Clinical and antibody responses after influenza immunization in systemic lupus erythematosus.

After immunization with A/New Jersey/76 and A/Victoria/75 influenza vaccines, 11 patients with systemic lupud erythematosus were serially evaluated for changes in disease activity, serologic abnormalities, and their capability to generate specific antibodies. One patient, with active disease, developed a diffuse, proliferative glomerulonephritis. None of the other patients or control subjects had significant local or systemic side effects. Significant levels of antibodies were generated to A/New Jersey/76 in eight of the 11 patients and in seven of eight control subjects and to A/Victoria/75 in seven of 11 patients and five of eight control subjects. The geometric mean responses of both total and IgG antibodies to each viral antigen were no different in patients with systemic lupus erythematosus than in control subjects. In patients with stable systemic lupus erythematosus, immunization with killed influenza viral vaccine appears to be safe and effective.     

Influenzal vaccine response in systemic lupus erythematosus.

The response of patients with systemic lupus erythematosus and normal subjects to systemic immunization and boosting with influenza A vaccines was studied. Symptoms after vaccination were somewhat more frequent in the patients than in the normal subjects; however, all symptoms were minor and no major flare of illness occurred. No significant induction or increase of pre-existing autoantibodies among the patients was detected after vaccination. The immunogenecity of the vaccinations, as assessed by antibody titers, was similar in the patient and control groups. No correlation between serologic response to influenzal antigens and HLA was found. Thus, in this group of patients with systemic lupus erythematosus, who were either in remission or had mild-to-moderate disease activity, killed influenzal vaccination caused no apparent worsening of disease activity.     

Effect of Belimumab on Vaccine Antigen Antibodies to Influenza, Pneumococcal, and Tetanus Vaccines in Patients with Systemic Lupus Erythematosus in the BLISS-76 Trial

OBJECTIVE: In patients with systemic lupus erythematosus (SLE), evidence suggests that most vaccines (except live-virus vaccines) are safe, although antibody response may be reduced. This substudy from the phase III, randomized, double-blind, placebo-controlled BLISS-76 trial evaluated the effects of belimumab on preexisting antibody levels against pneumococcal, tetanus, and influenza antigens in patients with SLE. METHODS: In BLISS-76, patients with autoantibody-positive, active SLE were treated with placebo or belimumab 1 or 10 mg/kg every 2 weeks for 28 days and every 28 days thereafter, plus standard SLE therapy, for 76 weeks. This analysis included a subset of patients who had received pneumococcal or tetanus vaccine within 5 years or influenza vaccine within 1 year of study participation. Antibodies to vaccine antigens were tested at baseline and Week 52, and percentage changes in antibody levels from baseline and proportions of patients maintaining levels at Week 52 were assessed. Antibody titers were also assessed in a small number of patients vaccinated during the study. RESULTS: Consistent with preservation of the memory B cell compartment with belimumab treatment, the proportions of patients maintaining antibody responses to pneumococcal, tetanus, and influenza antigens were not reduced. In a small group receiving influenza vaccine on study, antibody responses were frequently lower with belimumab, although titer levels were > 1:10 in all patients treated with 10 mg/kg and in the majority treated with 1 mg/kg. CONCLUSION: Treatment with belimumab did not affect the ability of patients with SLE to maintain antibody titers to previous pneumococcal, tetanus, and influenza immunizations. [ClinicalTrials.gov registration number NCT 00410384].     

Comparison of responses to influenza A/New Jersey/76-A/Victoria/75 virus vaccine administered intradermally or subcutaneously to adults with chronic respiratory disease.

