreement. Correlations between objectively measured and indirectly assessed physical activity levels in JDM and JSLE were weak, varying from R?=?0.03 to R?=?0.33 (all p?>?0.05). Total physical activity was correlated between accelerometer and IPAQ in JSLE (R?=?0.51, p?=?0.021). Bland–Altman analyses suggested that IPAQ tended to highly underestimate sedentary time and light physical activity in JDM (mean bias 105.7 and 199.8 min, respectively) and JSLE (mean bias 36.4 and 127.8 min, respectively). Mean biases of moderate-to-vigorous physical activity were also highly variable, ranging from ?42.9 to 54.9 min and ?59.4 to 89.8 min for JDM and JSLE, respectively. IPAQ was shown to not be valid to assess physical activity levels in patients with JDM and JSLE when compared against accelerometry. While the validation of reliable self-reported instruments that measure physical activity in pediatric rheumatic patients remains necessary, the use of validated tools that objectively measure physical activity is recommended in both clinical and research settings.     

Macrophage activation syndrome in children with systemic lupus erythematosus and children with juvenile idiopathic arthritis

Objective

To describe patient demographics, interventions, and outcomes in hospitalized children with macrophage activation syndrome (MAS) complicating systemic lupus erythematosus (SLE) or juvenile idiopathic arthritis (JIA).

Methods

We performed a retrospective cohort study using data recorded in the Pediatric Health Information System (PHIS) database from October 1, 2006 to September 30, 2010. Participants had International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for MAS and either SLE or JIA. The primary outcome was hospital mortality (for the index admission). Secondary outcomes included intensive care unit (ICU) admission, critical care interventions, and medication use.

Results

A total of 121 children at 28 children's hospitals met the inclusion criteria, including 19 children with SLE and 102 children with JIA. The index admission mortality rate was 7% (8 of 121 patients). ICU admission (33%), mechanical ventilation (26%), and inotrope/vasopressor therapy (26%) were common. Compared to children with JIA, those with SLE had a similar mortality rate (6% versus 11%, respectively; exact P = 0.6). More patients with SLE than those with JIA received ICU care (63% versus 27%; P = 0.002), received mechanical ventilation (53% versus 21%; P = 0.003), and had cardiovascular dysfunction (47% versus 23% received inotrope/vasopressor therapy; P = 0.02). Children with SLE and those with JIA received cyclosporine at similar rates, but more children with SLE received cyclophosphamide and mycophenolate mofetil, and more children with JIA received interleukin‐1 antagonists.

Conclusion

Organ system dysfunction is common in children with rheumatic diseases complicated by MAS, and more organ system support is required in children with underlying SLE than in children with JIA. Current treatment of pediatric MAS varies based on the underlying rheumatic disease.

     

Natural killer activity and antibody-dependent cellular cytotoxicity in patients with non-Hodgkin's lymphoma

Natural killer (NK) activity and antibody-dependent cellular cytotoxicity (ADCC) of peripheral blood lymphocytes from untreated non-Hodgkin's lymphoma patients were found to be depressed, when tested against the human erythroblastoid cell-line K562. The percentage of active killer (AK) cells and that of target binding cells (TBC) of the patients were also inhibited. Treatment of the patients lymphocytes with interferon (IFN) caused an augmentation in their NK activity which was comparable with that seen in the controls. Lymphocytes from some of the patients and controls were cocultured with K562 cells for production of natural killer cytotoxic factors (NKCF). The NKCF released by the patients lymphocytes showed a reduced lytic activity against K562 target cells. The depression in all the activities reported here showed a correlation with the clinical status of the patients except in the case of ADCC. These results indicate that further characterization of the properties of NKCF will contribute the understanding of the mechanism of NK cytotoxicity.     

Kawasaki disease and juvenile systemic lupus erythematosus

Kawasaki disease (KD) is a common vasculitis in childhood. To the authors' knowledge, only one case of juvenile systemic lupus erythematosus (JSLE)-like onset mimicking KD and another case of KD and JSLE association have previously been described. However, the prevalence of this association of the two diseases was not reported. Therefore, over 27 consecutive years, 5419 patients were followed at the Pediatric Rheumatology Unit and 271 (5%) of them met the ACR classification criteria for JSLE. Two (0.7%) of them were female. These also had KD according to European League against Rheumatism / Paediatric Rheumatology European Society (EULAR/PReS) consensus criteria and are described in this report. One case was a 13-year-old who presented all six KD criteria. Echocardiogram showed pericardial effusion, dilatation and tortuosity of right and left coronary, and her symptoms promptly improved after treatment with intravenous immunoglobulin (IVIG). Lupus diagnosis was established a few days later. Another case was a 4-year-old who had also met all six KD criteria, with improvement after IVIG, and lupus diagnosis was made 1 year later. In conclusion, the frequency of the association between these two autoimmune diseases was rare. The occurrence of a second autoimmune systemic disease in a patient with a history of KD should also be considered. Furthermore, the initial presentation of lupus may mimic KD.     

