Infection in patients with systemic lupus erythematosus

1326

INFECTION IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

Association with a Serum Inhibitor of Complement-Derived Chemotactic Activity

H. DANIEL PEREZ, RICHARD I. ANDRON, and IRA M. GOLDSTEIN

We have found subnormal amounts of chemotactic activity in zymosan-treated sera from 13 of 29 patients with systemic lupus erythematosus (SLE). As an explanation for this abnormality, the presence of a uniquely specific, heat-stable inhibitor of complement (C5)derived chemotactic activity has been documented in sera from 11 of these patients. Sera from 2 other patients contained elevated levels of nonspecific, heat-labile chemotactic factor inactivator (CFI) activity. The serum from 1 patient contained the heat-stable inhibitor as well as elevated levels of CFI. Patients with SLE whose sera contained the heat-stable inhibitor had more active disease clinically, but otherwise they were indistinguishable from patients without the inhibitor. When patients with the heat-stable inhibitor improved clinically, this usually was accompanied by a decrease in serum inhibitory activity. Only one episode of bacterial infection was observed among 16 patients with SLE whose sera yielded normal amounts of chemotactic activity after treatment with zymosan. In contrast, 7 of 11 patients with SLE whose sera contained the heat-stable

From the Department of Medicine, Division of Rheumatol- ogy, New York University Medical Center, New York, NY 10016.

Supported by grants from the National Institutes of Health (AM-18531, AM-11949, GM-2321 I, and HL-19721). the National Foundation-March of Dimes, and the National Science Foundation

H. Daniel Perez, MD: Instructor in Medicine, recipient of NIAMDD Clinical Investigator Award (AM-00463); Richard I. Andron, MD: Fellow, Division of Rheumatology; Ira M. Goldstein, MD, FACP Associate Professor of Medicine, recipient of a Career Scientist Award from the Irma T. Hirschl Trust.

Address reprint requests to H. Daniel Perez, MD, Depart- ment of Medicine, New York University Medical Center, 550 First Avenue, New York, NY 10016.

Submitted for publication March 6, 1979; accepted in revised form July 14, 1979.

(76-0562 I).

inhibitor suffered serious bacterial infections. The presence of this heat-stable inhibitor in sera from some patients with SLE may contribute, in part, to their increased susceptibility to infection.

Patients with systemic lupus erythematosus (SLE) appear to be particularly susceptible to infections caused by common pyogenic microorganisms (1-4). Whereas modem therapy with adrenal corticosteroids is undoubtedly a contributing factor (3,4), there is some evidence that the disease per se is associated with abnormalities of host defenses against infection (4- 10). We have recently reported one such abnormality involving complement-derived chemotactic activity for polymorphonuclear leukocytes (PMN) (1 1). We found that sera from 5 of 11 patients with SLE, when activated with zymosan, failed to attract normal human PMN comparably to zymosan-activated control serum. In- cubation of normal PMN with sera from those patients did not affect either the random motility of the cells or their ability to respond to chemoattractants. Serum from 1 patient, however, did contain elevated levels of a previously described nonspecific, heat-labile chemotactic factor inactivator (CFI) (12). Sera from the other 4 patients contained a previously unrecognized inhibitor of complement-derived chemotactic activity. The inhibitor was heat-stable and uniquely specific. It acted reversibly only on chemotactic peptides derived from the fifth component of complement (C5). It had no effect on the chemotactic activity exhibited by various concentrations (all suboptimal) of either the bacterial chemotactic factor from Escherichiu coli or the chemotactic synthetic peptide, N-formylmethionylleucylphenylalanine. Too few patients were examined to de-

Arthritis and Rheumatism, Vol. 22, No. 12 (December 1979)

INFECTION IN SLE PATIENTS I327

termine whether the presence of this heat-stable inhibitor was associated with any specific clinical or laboratory parameters of disease activity. Consequently, we have extended our studies and now report findings in 29 patients with SLE.