Serum HAI (hemagglutination inhibition) antibody responses were compared in two groups of 70 age-matched patients (age range, 17 to 82 years) who were vaccinated with bivalent influenza A/New Jersey/76-A/Victoria/75 whole-virus vaccine. The group that was vaccinated intradermally received 40 chick cell-agglutinating units of each viral antigen in 0.1 ml, and the group that was vaccinated subcutaneously received 200 chick cell-agglutinating units of each antigen in 0.5 ml. The serum HAI antibody response to A/New Jersey/76 antigen was significantly higher in the group that was vaccinated subcutaneously; this difference was particularly evident in patients less than or equal to 50 years old. The serologic response to A/Victoria/75 antigen did not differ significantly between the two groups. Levels of antibody before vaccination indicated previous widespread exposure of patients to influenza A/Victoria/75 virus, but not to influenza A/New Jersey/76 virus. Such differences in prior immunologic experience with a particular strain of influenza virus probably determine whether the intradermal route of vaccination is as effective as, or inferior to, the subcutaneous route.     

Hydralazine therapy in hypertensive patients with idiopathic systemic lupus erythematosus

Seven hypertensive patients with idiopathic systemic lupus erythematosus were treated with hydralazine. They received a mean daily dose of 203 mg for a mean duration of 21 months. All were taking prednisone alone or in combination with azathioprine. During therapy with hydralazine, there were no new symptoms nor exacerbation of pre-existing symptoms attributable to systemic lupus. Laboratory parameters, including antinuclear antibody titers and complement levels, either improved or remained stable. The results indicate that hydralazine can be safely used in hypertensive patients with systemic lupus who are receiving concomitant immunosuppressive therapy.     

Abnormalities in the content of nucleic acids of peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Relationship to dna antibodies

We have completed 59 cytofluorographic studies of DNA/RNA content in acridine orange-stained peripheral blood mononuclear cells from 44 patients with systemic lupus erythematosus, most of whom received no medications. Most such cells were in resting phases of the cell cycle, particularly those from patients with inactive disease. Nine patients with systemic lupus erythematosus had increased percentages of these cells in the synthesis and postsynthesis phases of the cell cycle; the B lymphocytes had the greatest proportions of activated cells. In 11 patients, we found that cells, particularly T lymphocytes, had increased RNA content without a proportional increase in DNA. This DNA block occurred primarily in patients with serum antibodies to DNA and it could be reproduced in normal mitogen-stimulated mononuclear cells incubated in heat-inactivated sera from patients with systemic lupus erythematosus whose own cells showed abnormalities of DNA/RNA content or in purified native DNA antibody. The DNA blocking potential of the DNA antibody was dependent on its Fc portion and on the presence of Fc receptors on T cells. Thus, saturation of Fc receptors by pretreatment with aggregated IgG or incubation with the whole antibody in the cold prevented the DNA block, indicating that it was an active process.     

Plasmapheresis in systemic lupus erythematosus. a cautionary note

Plasmapheresis was used as the sole treatment modality in 4 patients with systemic lupus erythematosus. The presence of circulating immune complexes in this group of patients was not predictive of response to plasmapheresis. Lymphocytotoxic antibody levels fell in 3 of the 4 patients, and no consistent changes in T lymphocytes, T lymphocyte subsets, complement, or immunoglobulin levels were observed. Followup during the subsequent 6 months showed deterioration in clinical and laboratory parameters in all 4 patients, and the protocol was discontinued. Plasmapheresis without concomitant therapy may be detrimental to certain patients with systemic lupus erythematosus.     

Specific antibody response after influenza immunization in systemic lupus erythematosus