Preliminary core sets of measures for disease activity and damage assessment in juvenile systemic lupus erythematosus and juvenile dermatomyositis

OBJECTIVE: To identify preliminary core sets of outcome variables for disease activity and damage assessment in juvenile systemic lupus erythematosus (JSLE) and juvenile dermatomyositis (JDM). METHODS: Two questionnaire surveys were mailed to 267 physicians from 46 different countries asking each member to select and rank the response variables used when assessing clinical response in patients with JSLE or JDM. Next, 40 paediatric rheumatologists from 34 countries met and, using the nominal group technique, selected the domains to be included in the disease activity and damage core sets for JSLE and JDM. RESULTS: A total of 41 response variables for JSLE and 37 response variables for JDM were selected and ranked through the questionnaire surveys. In the consensus conference, domains selected for both JSLE and JDM activity or damage core sets included the physician and parent/patient subjective assessments and a global score tool. Domains specific for JSLE activity were the immunological tests and the kidney function parameters. Concerning JDM, functional ability and muscle strength assessments were indicated for both activity and damage core sets, whereas serum muscle enzymes were included only in the activity core set. A specific paediatric domain called 'growth and development' was introduced in the disease damage core set for both diseases and the evaluation of health-related quality of life was advised in order to capture the influence of the disease on the patient lifestyle. CONCLUSIONS: We developed preliminary core sets of measures for disease activity and damage assessment in JSLE and JDM. The prospective validation of the core sets is in progress.     

Cardio-pulmonary involvement in juvenile systemic lupus erythematosus

Cardio-pulmonary manifestations of systemic lupus erythematosus (SLE) are well recognized in adults. We report the occurrence of clinically significant cardio-pulmonary disease in a cohort of predominantly Caucasian children with SLE. All children with SLE attending the Royal Liverpool Children's NHS Trust between 1995 and 2003 were reviewed. Of 29 children with SLE, 27 (93%) were Caucasian. Nine (31%) had cardio-respiratory complications: cardiac only (n = 1); respiratory only (n = 4); both cardiac and respiratory manifestations (n = 4). Median (range) duration of follow-up of affected children: four years (six months to 11 years). Six out of eight (75%) presented with respiratory complications before SLE was diagnosed. Three children had pericardial effusions, one requiring pericardiocentesis for tamponade. One had cardiac conduction defects and another significant pulmonary hypertension. Respiratory complications comprised: interstitial lung disease (n = 4), with two showing evidence of pulmonary fibrosis; pleural effusions (n = 2), pulmonary haemorrhage (n = 1) and lupus pneumonitis (n = 1). Disease course was complicated by CMV infection in one child. Lung biopsy was performed in five cases. Seven were treated with cyclophosphamide with significant improvement in symptoms/lung function. Of this predominantly Caucasian paediatric cohort with SLE, 31% had significant cardio-pulmonary involvement. All children with SLE should have regular monitoring of their cardio-respiratory status.     

Superoxide release in juvenile systemic lupus erythematosus

The objective of this study was to analyze the un-stimulated and stimulated release of superoxide anion (O₂ ^?) by granulocytes and monocytes in juvenile systemic lupus erythematosus (jSLE). The un-stimulated and phorbol myristate acetate (PMA, 30 nM)-induced O₂ ^?by granulocytes and monocytes were determined in six different times of incubation in patients with 23 jSLE and 28 controls. The analysis compared the jSLE group, which was classified into two subgroups by SLEDAI in one inactive subgroup (score <3) (n?=?13 patients) and one active subgroup (score ≥3) (n?=?10 patients) to the same control group. At time of blood withdrawal, 13 (56.52%) had inactive and 10 (43.47%) patients had active SLE. jSLE patients’ granulocytes and monocytes had always a lower un-stimulated O₂ ^? production when compared to controls. Stimulated granulocytes had an increased O₂ ^? production at baseline followed by a significant lower production at 60?min in jSLE when compared to controls. Stimulated monocytes had a similar O₂ ^? production among patients with jSLE and controls. The results suggest a defect in phagocytic function in jSLE. The significant higher release of O₂ ^? in the assays of the stimulated granulocytes, in the initial instances, the so-called respiratory burst, could be attributed to the inflammatory state of phagocytes.     

