IMPAIRED RESPONSE TO PNEUMOCOCCAL VACCINE IN SYSTEMIC LUPUS ERYTHEMATOSUS

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1 1287 IMPAIRED RESPONSE TO PNEUMOCOCCAL VACCINE IN SYSTEMIC LUPUS ERYTHEMATOSUS MARK P. JARRETT, GERALD SCHIFFMAN, PETER BARLAND, and ARTHUR I. GRAYZEL An immunization program with pneumooal vaine was arried out in 38 patients with systemi lupus erythematosus (SLE). Mean antibody levels at 1 month and 1 year were signifiantly lower than in normal ontrols. This dereased response did not orrelate with drug therapy at the time of immunization. Other parameters suh as anergy state, renal funtion, and serum immunoglobulin levels also did not orrelate with antibody response. There were no adverse effets noted in the vainated group in omparison to mathed nonvainated SLE patients. Previous studies of the in vivo response to antigeni stimulation in SLE patients have demonstrated hyperresponsiveness (5,6), hyporesponsiveness (7-lo), and no differene in response in omparison to normal ontrols (1 1-15). Early investigators felt there was danger in immunizing this patient population, although reent reports have not supported this view. Finally, it has not been learly shown how drug therapy and disease ativity may alter the immune response of SLE patients. Our immunization program with Pneumovax vaine was designed to help larify these issues. At the present time, infetion is a leading ause of morbidity and mortality in patients with systemi PATIENTS AND METHODS lums ervthematosus (SLE) 1 ). Immunosumressive Thirty-eight patients who met at least four Amerian I \ I I. therapy is only Partially responsible; untreated patients Rheumatism Assoiation (ARA) riteria for SLE (16) and who were being followed in the Lupus Clini at Montefiore are also at risk (2,3)' Although opportunisti Hospital and Medial Center agreed to vaination, and inorganisms are frequently found, the greatest threat re- formed onsent was obtained. Another 23 Datients who remains the ommon infetious agents (4). In view of this fused vaination served as ontrols for disease ativity during risk. a Drogram of immunization of SLE Datients with the postvaination period. The normal ontrol population I L V pneumooal vaine (Pneumovax) was undertaken. ons&ed of 17 healthy volunteers used in a previous study (17). Five healthy volunteers from our laboratory were also studied. A summary of the linial and laboratory data of the From the Division of Rheumatology, Department of Mediine, Montefiore Hospital and Medial Center, Albert Einstein Col- SLE patients is presented in Table 1. Mild disease ativity was lege of Mediine, Bronx, New York; and the Department of Miro- defined as the new onset of skin rash, alopeia, arthritis, or biology and Immunology, Downstate Medial Center, Brooklyn, New oral ulers. Major disease ativity was defined as serositis, York. unexplained fever, entral nervous system disease, or evidene Supported in part by NIH training grant #AM7273 and a of newly ative lupus nephritis. No patient had evidene of grant from the New York Chapter of the Arthritis Foundation. major disease ativity at the time of immunization. Similarly, Mark P. Jarrett, MD: Montefiore Hospital and Medial Cen- no patient had ative nephritis when vainated, but 24 had ter; Gerald Shiffman, PhD: Downstate Medial Center; Peter Bar- evidene of renal disease as defined by proteinuria (>.3 gm/ land, MD: Montefiore Hospital and Medial Center; Arthur I. Gray- 24 hours), dereased reatinine learane, or an abnormal zel, MD: Montefiore Hospital and Medial Center. Address reprint requests to Arthur I. Grayzel, MD, Division renal biopsy. of Rheumatology, Montefiore Hospital and Medial Center, 1 I1 East The vaine (Merk, Sharp and Dohme, West Point, 21 Street, Bronx, NY NY) was a 14-valent preparation of purified pneumooal Submitted for publiation April 21, 198 aepted in revised apsular polysaharide ontaining the following Danish form June 18, 198. types: 1, 2, 3,4,6A, 7F, 8,9N, 12F, 14, 18C, 19F, 23F, and 25. Arthritis and Rheumatism, Vol. 23, No. 11 (November 198)