OBJECTIVE: To determine the efficacy of influenza virus vaccine in patients with systemic lupus erythematosus (SLE). METHODS: The study population comprised 24 patients with SLE who received the split-virion, inactivated vaccine containing 15 micro g hemagglutinin (HA)/dose of each of A/Beijing/262/95(H1N1), A/Sydney/05/97(H3N2), and B/Harbin/07/94. Hemagglutination inhibition (HI) antibodies were tested using the HI test according to a standard World Health Organization procedure. Immune response was defined as 4-fold or greater rise in HI antibodies 6 weeks after vaccination. Geometric mean titers (GMT) were calculated to assess the immunity of the whole group. RESULTS: All patients were women. Prior to vaccination, the percentage of SLE patients with protective levels of HI antibodies and the GMT of HI antibodies were similar to those of age matched healthy women. Six weeks after vaccination, 75% of the patients had immune response to at least one of the 3 antigens; 58.3% and 62.5% of the patients responded to A/Sydney/05/97(H3N2) and B/Harbin/07/94, respectively. However, only 37.5% of the patients responded to A/Beijing/262/95(H1N1). Six weeks after immunization, the SLE patients generated immune response against a mean number of 1.5 of the 3 influenza vaccines. There was a trend toward a lower immune response in patients with age > or = 50 years, prednisone dosage > or = 10 mg daily, and who used azathioprine. However, methotrexate therapy was not associated with decreased response. CONCLUSION: The immune response to influenza vaccine of patients with SLE is lower than that seen in adults in the general population, in particular among older patients and those treated with immunosuppressive therapy.     

Incomplete lupus erythematosus

Thirty-eight patients with incomplete lupus erythematosus (ILE) (defined as the presence of fewer than four of the criteria of the American College of Rheumatology for systemic lupus erythematosus [SLE]) were identified and compared with 42 patients with SLE. Both groups were comparable with respect to age, sex, and race. Patients with ILE had symptoms for an average of 38 months before seeking rheumatologic care and were followed up for a mean of 19 months; patients with SLE averaged 9 months with symptoms before their diagnosis was made and were followed for a mean of 30 months. Characteristic clinical features of patients with ILE included positive antinuclear antibody titers (83%), polyarticular nonerosive arthritis (47%), and cutaneous findings (61%). These were comparable with findings in the the SLE group. However, patients with ILE had significantly fewer systemic manifestations than did those with SLE. Patients with ILE were treated with nonsteroidal anti-inflammatory drugs more frequently (47%) than were patients with SLE, while the latter group received more topical and oral corticosteroids and immunosuppressives. Only two of the patients with ILE went on to have typical SLE. Thus, ILE may be frequent, mild, and relatively stable or benign, apparently evolving slowly if at all into SLE or other rheumatic disease.     

Occlusion of small hepatic veins associated with systemic lupus erythematosus with the lupus anticoagulant and anti-cardiolipin antibody

We report the case of a woman with lupus anticoagulant-positive systemic lupus erythematosus who developed small hepatic vein occlusion. Since the age of 34, she had been known to have hepatomegaly. A definitive diagnosis of systematic lupus erythematosus was made eight years later. Histological evaluation of the liver biopsy specimen was not fully diagnostic of prominent hepatomegaly during this period. Occlusion of the small hepatic veins was confirmed by hepatic venography, but the lumen of the large hepatic veins showed a smooth appearance. The lupus anticoagulant and anti-cardiolipin antibody were both positive. Since a high incidence of thromboembolic diseases in patients with the lupus anticoagulant or anti-cardiolipin antibody has been reported, the presence of this type of anticoagulant may provide an explanation for hypercoagulability and subsequent development of hepatic vein thrombosis in this patient. This is the first report of a patient with systemic lupus erythematosus who developed an occlusion of small hepatic veins attributable to the lupus anticoagulant and anticardiolipin antibody. This case suggested that a systematic search for hepatic vein occlusion should be made in patients with systemic lupus erythematosus who have developed inexplicable hepatomegaly, especially in those with positive tests for the lupus anticoagulant and/or anti-cardiolipin antibody.     