MATERIALS AND METHODS Patient population. Twenty-nine patients with well

documented SLE who were followed by the Rheumatology Division at New York University Medical Center were studied. The only criteria used to select patients for study were the availability of samples of blood for laboratory testing and the absence of severe impairment of renal function (blood urea nitrogen greater than 35 mg/dl or serum creatinine greater than 2.0 mg/dl). The criteria for diagnosis of SLE were those of the American Rheumatism Association (13). The patients ranged in age from 18 to 56 years (mean 34 years) and all were women. Duration of disease ranged from 6 months to 23 years (mean 6 years). The extent of disease activity in these patients was assessed according to the criteria of Rothfield and Pace (14). Grade 0 was assigned to patients without clinical evidence of disease activity; Grade 1 to patients with disease activity involving one organ system without fever; Grade 2 to patients with active involvement of one system with fever or involvement of more than one system; and Grade 3 to patients with involvement of at least two systems with fever. Re- missions were classified as either partial or complete. Partial remission was defined as a transition from Grade 2 or Grade 3 disease activity to Grade 1. Complete remission corresponded to Grade 0.

Eighteen patients with rheumatoid arthritis (RA) were also studied. All were seropositive and met the criteria for the diagnosis of classic rheumatoid arthritis established by the American Rheumatism Association (15). There were 10 women and 8 men in this group, ranging in age from 42 to 65 years (mean 55 years). Duration of disease ranged between 1 and 21 years (mean 8 years). None of these patients had abnormal renal function and none was receiving therapy with corticosteroids.

Two additional groups of patients were studied. The first consisted of 17 patients admitted to New York University Medical Center for treatment of systemic bacterial infections. All infections were documented by blood cultures and were similar to those observed in patients with SLE. None of these patients had clinical or laboratory evidence of either rheu- matic or hematologic disease. There were 8 men and 9 women in this group, ranging in age from 23 to 80 years (mean 52 years). The second group included 21 healthy volunteers, 18 women and 3 men, ranging in age from 20 to 40 years (mean 29 years).

Preparation of leukocyte suspensions and sera. Hu- man PMN were isolated from venous blood by dextran sedimentation, as described previously (1 1). Cell pellets were washed once with isotonic saline and finally suspended in 10 mM phosphate-buffered saline (Grand Island Biological Co., Grand Island, New York) supplemented with 0.6 mM CaCl,, 1.0 mM MgCl,, and 2% (wt/vol) bovine serum albumin. This buffer was adjusted to pH 7.4 and was used throughout. Cell

suspensions contained approximately 85% PMN. Sera were obtained from clotted blood after centrifugation and either used fresh or stored in aliquots at -7OOC.

Chemotactic factors. Chemotactic activity was generated in sera by adding zymosan (1 .O mg/ml, ICN Nutritional Biochemicals Division, International Chemical and Nuclear Corp., Cleveland, Ohio) (1 1). After 15 minutes of incubation at 37OC, the zymosan-sera suspension was centrifuged at 3000g for 10 minutes, and the particle-free supernate was used directly (diluted with buffer as indicated for each experiment). Chemotactic activity in zymosan-treated sera is attributable primarily to C5-derived peptides (16). Partially purified C5- derived chemotactic peptides were isolated as previously described (1 1) by molecular sieve chromatography of zymosan- activated normal sera.

Other chemoattractants included the synthetic peptide, N-Formylmethionylleucylphenylalanine (N-formyl-met- leu-phe; Peninsula Laboratories, Inc., San Carlos, California) (17) and a bacterial chemotactic factor from E coli. The latter was prepared according to the method described by Ward et a1 (18).

PMN chemotaxis. PMN random motility and directed migration (chemotaxis) were assessed as desctibed previously (1 1) by employing the “leading front” method of Zigmond and Hirsch (19). Modified Boyden chambers containing cells and chemoattractants were incubated at 37°C for 45 minutes in an atmosphere of 5% C02 and 100% humidity. The response of PMN either to buffer alone (random motility) or to chemotactic stimuli was measured as the distance the leading front of cells migrated into the filter &m/45 minutes). Trip- licate chambers were employed in each experiment, and 10 fields were examined in each filter.