2 1288 JARRETT ET AL Table 1. Clinial and serologi data of study patients* Vainated SLE Non-vainated SLE Number Sex 37F/lM 22F/lM Mean age Disease inative Disease mildly ative LO 6 Renal disease Hypoomplementemia 8 13 Elevated antidna 1 2 antibody level No mediations 5 3 Prednisone alonet 29 ( 14 mg/day) 11 (15 mg/day) Prednisone/ azathioprinet 9 (2 mg/78 mg) 9 (16 mg/18 mg) * Normal ontrols = 17 (mean age = 32). t Mean dose per day. Eah patient reeived.5 ml of the vaine subutaneously, whih delivered 5 pg of apsular polysaharide per pneumooal type. Patients underwent routine history and physial examination at the time of immunization. Subsequent evaluations were performed at 4-week intervals for a total of 24 weeks. The following laboratory parameters were followed during this period: hematorit, leukoyte ount with differential, platelet ount, erythroyte sedimentation rate, serum reatinine, antidna antibody level (nitroellulose membrane filtration method), total hemolyti omplement (CH5), and urinalysis. Serum immunoglobulins were quantitated by radial immunodiffusion at the time of vaination. Delayed hypersensitivity was evaluated by skin tests with purified protein derivative (PPD) 5 tuberulin units (TU) and streptokinase-streptodornase. Patients had antibody levels determined prevaination, and 4 weeks and 1 year after vaination. Serum antibodies to 12 polysaharide types were measured by a ra- dioimmunoassay method previously desribed (1 8). Radiolabeled I4C apsular polysaharides were prepared biosynthetially and diluted to give a solution ontaining 2, pm/ml. Twenty-miroliter aliquots of serum were mixed with.5 ml(l,ooo pm) of the labeled antigen and inubated for 15 minutes at 37 C. The antigen-antibody omplexes were preipitated by adding.5 ml of ammonium sulfate saturated at 37 C followed by entrifuging at 27,OOOg at 4 C for 15 minutes (Farr tehnique). The resulting pellet was resuspended in 5 pl of 1% aqueous Triton X-1 (Rohm & Haas Co., Philadelphia, Pennsylvania), 1 ml sintillant added, and the ativity measured in a liquid sintillation ounter. Speifi dilutions of a standard rabbit antiserum of known antibody ontent were treated in the same way. A urve was onstruted by plotting the ounts per minute in exess of a blank sample ontaining no antibody against the amount in nanograms of antibody nitrogen added. Nanograms of antibody nitrogen per milliliter (ng AbN/ml) in test sera were measured by referene to the standard urve. Eah assay inluded ontrol tubes ontaining aliquots of the referene antibody as well as tubes ontaining labeled antigen only. The within-assay oeffiient of variation of standard samples measured repeatedly was 2.1% to 4.3% over the range of onentrations assayed. Streptoous pneumoniae isolates were typed by using Danish antisera and subtyped with radioimmunoassay inhibition tehnique. Beause immunoglobulin and antibody levels generally have a log-gaussian distribution, individual data were onverted to logarithms to ompare geometri means, as in Table 2. Arithmeti means listed in the text are followed by their estimated standard deviations. Signifiane, unless stated, was determined by Student s t-test. RESULTS Antibody response to vaination. Geometri mean antibody levels to the 12 different pneumooal apsular polysaharides before and after immunization Table 2. Geometri mean antibody levels in SLE and normal ontrol subjets Normal ontrol subjets* SLE patients* Pneumooal Pre- 1 month post- Pre- 1 month post- P apsular type immunization immunization immunization immunization valuet , to , ,819 NS 4 1,129 3, ,615 t.5 6A 162 1,226 I to.1 7F to.oo , to.1 9N NS 12F NS , ,58 t.5 18C 554 1, t.1 19F NS 23F 1,9 5, ,45 to.o1 * Values given are ng antibody N/ml serum. t Comparison of normal ontrol subjets and SLE patients 1 month post-immunization levels. NS = not signifiant at the.5 level.