Efficacy of influenza vaccine among geriatric inpatients: effect of previous vaccination and antibody induction by single and twice injections

To investigate the effect of previous influenza vaccination and the difference in antibody induction by single and twice injection of influenza vaccine in the elderly, hemagglutination inhibition (HI) antibody titers of the three types of influenza viruses were measured. Influenza vaccination was done for 217 inpatients. For the patients who had influenza vaccination in the year prior to the study, influenza vaccine was administered once to 77 patients and twice to another 70 patients. Influenza vaccine was injected twice to 70 patients who had not received influenza vaccine in the previous years. The influenza vaccine induced an increase in HI titer in almost all patients. The geometric mean of the HI titer and the frequency of patients with HI titers over 128x were similar after vaccination in the groups of patients who were injected twice, irrespective of whether or not influenza vaccination was given in the year prior to the study. The geometric means of the HI titers for influenzas A/H3N2 and B and the frequency of HI titers over 128x for influenza A/H3N2 after vaccination were lower in the patients who received vaccine once than in the patients vaccinated twice. These results suggest that prior vaccination does not diminish antibody response to influenza vaccine significantly in the elderly when influenza vaccine is injected twice. Although single injection is inferior to twice injection in antibody induction with some vaccine virus strains, induction of HI titers over 128x is found in more than 70% of elderly. Single injection of influenza vaccine may be practically effective and useful for protection of influenza infection in the elderly.     

Clinical features of Sjögren’s syndrome associated with recurrent annular erythema

Our objective was to describe the clinical features of Sjögren’s syndrome (SS) with recurrent annular erythema which resembles subacute cutaneous lupus erythematosus (SCLE), and determine a possible association of anti-SS-A/Ro and/or SS-B/La antibody titers with the episodes of cutaneous manifestation. Recurrent annular erythema was observed in 4% (six patients; five females and one male) of our 143 patients diagnosed as primary SS. All the patients developed annular erythema on the facial area as their initial manifestation when they were between 21 and 31 years old. They had few subjective sicca symptoms, but both anti-SS-A/Ro and SS-B/La antibodies were positive and parotid sialography showed typical findings for SS (subclinical SS). Parotid gland swellings had developed in five of the patients during their follow-up periods, (3–12 years). In addition to the facial area, most patients repeated the cutaneous episodes on extremities and palmar, plantar or auricular areas. Skin biopsy was performed in three patients and the common findings were mononuclear cell infiltrations in the dermis with few epidermal changes. Transient leukopenia (four patients), low titers of anti-DNA antibodies (one patient) and chronic false-positive results of serological tests for syphilis (one patient) were observed. Two of our patients, therefore, temporarily fulfilled four items of the ARA classification criteria for systemic lupus erythematosus (SLE), if their facial erythema was considered as malar rash. Serum antibodies to 52 kDa SS-A/Ro peptides (80%) were more frequently detected in the five patients examined by enzyme-linked immunosorbent assays (ELISA), compared with those to 60 kDa SS-A/Ro peptides (40%). Furthermore, we could serially determine serum anti-SS-A/Ro and SS-B/La antibody titers in three patients by using ELISA for 3 or 4 years. Annular erythema usually developed when the antibody titers became relatively high and disappeared after the treatment with oral prednisolone which suppressed the antibody titers. We could observe five pregnancies in our three patients and all the patients developed annular erythema during their pregnant periods. Their five infants, however, were free from any complications such as neonatal lupus erythematosus and congenital heart block. We conclude that annular erythema is a rare manifestation of SS and develops in relatively young patients who are subclinical for sicca symptoms. The cutaneous episodes seemed to relate with anti-SS-A/Ro and/or SS-B/La antibody titers. Some of the erythema observed in SS patients may belong to SCLE, but they do not usually develop typical SLE. The possibility that SS may be more frequent in the SCLE patients remains to be determined.     

Serum thrombomodulin and anticardiolipin antibodies in patients with systemic lupus erythematosus.