For experiments in which unactivated sera were added to the lower compartments of the modified Boyden chambers, concentrations were selected that did not by them- selves enhance PMN migration in excess of that observed when albumin-containing buffer was employed alone (20).

.

RESULTS Chemotactic activity in zymosan-treated SLE

serum. Sera obtained from 29 patients with SLE were activated with zymosan and examined for the presence of chemotactic activity. Zymosan-treated sera from 13 patients failed to attract PMN comparably to zymosan- treated normal sera (Table 1). Whereas it was possible that the subnormal amounts of chemotactic activity in zymosan-treated sera from these 13 patients resulted from abnormalities involving the complement system, this possibility was not explored further. We have dem- onstrated previously (1 1) that decreased chemotactic activity in some zymosan-treated SLE sera could not be attributed either to modestly depressed levels of serum complement or to failure of zymosan to activate the al- ternative complement pathway. Consequently, all sera were examined for the presence of heat-stable inhibitory activity directed specifically toward CS-derived

1328 PEREZ ET AL

Table 1. Decreased chemotactic activity in zymosan-treated SLE serum

Stimulus PMN migration m / 4 5 min)*

Buffer alone (random motility) Zymosan-treated normal sera? Zymosan-treated SLE sera:?

99.6 f 2.9 135.9 f 2.2

DS 113.5 f 1.6 LM 112.1 f 3.1 PG 107.3 f 2.7 RJ 106.0 * 2.0 LN 112.4 * 2.6 JH 114.5 f 2.8 EL 109.7 f 2.3 AJ 108.1 f 2.2 MC 109.5 f 2.3 cs 111.1 f 3 . 5 AT 110.2 f 2.0 MR 113.3 f 4.0 IV 123.4 f 3.6

* Results represent the mean f SEM of three experiments using

t Zymosan-treated sera were used at a concentration of 2.0% (vol/ polymorphonuclear leukocytes (PMN) from different normal donors.

vol).

chemotactic peptides as well as for elevated levels of heat-labile CFI activity. Fresh and heated (56°C for 30 minutes) sera were incubated with suboptimal concentrations of CS-derived peptides, the bacterial chemotactic factor from E cdi , and the chemotactic synthetic peptide, N-formyl-met-leu-phe. Heat-stable inhibitory activity directed specifically toward CS-derived chemotactic peptides was found in sera from 11 patients.

Heated sera from each of these patients inhibited the chemotactic activity generated in zymosan-treated normal serum (Table 2). Only 3 patients with SLE were found to have elevated levels of heat-labile CFI activity. Only unheated sera from these 3 patients inhibited the chemotactic activity of the bacterial factor and N-formyl-met-leu-phe (Table 3). Serum from 1 of these 3 patients also contained the heat-stable inhibitor. Neither the heat-stable inhibitor nor elevated levels of CFI activity (not shown) were detected in sera from 18 patients with RA, 17 non-SLE patients with systemic bacterial infection, or 2 1 healthy volunteers (Figure 1).

Clinical and laboratory findings in patients with SLE. The patients with SLE were divided into two groups based on whether their sera, after activation with zymosan, contained normal amounts of chemotactic activity (Table 4). Assignment to either group was determined by the results obtained by examining the initial sample of serum available from eeach patient. Both groups proved to be comparable in age and duration of disease. Furthermore, there were no significant differ- ences when erythrocyte sedimentation rates, levels of C3 and C4 (determined immunochemically) (21), and therapy with corticosteroids were compared. The two groups did differ, however, with respect to the clinical activity of their SLE. Based on the criteria of Rothfield and Pace (14), the SLE patients with abnormal chemotactic activity in their zymosan-treated sera also tended

Table 2. Effect of normal and SLE sera on C5-derived chemotactic activity

Stimulus PMN migration Percent inhibition of m / 4 5 min)* chemotactic activity?