3 PNEUMOCOCCAL VACCINE IN SLE E \ z 2 > 15 ') 9 a, W -J ') e 5 I" n.17 n= I7 I Normal Controls n=5 5 Pro-Immunization Levels Post-Immunization Levels (One Month) E3 One Year Post-Immunization SLE Figure 1. Mean antibody levels of SLE patients versus normal ontrols pre-immunization, 1 month and 1 year post-immunization. are shown in Table 2. Pre-immunization antibody levels were signifiantly lower in SLE patients than in normal ontrol subjets for pneumooal types 6A,7,8, 12F, 18,19,23 (P value at least <.5). Post-immunization antibody levels at 1 month were far lower in SLE patients than in normal ontrol subjets for serotypes 1,4, 6A,7,8, 14,18C,23F (P value at least <.5). The mean antibody level to all 12 types measured was signifiantly lower in SLE patients (918 k 45 ng AbN/ml) in omparison to the normal ontrol subjets (1,787 f 694 ng AbN/ml, P.1 (Figure 1). This depressed response was also found in omparison to the normal ontrol populations omposed of our own laboratory personnel (1,87 1 ng AbN/ml). The data were also analyzed in terms of how often vaination ahieved a 2-fold (1%) inrease in type-speifi antibody levels. Inreases in antibody levels of less than 2-fold may be insuffiient to protet against pneumooal infetion. Fourteen of 17 ontrol subjets had greater than 2-fold inreases to at least 8 of 12 pneumooal serotypes, while 28 of 38 SLE patients had similar antibody inreases (no signifiant differene by hi square analysis). Fators affeting antibody response. The SLE patients were divided into the following three treatment groups: Group I, those reeiving less than 2 mg/day of prednisone (mean dose = 6.7 -e 6.2); Group 11, those reeiving more than 2 mg/day of prednisone (mean dose = 28.7 & 11.8); Group 111, those reeiving both prednisone and azathioprine (mean dose = 2. -e 21.1 prednisone, 77.8 k 29.2 azathioprine). The antibody response of these three groups are presented in Figure 2. All three had signifiantly lower mean post-immunization antibody levels than normal ontrol subjets. However, there was no signifiant differene between the three treatment groups in antibody response. Five patients in group I were on no treatment at the time of immunization. If they are onsidered a separate ategory, their mean post-immunization antibody level (1,29 f 472 ng AbN/ ml) is higher than that of groups I1 or I11 (P.5), but far below that of normal ontrol subjets. It has been well doumented that SLE patients are often hypergammaglobulinemi. Seventeen of the vainated patients with SLE had elevated levels of either IgG or IgM. There was no signifiant differene in antibody response between this group and the 13 SLE patients with normal levels of serum immunoglobulins (Table 3). Although there have been some reports to the ontrary, it is now apparent that patients with SLE frequently have impaired delayed hypersensitivity (19, 2). Eighteen of 3 vainated patients tested had impaired delayed hypersensitivity at the time of immunization, a proportion similar to that found in previous reports. 2 - E i n=17 Pre-Immunization Level Post -Immunization Level \ (One Month) z 6 15 e Group I II a r m n=16 n= ll nn ) > J 5 a f Normal SLE SLE SLE Controls Prednisone Prednisone Prednisone t <2rng/doy >2mg/day Azothioprine Figure 2. Relationship of antibody response to therapy at 1 month post-immunization.

4 129 JARRETT ET AL Table 3. Fators affeting antibody response 1 month post-immunization No. level Fator patients (ng AbN/ml) Serum immunoglobulin level Normal k 38 Inreased f 43 Delayed hypersensitivity Normal f 418 Impaired f 282 Renal status No renal disease f 313 Renal disease* f 447 Creatinine mg/dl 6 1,23. f 47 Proteinuria (> 3 mg/24 hrs) f 417 No proteinuria f 419 * Ative urinary sediment, proteinuria, abnormal reatinine learane, or abnormal renal biopsy. There was no differene in antibody response between the patients with normal and impaired delayed hypersensitivity. At the time of immunization, 24 patients had evidene of renal disease. Their post-immunization antibody level was not different from the SLE patients without evidene of nephritis. In fat, the 6 patients who had a serum reatinine level of >IS mg/dl had a slightly higher antibody post-immunization level than the mean for all SLE patients. Proteinuria (>.3 gm/24 hours) was present in 12 patients, but their response was not different from those without proteinuria. Disease ativity (inative versus mild) did not alter antibody response (data not shown). Eight patients were hypoomplementemi (<I5 p/ml) at the time of vaination, but their antibody response was similar to those patients with normal CH5. There was no orrelation between patient age and antibody