Since thrombomodulin (TM) is a specific cell surface glycoprotein for vascular endothelial cells, serum TM (s-TM) might be a useful marker of endothelial cell damage. Antiphospholipid antibodies (aPL) frequently detected in systemic lupus erythematosus (SLE) have been associated with vascular occlusive diseases. Therefore we measured the s-TM in 60 patients with SLE, in 23 patients with other diseases including aPL (disease control group) and in 26 healthy subjects, by means of an enzyme immunoassay using monoclonal antibodies to human TM. A significant positive correlation was found between s-TM and serum creatinine levels in SLE patients (r = 0.813, p less than 0.001). When the s-TM level was divided by the serum creatinine level (TM/Cr) to exclude the effect of renal clearance, the TM/Cr ratios were significantly increased in SLE patients with active lupus nephritis (LN) compared to those without LN (p less than 0.05). The ratios did not correlate with the presence of aPL or antiphospholipid antibody syndrome (APLS) in SLE patients or in the disease control group, although a weak correlation between the TM/Cr ratios and IgG-anticardiolipin antibody titers was found in the SLE patients without LN (r = 0.449, p less than 0.01). The present results suggest that elevated TM/Cr ratios reflect renal and possibly extra-renal endothelial cell damage in SLE patients with active LN, but that s-TM levels do not associate with the presence of aPL or a history of APLS.     

Partial purification and characterization of plasma DNA and its relation to disease activity in systemic lupus erythematosus

This study reports the partial isolation and characterization of plasma DNA by phenol extraction and concentration of the extract. DNA, identified by immunologic and chemical methods, was found in plasma from both normal persons and patients with systemic lupus erythematosus in amounts varying from 0.004 to 0.4 μ/ml. The DNA was predominantly of low molecular weight, approximating 100 to 200 base pairs. Patients with lupus tended to have higher concentrations of plasma DNA than normal persons, with considerable overlap between the groups. Plasma DNA concentrations correlated inversely with titers of antibody to DNA but not strongly enough for prediction of either variable in individual cases. Many patients had high levels of plasma DNA and its antibody without clinical nephritis. These results indicate the ubiquity of plasma DNA and suggest the necessity of factors other than mere presence of DNA and its antibody for initiation of glomerular damage in systemic lupus erythematosus.     

Occlusive vasculopathy in systemic lupus erythematosus. Association with anticardiolipin antibody

Patients with systemic lupus erythematosus and with antiphospholipid antibody are subject to sudden occlusion of multiple blood vessels. We describe two patients with systemic lupus erythematosus with acute, catastrophic, widespread non-inflammatory visceral vascular occlusions associated with high-titer antiphospholipid antibody. The histopathologic features clearly distinguished these patients from classic systemic lupus erythematosus vasculitis. We further suggest that, based on a probable pathogenesis related to the presence of antiphospholipid antibody, and based on the non-inflammatory vascular occlusion, steroids and other immunosuppressive medications are of limited value. Plasmapheresis along with anticoagulant therapy should be considered.     

Antinuclear antibody in pericardial fluid from a patient with primary cardiac lymphoma

Pericarditis may be the initial manifestation of systemic lupus erythematosus. Although it is known that antinuclear antibody can be detected in the serum of patients with a wide variety of diseases, it has been proposed that the detection of antinuclear antibody in serosal fluid is a sensitive and specific test for determining that effusions are due to systemic lupus erythematosus. A case is presented in which antinuclear antibody in high titer was identified in the pericardial fluid of a patient who was found at autopsy to have a primary cardiac lymphoma. The case indicates that antinuclear antibody detected in serosal effusions should not be considered pathognomonic for systemic lupus erythematosus.     

Abnormalities in the content of nucleic acids of peripheral blood mononuclear cells from patients with systemic lupus erythematosus