Buffer alone (random motility) Zymosan-treated normal sera

+ heated normal serum$ + heated SLE serum:$

DS LM PG RJ LN JH EL AJ MC cs AT

100.1 f 1.3 137.0 f 2.0 136.1 f 3.1

116.4 f 1.1 111.1 f 3 . 7 110.8 f 4.0 106.0 f 2.4 116. I f 1.0 117.7 f 1.2 110.5 f 4.0 107.7 f 2.3 113.6 f 1.9 113.9 f 1.3 112.7 f 1.0

- - -

66.8% 70.0% 71.0% 83.8% 66.5% 52.2% 72.5% 79.2% 63.3% 62.5% 65.7%

* Results represent the mean f SEM of five experiments in which PMN from different normal donors was used.

t Net PMN chemotaxis (minus random motility) in the presence of SLE sera/net PMN chemotaxis in the presence of normal sera X 100.

$ Zymosan-treated sera were preincubated ( I : I, vol/vol) for 30 minutes at 37°C with heated (56OC for 30 minutes) normal or SLE sera. The final concentration of zymosan-treated sera was adjusted to 2.0% (vol/vol).

INFECTION IN SLE PATIENTS

-

1329

Table 3. Elevated levels of chemotactic factor inactivator (CFI) activity in sera from three patients with SLE

~ ~~

% inhibition of chemotactic activity by SLE sera?

Chemotactic stimulus* MR IV EL* Zymosan-treated normal sera (2.055, vol/vol)

+ SLE sera 35 34 63 + heated SLE sera None None 60$

Bacterial chemotactic factor (5.0%, vol/vol) + SLE sera 86 35 41 + heated SLE sera None None None

+ SLE sera 60 44 80 + heated SLE sera None None None

N-formyl-met-leu-phe (1 x lo-%)

Chemotactic stimuli were incubated with equal volumes of fresh or heated (56OC for 30 minutes)

t PMN chemotaxis @/45 min) in the presence of SLE sera/PMN chemotaxis @/45 min) in the

* Patient EL serum contained heat-labile CFI activity as well as the heat-stable inhibitor of CS-derived

SLE sera at 37°C for 30 minutes.

absence of SLE sera X 100.

chemotactic peptides.

to have more active disease clinically. Seven of 13 were assigned to Grade 3, 4 to Grade 2, and 2 to Grade 1. Seven of the 11 patients in this group whose sera contained the heat-stable inhibitor had Grade 3 clinical activity. One of the patients with heat-labile CFI activity

100 7

SLE (291

d K u M L Rheumatoid Arthr i t is (181

Figure 1. Presence of a heat-stable inhibitor of complement (CS)-derived chemotactic activity in sera from some patients with SLE. Zymosan-treated normal sera were incubated at 37°C for 30 minutes with equal volumes of heated (56°C for 30 minutes) SLE, non-SLE, RA, and normal sera. The final concentration of zymosan-treated sera was 2.0% (vol/vol). Results are expressed as percent inhibition of the chemotactic activity observed in zymosan-treated sera alone (see Table 2).

in the serum was classifled as having Grade 2 clinical activity, whereas the other 2 were assigned to Grade 1. In contrast, of the 16 patients with normal chemotactic activity in their zymosan-treated sera, only 3 fulfilled the criteria for Grade 3 activity. Twelve of these patients were classified as Grade 2 and l as Grade l. Only among the group of 11 patients with the heat-stable inhibitor was the incidence of Grade 3 clinical activity increased significantly (P ~0.05, chi-square analysis with Yates' correction) (22).

Serial determinations of inhibitory activity were performed in sera from 21 of the 29 patients with SLE. Interestingly, of 10 patients who were initially free of the heat-stable inhibitor, none was found to acquire the inhibitor despite changes in the activity of their disease (28 determinations in 10 patients). In contrast, in all of the patients in whom the heat-stable inhibitor was pres- ent initially, inhibitory activity either diminished markedly or disappeared completely when partial or complete remission of their disease was achieved (Fig- ure 2). Sera from patients with active disease (Grade 2 or 3) inhibited the chemotactic activity in zymosan- treated normal skra by 68.5 & 2.5%. This decreased to 21.2 f 15.6% with complete or partial remission (P ~0.01 , Student's t test). In 3 patients, maximum inhibitory activity appeared in sera within 1 week of an episode of infection and coincidentally with an exacerbation of their SLE. The inhibitor subsequently disappeared from the sera of these patients when their disease activity was controlled with corticosteroid therapy. Two of these patients were not receiving corticosteroids, and the third was receiving 20 mg of prednisone