response. Twelve-month antibody levels. In order to further assess the antibody response of this group, serum samples were obtained 1 year after vaination in 31 of 38 vainated patients. Their 1-year mean level of ng AbN/ml was omparable to their 1 -month post-immunization level. Only 4 of the 3 1 patients had an antibody titer hange of more than 5% versus their I-month level. Only one of these patients had a rise in antibody level, and her I-year level was far below the mean of all SLE patients. Two others had a fall in antibody level below their preimmunization level. Both of these patients had major linial flares during the year neessitating major immunosuppressant therapy. One-year antibody levels in 5 normal ontrols from our labora- tory were still signifiantly higher than the SLE patients (1,34 ng AbN/ml, P <.5). Clinial effets of vaination. It has been reported that up to 86% of normal subjets have at least a loal reation to vaination with pneumooal polysaharides (2 1). Severe febrile reations are fortunately extremely rare. It is interesting that less than 5% of the SLE patients reported any side reations, and only 3 reported a low grade fever lasting less than 48 hours. Reations were not onfined to patients in the low dose prednisone group. During the 6-month period following immunization, 3 of 38 vainated SLE patients had a major linial flare. One patient developed myoarditis 3 weeks post-immunization and expired from left ventriular failure 1 week later. A seond patient developed persistent fevers and entral nervous system disease approximately 3 months post-immunization. She died 3 months later from Gram negative sepsis. The third patient, who was on no treatment at the time of vaination, developed a rash, nephroti syndrome, and azotemia 9 weeks post-immunization. This patient responded to steroid and azathioprine therapy. In the non-vainated SLE ontrol group, 2 patients developed evidene of a major linial flare in this time period. One patient developed ative nephritis and the seond a severe hemolyti anemia. There were two deaths in the vainated group (vide supra). The one death in the non-vainated SLE group was seondary to aute pneumooal meningitis. The organism was serotype 14, a type proteted by the vaine. The patient had a serum level of 183 ng AbN/ml approximately 1 month before she died. There was no differene in the number of minor flares between the two groups. As seen in Table 4, there was no signifiant differene in CH5 or antidna antibodies between vainated and nonvainated SLE patients pre- and 6 months post-immunization. Similarly, there was no differene in hematorit, serum reatinine, or erythroyte sedimentation rate. DISCUSSION The pneumooal vaine was developed and liensed in the late 194s. Due to the simultaneous widespread use of peniillin, however, interest in this vaine waned, and it was withdrawn from the market by 195. In reent years, the emphasis on preventive mediine has brought about a redevelopment of this and other vaines for patient populations with hroni illness. Patients with SLE both on and off therapy are

5 PNEUMOCOCCAL VACCINE IN SLE 1291 Table 4. The effet of vaination on serologi and linial parameters in SLE Vainated SLE Nonvainated SLE Pre Post* Pre Post* Mean 177 f f f f 55 Mean anti-dna antibody C C & k.86 Mean serum reatinine (mddl) 1.8k C.64.96k.29.98k.31 Mean hematorit 38.2 f k f f 4.3 ESR (Westergren) 36 k f k f 26 * Six months post-immunization prone to infetions, and prophylaxis with a safe and effetive vaine is indiated. For this reason, we immunized all willing SLE patients with the pneumooal vaine, Pneumovax, a dodeavalent vaine. The effetiveness of the immunization program ould not be predited from earlier studies of in vivo antigeni stimulation of SLE patients. Using baterial antigens, Lee et a1 (22), Meiselas et a1 (1 l), and Sarkan (12) demonstrated a response omparable to those of normal ontrols. Zinagle et a1 used blood group substanes to demonstrate an inreased antibody response in SLE patients (5). Stevens et al had similar results with Vi antigen (6). Baum and Ziff, using Bruella antigen as a stimulus, found that SLE patients had a redued antibody response, espeially in the IgM fration (8). In 1978, there were several reports on influenza vaination in SLE patients. While Brodman et a1 (14) and Louie et a1 (1 5) found their SLE patients had normal antibody responses, Williams et a1 (9) and Ristow et a1 (1) demonstrated hyporesponsiveness. Our data learly demonstrate that SLE patients have a redued antibody response to pneumooal apsular polysaharides. Klippel et a1 at the National Institutes of Health vainated 2 SLE patients with