We have completed 59 cytofluorographic studies of DNA/RNA content in acridine orange-stained peripheral blood mononuclear cells from 44 patients with systemic lupus erythematosus, most of whom received no medications. Most such cells were in resting phases of the cell cycle, particularly those from patients with inactive disease. Nine patients with systemic lupus erythematosus had increased percentages of these cells in the synthesis and postsynthesis phases of the cell cycle; the B lymphocyte had a greatest proportions of activated cells. In 11 patients, we found that cells, particularly T lymphocytes, had increased RNA content without a proportional increase in DNA. This DNA block occurred primarily in patients with serum antibodies to DNA and it could be reproduced in normal mitogen-stimulated mononuclear cells incubated in heat-inactivated sera from patients with systemic lupus erythematosus whose own cells showed abnormalities of DNA/RNA content or in purified native DNA antibody. The DNA blocking potential of the DNA antibody was dependent on its Fc portion and on the presence of Fc receptors on T cells. Thus, saturation of Fc receptors by pretreatment with aggregated IgG or incubation with the whole antibody in the cold prevented the DNA block, indicating that it was an active process.     

Peripheral vascular disease in patients with systemic lupus erythematosus.

Patients with systemic lupus erythematosus may develop premature atherosclerosis, notably coronary artery disease. A group of 10 patients with peripheral vascular disease presenting with intermittent claudication or gangrene were studied from a group of 563 patients followed prospectively at the Wellesley Hospital Lupus Clinic. These 10 patients were compared with the next lupus clinic patient matched for age and sex, with respect to demographic characteristics and risk factors. The patients and controls did not differ significantly in lupus activity criteria count, partial thromboplastin time, the number with antibody to cardiolipin, number receiving steroids or mean steroid dose, family history of atherosclerosis, hyperlipidaemia, smoking, hypertension or use of oral contraceptives. The risk factors for developing peripheral vascular disease were a longer duration of systemic lupus erythematosus and a longer duration of use of steroids. Eight of the 10 patients had coexistent coronary artery disease or transient ischaemic attack.     

High titer of antibody to the Epstein-Barr virus membrane antigen in sera from patients with rheumatoid arthritis and systemic lupus erythematosus

Sera from patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) contained more antibody to the Epstein-Barr virus membrane antigen (EBV MA) than sera from healthy controls. Since antibody titer to EBV MA closely correlates with viral neutralization, it was inferred that these patients were frequently exposed to infectious EBV, producing high titers of neutralizing antibody.     

Studies of cell‐mediated immune responses to influenza vaccination in systemic lupus erythematosus

Objective

Both antibody and cell‐mediated responses are involved in the defense against influenza. In patients with systemic lupus erythematosus (SLE), a decreased antibody response to subunit influenza vaccine has been demonstrated, but cell‐mediated responses have not yet been assessed. This study was therefore undertaken to assess cell‐mediated responses to influenza vaccination in patients with SLE.

Methods

Fifty‐four patients with SLE and 54 healthy control subjects received subunit influenza vaccine. Peripheral blood mononuclear cells and sera were obtained before and 1 month after vaccination. Cell‐mediated responses to A/H1N1 and A/H3N2 vaccines were evaluated using an interferon‐γ (IFNγ) enzyme‐linked immunospot assay and flow cytometry. Antibody responses were measured using a hemagglutination inhibition test.

Results

Prior to vaccination, patients with SLE had fewer IFNγ spot‐forming cells against A/H1N1 compared with control subjects and a lower frequency of IFNγ‐positive CD8+ T cells. After vaccination, the number of IFNγ spot‐forming cells increased in both patients and control subjects, although the number remained lower in patients. In addition, the frequencies of CD4+ T cells producing tumor necrosis factor and interleukin‐2 were lower in patients after vaccination compared with healthy control subjects. As expected for a subunit vaccine, vaccination did not induce a CD8+ T cell response. For A/H3N2‐specific responses, results were comparable. Diminished cell‐mediated responses to influenza vaccination were associated with the use of prednisone and/or azathioprine. The increase in A/H1N1‐specific and A/H3N2‐specific antibody titers after vaccination was lower in patients compared with control subjects.

Conclusion

In addition to a decreased antibody response, cell‐mediated responses to influenza vaccination are diminished in patients with SLE, which may reflect the effects of the concomitant use of immunosuppressive drugs. This may render these patients more susceptible to (complicated) influenza infections.