1330 PEREZ ET AL

Table 4. Clinical and laboratory findings in patients with SLE

Chemotactic activity in zymosan-treated sera*

~~ ~

Abnormal Normal

Age, years 34.5 f 11.0 Duration of disease, years Erythrocyte sedimentation ratet Serum C3, mg/dl$ Serum C4, mg/dl$ Prednisone therapy, &day Disease activity (number of patients)

2.4 f 3.1 71.4 f 37.2 85.3 f 48.7 20.6 f 13.8 19.9 f 25. I

Grade 0 0 Grade I 2 Grade 2 4 Grade 3 7

Values are mean f SD. t Westergren (mm/hour). + Normal values for C3 = 93 f 21; C4 = 26 f 8.

34.6 f 10.7 4.1 f 4.9

59.9 f 36.8 82.0 f 36.7 3 I .3 f 22.4 3 I .2 f 23.9

0 I

12 3

daily when infection and maximum inhibitory activity were documented.

Elevated levels of heat-labile CFI activity in sera from 3 patients remained constant in multiple determinations and did not appear to correlate with either disease activity or episodes of bacterial infection. Inter- estingly, all 3 patients with elevated levels of CFI in their serum were anergic (23-26).

Incidence of infections. Episodes of bacterial infection were recorded in both groups of patients. All infections were documented clinically and by bacterio- logic cultures, and all responded to appropriate antimicrobial therapy. Presumed viral infections were not tabulated due to insufficient documentation by cul- ture or serology. Only those infections that occurred within 2 weeks of examining sera (initial or followup samples) for chemotactic activity were considered. Bac- terial infections were documented in 7 of the 13 patients whose sera yielded abnormal chemotactic activity after treatment with zymosan (Table 5) . Sera from all 7 patients contained the heat-stable inhibitor of C5-derived chemotactic activity. Serum from 1 patient also contained elevated levels of CFI (Table 3). Of these 7 patients, 3 were not receiving therapy with corticosteroids at the time that infection was documented. Two other patients were receiving less than 20 mg of prednisone daily, while the remaining 2 were receiving 40 mg and 60 mg of prednisone a day, respectively. No patients were receiving therapy with other immunosuppressive or cytotoxic agents. The 4 patients in this group in whom bacterial infections were not documented were receiving therapy with corticosteroids in doses ranging from 20 to 60 mg of prednisone daily. Serum levels of

complement (C3 and/or C4) were moderately reduced in only 3 patients at the time that infection was documented.

Only one episode of infection was recorded among the group of SLE patients whose sera contained normal chemotactic activity after treatment with zymosan (P <0.02, chi-square analysis with Yates' correction). A urinary tract infection developed in a patient receiving 60 mg of the prednisone daily as therapy for cutaneous vasculitis. All patients in the group with nor ma1 serum chemotactic activity were receiving corticosteroids at the time that the determinations were performed. Two were receiving less than 10 mg of prednisone a day, 3 were being treated with prednisone in doses ranging from 15 to 25 mg daily, and the remain- der were receiving greater than 30 mg of prednisone daily.

DISCUSSION We have found subnormal amounts of chem-

otactic activity in zymosan-treated &a from 13 of 29 patients with SLE. These results are remarkably similar to those reported previously by Clark et a1 (10). These investigators noted significantly reduced amounts of chemotactic activity in endotoxin-activated sera from 10 of 23 patients with SLE, and they suggested as one pos-

* >

V

c .- .- c

4

V

0 0

0

W c 0

0

c 0

.- c

c

E

.c

.- c .- 5 c c - c c 0) 0

aD 0

L

100 1

Part ia l or Active Disease Complete Remission

Figure 2. Relation between heat-stable inhibitory activity in SLE sera and degree of clinical disease activity. Assay conditions were the-same as those described in the legend of Figure I .