Bone status in juvenile systemic lupus erythematosus

Osteoporosis is a well-recognized major health problem in adult patients with systemic lupus erythematosus (SLE). Children and adolescents with SLE, however are at even higher risk of developing osteoporosis later in life, since they develop the disease before achieving peak bone mass, which serves as a 'bone bank' for the rest of life. There is still a paucity of studies on bone mass in pediatric SLE, but those studies available provide evidence of reduced bone mass in this age group. A frequency of osteopenia of 40% measured by dual energy X-ray absorptiometry at one or more skeletal sites has been reported, and the lumbar spine is most seriously affected. Peak bone mass seems to be lower in childhood-onset SLE patients compared to healthy controls, and there are no signs of catch-up of bone mass in young adult patients with a history of pediatric SLE. Glucocorticoid therapy has been found to have a major negative effect on bone mass in these patients, thus the importance of keeping corticosteroid doses down to the lowest possible dose whenever possible. Interestingly, studies of oral alendronate therapy in children with rheumatic childhood diseases have shown promising results with increases of 15-33% during one year of treatment with no major side effects reported. Finally, there is a hope that new biologic therapies, which are more specific and steroid-sparing, will also have a beneficial effect on bone health in SLE in the future.     

Outcome in juvenile onset systemic lupus erythematosus

PURPOSE OF REVIEW: Over the past 2 decades, there has been a marked improvement in survival among patients with juvenile-onset systemic lupus erythematosus. As a result of the increased life expectancy, children and adolescents with systemic lupus erythematosus are now faced with considerable morbidity resulting from sequelae of disease activity, side effects of medications, and comorbid conditions. This morbidity affects physical and psychosocial well-being. Therefore, the need is increasing for monitoring the development of irreversible organ damage and the effect of the disease and its treatment on daily life. This review summarizes the recent advances in the investigation on survival, accumulated damage, and health-related quality of life in patients with juvenile-onset systemic lupus erythematosus. RECENT FINDINGS: The 5-year survival rate of patients with juvenile-onset systemic lupus erythematosus approaches 100%, and the 10-year survival rate is close to 90%. The development of cumulative organ damage has been observed in 50-60% of patients. Children and adolescents with systemic lupus erythematosus have been found to have poorer health-related quality of life, particularly in the physical domain, and lower socioeconomic achievements than their healthy peers. SUMMARY: The prolongation of the life span of patients with juvenile-onset systemic lupus erythematosus has been accompanied by a substantial risk of damage accumulation and has not been paralleled by an improvement in health-related quality of life. This problem highlights the need of measuring cumulative organ damage and health-related quality of life in the long-term follow-up of patients with juvenile-onset systemic lupus erythematosus and of designing new treatments and treatment strategies that are aimed not only at improving control of disease activity but also at minimizing the development of nonreversible damage.     

Musculoskeletal sonography in juvenile systemic lupus erythematosus

Objective

To demonstrate the role of sonography in depicting periarticular changes in juvenile systemic lupus erythematosus (SLE) and to find out whether certain tendons in juvenile SLE patients were different from those of healthy controls.

Methods

Thirty juvenile SLE patients (27 female, 3 male) were recruited for this study. Sonographic evaluations were performed in the knee, ankle, elbow, wrist, and metacarpophalangeal (MCP) joints on the nondominant sides of the individuals. For comparison, 32 healthy volunteers were included as a control group.

Results

Knee effusion was observed more frequently in the juvenile SLE group compared with the control group (P = 0.00). When tendon thickness measurements were compared between the groups, flexor and extensor tendons of the third finger (at MCP joint level) of juvenile SLE patients were found to be thinner (P = 0.04 and P = 0.03, respectively). Tendon thickness values did not correlate with disease duration or SLE disease activity index scores (P > 0.05).

Conclusion

The main findings of our study were relevant with 1) increased involvement of the knee, ankle, hand extensor tendons, wrist, elbow, and hand flexor tendons (in decreasing order of frequencies) in juvenile SLE, and 2) decreased extensor/flexor tendon thicknesses in the hands of juvenile SLE patients. Physicians should be aware of the potentially disabling scenario of tendon pathologies. Defining the extent of joint and tendon pathologies in juvenile SLE may guide us in the management of the disease.