pneumooal vaine (23). Their study involved patients on less than 25 mg per day of prednisone and none on immunosuppressants. They found both pre- and post-immunization antibody levels were signifiantly lower than normal healthy ontrols. In fat, their 1-month postimmunization level (1,45 ng AbN/ml) was very similar to ours (9 18 ng AbN/ml). In ontrast, their patients had greater responses to immunization in terms of the ratio of post- to pre-immunization onentrations. In a 1- month followup, they found no untoward effets of vaination on their patients. There are several possible explanations why SLE patients have a diminished antibody response. Theoretially, drug therapy plays a major role. In vitro studies have shown that steroids lower the immune response to antigeni stimulation (24). When the antibody response in our vainated patients was analyzed on the basis of their treatment, there was no signifiant differene between patients on low dose prednisone and patients on prednisone and azathioprine. The 5 patients reeiving no therapy, however, had a higher post-immunization antibody level, albeit still lower than normal ontrols. Renal transplant patients, who are often on similar doses of prednisone and azathioprine, have been found to have a normal antibody response to pneumooal vaination (25). Thus drug therapy plays a role in antibody response but is not the sole ause of the diminished response. It has been shown that SLE patients make an exess amount of immunoglobulins, and that in some patients a large proportion of these may be autoantibodies (26). There was no orrelation of antibody response with the level of antiena or antidna antibodies. On the other hand, it has been postulated that the hypergammaglobulinemia in SLE is seondary to an abnormally high response to ommon antigens. This is supported by studies showing high antibody levels to various viral and baterial antigens (27,28). The vainated SLE patients, however, did not differ in antibody response, no matter what their level of immunoglobulins. A possible ause of the low antibody levels in the SLE patients is inreased atabolism of immunoglobulins. Levy et a1 demonstrated a dereased half-life of IgG in 1 SLE patients in omparison to normal ontrols (29). Turnover of IgM, however, was normal. Response in mie to pneumooal apsular polysaharides is predominately IgM (3), and therefore, it is important to determine whih lass of immunoglobulin responds in humans. In view of the low serum onentrations of pneumooal antibody in the SLE group with hypergammaglobulinemia, it seems unlikely that

6 1292 JARRETT ET AL even with inreased turnover of IgG these SLE patients had an inreased rate of pneumooal speifi antibody synthesis. Although response to baterial polysaharides had been onsidered a pure B ell funtion, it is now apparent that in mie T helper and T amplifier ells are needed for an adequate response (3 1). Delayed hypersensitivity to intradermal antigens, a rude measure of T ell funtion, was impaired in more than one-half of the SLE patients. The defet did not orrelate with an altered antibody response. Further researh will be neessary to pinpoint the immune defet resulting in this impaired antibody response of SLE patients. A final explanation for a dereased response in SLE patients is that they are suffering from a hroni disease and therefore are not able to mount an effetive immune response. Studies of pneumooal vaination in patients with other hroni diseases suh as sikle ell anemia do not demonstrate a similar diminished response (32). The question of whether SLE patients ahieve a protetive level of immunity to pneumooal infetion is diffiult to answer. It is not lear at this time what is a minimal antibody level for protetion against the pneumoous. Moreover, it is apparent that antibody level by itself is not the sole determinant of protetion. Polymorphonulear ell response and other fators must be adequate in order to defend against infetion. Thus, only a prospetive long-term followup of these patients will demonstrate if the vaine has been effetive. Sine Ayvazian s report of SLE developing in student nurses following multiple vainations, there has been a fear of immunizing SLE patients (33). Although there is an inreased risk in immunizing immunosuppressed patients with a live vaine, no lear demonstration of any risk from the killed vaines in SLE has been reported. Reent studies suh as with the influenza vaine have not shown any inrease in the number of flares or side effets. Our data support this view. Only one vainated patient developed a linial flare in the first month following immunization. It is diffiult to impute vaination as