INFECTION IN SLE PATIENTS 1331

Table 5. SLE patients with abnormal chemotactic activity in zymosan-activated sera

Duration of Activity of Age, disease, disease, Prednisone, C3, a,

Patient years years grade mg/day mg/dl mg/dl Infection

DS 18 0.6 3 None 56 4 Streptococcus viridans septicemia LM 46 2 3 10 21 15 Listeria monocytogenes septicemia PG 28 5 3 60 100 39 Stophylococcus aureus septicemia RJ 28 1 3 None 31 4 Staphylococcus oureus cellulitis LN 49 1 3 40 154 32 Escherichio coli pyelonephritis JH 50 2 2 None 160 48 Diplococcus pneumonioe pneumonia EL* 41 2 3 20 144 20 Diplococcus pneumoniae pneumonia AJ 35 2 2 None 120 I4 None MC 23 I2 2 6 - - None cs 45 1.5 2 16 98 16 None AT 38 0.6 3 60 30 4 None MR* 22 2.5 I 2.5 100 24 None IV* 23 4 1 45 87 52 None

Serum contained heat-labile CFI activity EL serum and sera from the other patients contained the heat-stable inhibitor of C5-derived chemotactic activity.

sible explanation for this abnormality the presence in some SLE serum of either inhibitors or inactivators of chemotactic factors. We have found this explanation to be correct and have documented the presence in sera from 11 patients with SLE of a uniquely specific, heat- stable inhibitor of CS-derived chemotactic activity. As we have reported previously (1 l), this inhibitor does not affect the motility of normal PMN but acts reversibly on CS-derived peptides in such a fashion as to interfere with expression of chemotactic activity. We have suc- cessfully isolated and purified this inhibitor from the sera of several patients with SLE (27) and have found it to be a highly cationic protein with a molecular weight of 69,000, as determined by polyacrylamide gel elec- trophoresis. Its precise identity, however, is as yet un- known.

Sera from 3 patients with SLE were found to contain elevated levels of nonspecific, heat-labile chemotactic factor inactivator (CFI) activity (12). Serum from 1 patient contained the heat-stable inhibitor as well as elevated levels of CFI. Our assay conditions pre- cluded detection of minor elevations of normal serum CFI activity. Elevated levels of CFI activity have been reported previously in patients with sarcoidosis (23), Hodgkin's disease (24), hepatic cirrhosis (25), and lepromatous leprosy (26). Only incidentally have elevated levels been noted in patients with SLE (1 1,28). Neither the heat-stable inhibitor nor elevated levels of CFI activity were detected in sera from 21 healthy control sub- jects, 17 non-SLE patients with systemic bacterial infections, or 18 patients with RA. The patients with RA all had active polyarticular disease and were being treated only with nonsteroidal antiinflammatory agents. None

of these patients was febrile and none had prominent extraarticular manifestations of RA at the time of the study.

Patients with SLE whose sera contained the heat-stable inhibitor of CS-derived chemotactic peptides had more active disease clinically but otherwise were indistinguishable from patients without the inhibitor. When examined initially, the two groups were comparable with respect to age, duration of disease, serum levels of complement (C3 and C4), and therapy with corticosteroids. Although some patients in both groups had evidence of SLE nephritis, none was significantly azotemic at the time of the study. Abnormal gen- eration of chemotactic activity in sera from patients with renal failure has been reported previously (29). When the patients with the heat-stable inhibitor improved clinically (generally in response to therapy with corticosteroids), this usually was accompanied by a decrease in serum inhibitory activity. It is unclear why the converse was not observed in the group of SLE patients without the inhibitor. It is quite possible, however, that this occurred by chance alone since sera from only 10 patients in this group were examined serially (28 determinations). Furthermore, none of these 10 patients was examined when they had Grade 3 disease activity. It is not possible to conclude from these data whether changes in serum inhibitory activity were, in fact, mediated directly by therapy with corticosteroids or merely paralleled changes in clinical disease activity.

Complement-derived chemotactic peptides prob- ably are essential for normal host defenses against in- vading microorganisms (30,3 1). consequently, inhibitors or inactivators of such chemotactic peptides might

1332 PEREZ ET AL

be expected to affect host defenses adversely and thereby contribute to an increased susceptibility to bacterial infections. Our data suggest that this may be the case in some patients with SLE. We observed only one episode of bacterial infection among a group of 16 patients with SLE whose sera contained normal amounts of chemotactic activity after activation with zymosan. In contrast, 7 of 11 patients with SLE whose sera contained the heat-stable inhibitor of CS-derived chemotactic peptides suffered serious bacterial infections. Three of these patients were not receiving corticosteroids at the time that infection was documented, and 2 patients were receiving less than 20 mg of prednisone daily. These observations also are in accord with the findings of Clark et a1 (10) and support the suggestion made by others (4-9) that some patients with SLE have an increased susceptibility to bacterial infections inde- pendently of corticosteroid therapy. It should be noted that in 2 untreated patients with SLE, high levels of heat-stable inhibitory activity were detected initially in sera obtained one week prior to an episode of bacterial infection and coincidentally with an exacerbation of their primary disease. In both patients, serum inhibitory activity decreased markedly when the clinical activity of their SLE was subsequently controlled with corticosteroids.

Only 1 of 3 patients with elevated levels of heat- labile CFI activity became infected. Interestingly, this patient’s serum also contained the heat-stable inhibitor just prior to the time that infection was documented. When the clinical activity of her SLE was subsequently controlled with corticosteroids, heat-stable inhibitory activity disappeared from her serum while CFI activity remained unchanged.

It is not possible to establish conclusively in patients with SLE a direct relationship between increased susceptibility to bacterial infections and the presence in serum of inhibitors or inactivators of complement-derived chemotactic peptides. There are simply too many variables to be considered. Nevertheless, our data and the data of others (10,28) strongly suggest that such a relationship exists. Furthermore, it is likely that patients with SLE will be found to have other humoral and cel- lular defects involving host defense mechanisms that contribute to their altered susceptibility to infections caused by bacteria and fungi.

ACKNOWLEDGMENT We wish to thank Mr. Martin Tanner for performing

the antinuclear antibody and complement determinations.

REFERENCES 1. Dubois EL, Wierzchowiecki M, Cox MB, Weiner M: Du-

ration and death in systemic lupus erythematosus: an analysis of 249 cases. JAMA 227:1399-1402, 1974

2. Urowitz MB, Bookman AAM, Koehler BE, Gordon DA, Smythe HA, Ogryzlo MA: The bimodal mortality pattern of systemic lupus erythematosus. Am J Med 60221-225, 1976

3. Lee P, Urowitz MB, Bookman AAM, Koehler BE, Smythe HA, Gordon DA, Ogryzlo MA: Systemic lupus erythematosus: a review of 110 cases with reference to nephritis, the nervous system, infections, aseptic necrosis and prognosis. Quart J Med 18 1 : 1-32, 1977

4. Staples PJ, Gerding DN, Decker JL, Gordon RS: In- cidence of infection in systemic lupus erythematosus. Ar- thritis Rheum 17:l-10, 1974

5. Jasin HE, Orozco JH, Ziff M: Serum heat-labile opsonins in systemic lupus erythematosus. J Clin Invest 53:343- 353, 1974

6. Brandt L, Hedberg H: Impaired phagocytosis by periph- eral blood granulocytes in systemic lupus erythematosus. Scand J Haematol6:348-353, 1969

7. Landry M: Phagocyte function and cell-mediated immu- nity in systemic lupus erythematosus. Arch Dermatol

8. Zurier RB: Reduction of phagocytosis and lysosomal enzyme release from human leukocytes by serum from patients with systemic lupus erythematosus. Arthritis Rheum 19:73-78, 1976

9. Goetzl EJ: Defective responsiveness to ascorbic acid of neutrophil random and chemotactic migration in Felty’s syndrome and systemic lupus erythematosus. AM Rheum Dis 35510-515, 1976

10. Clark RA, Kimball HR, Decker J L Neutrophil chemotaxis in systemic lupus erythematosus. Ann Rheum Dis

11. Perez HD, Lipton M, Goldstein IM: A specilk inhibitor of complement (C5)-derived chemotactic activity in serum from patients with systemic lupus erythematosus. J Clin Invest 62:29-38, 1978

12. Berenberg JL, Ward PA: The chemotactic factor inactivator in normal human serum. J Clin Invest 52:1200- 1206, 1973

13. Cohen AS, Reynolds WE, Franklin EC, Kulka JP, Ropes MW, Shulman LE, Wallace SL: Preliminary criteria for the classification of systemic lupus erythematosus. Bull Rheum Dis 21:643-648, 1971

14. Rothfield NF, Pace N: Relation of positive LE cell prepa- rations to activity of lupus erythematosus and corticosteroid therapy. N Engl J Med 266535-538, 1962

15. Ropes MW, Bennett GA, Cobb S, Jacox R, Jessar RA: Revision of diagnostic criteria for rheumatoid arthritis. Arthritis Rheum 2:16-20, 1958

16. Goldstein I, Hoffstein S, G a b J, Weissmann G: Mecha-

113:147-154, 1977

33~167-172, 1974

INFECTION IN SLE PATIENTS 1333

nisms of lysosomal enzyme release from human leukocytes: microtubule assembly and membrane fusion in- duced by a component of complement. Proc Natl Acad Sci USA 702916-2920, 1973

17. Schiffmann E, Corcoran BA, Wahl SM: N-Formyl- methionyl peptides as chemoattractants for leukocytes. Proc Natl Acad Sci USA 79:1059-1062, 1975

18. Ward PA, Lepow IH, Newman LJ: Bacterial factor chemotactic for polymorphonuclear leukocytes. Am J Path01

19. Zigmond S, Hirsch JG: Leukocyte locomotion and chemotaxis: new methods for evaluation and demonstra- tion of a cell-derived chemotactic factor. J Exp Med 137:387410, 1973

20. Keller HU, Hess MW, Cottier H: The chemokinetic effect of serum albumin. Experientia 33: 1386-1387, 1977

21. Kohler PF, Muller-Eberhard HJ: Immunochemical quan- titation of the thud, fourth and fifth components of human complement: concentrations in the serum of healthy adults. J Immunol99:1211-1216, 1967

22. Mainland D: Elementary Medical Statistics. Second edi- tion. Philadelphia, W.B. Saunders Co., 1963, pp 218-240

23. Maderazo EG, Ward PA, Woronick CL, Kubik J, DeGr- aff AC: Leukotactic dysfunction in sarcoidosis. Ann In- tem Med 84:414419, 1976

24. Ward PA, Berenberg JL: Defective regulation of inflam-

52:725-736, 1968

matory mediation in Hodgkin’s disease: supernormal levels of chemotactic factor inactivator. N Engl J Med

25. Maderazo EG, Ward PA, Quintilliani R: Defective regulation of chemotaxis in cirrhosis. J Lab Clin Med 85:62 1- 630, 1975

26. Ward PA, Goralnick S, Bullock WE: Defective leukotaxis in patients with lepromatous leprosy. J Lab Clin Med

27. Perez HD, Goldstein IM, Andron R, Chernoff D: Mecha- nism of action of a specific inhibitor of complement (C5)- derived chemotactic activity in serum from patients with systemic lupus erythematosus. Clin Res 27:333A, 1979

28. Alvarez I, Vazquez JJ, Fontan G, Gil A, Barbado J, Ojeda J A Neutrophil chemotaxis and serum chemotactic activity in systemic lupus erythematosus. Scand J Rheumatol 7:69-74, 1978

29. Siriwatratananonta P, Sinsakul V, Stem K, Slavin RG: Defective chemotaxis in uremia. J Lab Clin Med 92402- 407, 1978

30. Rosenfeld S, Kelly ME, Leddy J P Hereditary deficiency of the fifth component of complement in man. I. Clinical, immunochemical and family studies. J Clin Invest

31. Johnston RB, Stroud RM: Complement and host defenses

290~76-80, 1974

87:1025-1032, 1976

57~1626-1634, 1976

against infection. J Pediatr 90169-179, 1977

Documents

Infection in patients with systemic lupus erythematosus