responsible for the flares 2 or more months later. In addition, our patients had no inreased inidene of side reations to the vaination. In onlusion, SLE patients vainated with a pneumooal vaine demonstrate a dereased antibody response in omparison to normal ontrols. This diminished response is only partially due to drug therapy with steroids and azathioprine. Despite this lower response, these patients seem to ahieve a protetive antibody level. Finally, the vaine appears to be safe in this patient population. ACKNOWLEDGMENT The authors wish to thank Mrs. Lynne Enoh for her expert manusript preparation. REFERENCES 1. Ropes MW: Observations on the natural ourse of disseminated lupus erythematosus. Mediine 43: , Myers AR, Mills JA, Ropes MW: The problem of infetion in systemi lupus erythematosus. Arthritis Rheum 1:3-38, Staples PJ, Gerding DW, Deker JL, Gordon RS: Inidene of infetion in systemi lupus erythematosus. Arthritis Rheum 17:l-1, Carpenter RR, Sturgill BC: The ourse of systemi lupus erythematosus. J Chron Dis 19: , Zinagle SB, Sanhez Avalos JC, Andrada JA, Stringa SG, Manni JA: Appearane of antioagulant fators and ertain autoimmune antibodies following antigeni stimulation with blood group substanes in patients with systemi lups erythematosus. Arthritis Rheum 6: , Stevens MB, Urowitz MB, Mulhern LM, Shulman LE Response to immunization in systemi lupus erythematosus. Arthritis Rheum 1:317, Baum J: Hyporeativity to an exogenous antigen in systemi lupus erythematosus. Arthritis Rheum 1: , Baum J, Ziff M: Dereased 195 antibody response to baterial antigens in systemi lupus erythematosus. J Clin Invest 48: , Williams GW, Steinberg AD, Reinersen JL, Klassen LW, Deker JL, Dolin R: Influenza immunization in systemi lupus erythematosus-a double blind trial. Ann Intern Med 88: , Ristow SC, Douglas RG, Condemi JJ: Influenza vaination of patients with systemi lupus erythematosus. Ann Intern Med 88: , Meiselas LE, Zingale SB, Lee SL, Rihman S, Siegal M: Antibody prodution in rheumati diseases: the effet of bruella antigen. J Clin Invest , Sarkan I: Cirulating antibody formation in lupus erythematosus. Arh Dermatol 84: , Abe T, Homma M: Immunologial reativity in patients with systemi lupus erythematosus. Ata Rheum Sand 17:3546, Brodman R, Gilfillan R, Glass D, Shur P: Influenza vaine response in systemi lupus erythematosus. Ann Intern Med 88:735-74, Louie JS, Nies KM, Shoj KT, et al: Clinial and antibody responses after influenza immunization in systemi lupus erythematosus. Ann Intern Med 88:79-792, Cohen AS, Reynolds WE, Franklin EC, et a1 Preliminary riteria for the lassifiation of systemi lupus erythematosus. Bull Rheum Dis 21: , Minor DR, Shiffman G, MIntosh LS: Response of pa-

7 PNEUMOCOCCAL VACCINE IN SLE 1293 tients with Hodgkin's disease to pneumooal vaine. Ann Intern Med 9: , Shiffman G, Austrian R: A radioimmunoassay for the measurement of pneumooal apsular antigen antibodies thereto. Fed Pro 3:658, Horowitz DA: Impaired delayed hypersensitivity in systemi lupus erythematosus. Arthritis Rheum 15: , Hahn BH, Bagby MK, Osterland CK: Abnormalities of delayed hypersensitivity in systemi lupus erythematosus. Am J Med , Hales K, Barriere SL: Polyvalent pneumooal vaines: a review. Am J Hosp Pharm 36: , Lee SL, Meiselas LE, Zingale SB, Rihman R: Antibody prodution in systemi lupus erythematosus and rheumatoid arthritis. J Clin Invest 39:15, Klippel JH, Karsh J, Stahl NI, Deker JL, Steinberg AD, Shiffman G: A ontrolled study of pneumooal polysaharide vaine in systemi lupus erythematosus. Arthritis Rheum 22: , Faui AS, Dale DC, Balow J E Gluoortiosteroid therapy: mehanism of ation and linial onsiderations. Ann Intern Med 84:34-315, Dailey MP, Shiffman G, Piering WF, Hoffman RG, Rytel MW: Polyvalent pneumooal vaine in renal allograft reipients and dialysis patients (abstrat). 1 lth International Congress of Chemotherapy. Boston, Maddison PJ, Reihlin M: Quantitation of preipitating antibodies to ertain soluble nulear antigens in SLE. Arthritis Rheum 2:s , Phillips PE, Christian CL: Virus antibodies in systemi lupus erythematosus and other onnetive tissue diseases. Ann Rheum Dis 32:45-456, Rothfield NF, Evans AS, Niederman JC: Clinial and laboratory aspets of raised virus antibody titers in systemi lupus erythematosus. Ann Rheum Dis 32: , Levy J, Barnett EV, MaDonald NS, Klinenberg J R Altered immunoglobulin metabolism in systemi lupus erythematosus and rheumatoid arthritis. J Clin Invest 49:78-715, Baker PJ, Stashak PW: Quantitative and qualitative studies on the primary antibody response to pneumooal polysaharide at the ellular level. J Immunol 13: , Markham RB, Stashak PW, Presott B, Amsbaugh DF, Baker PJ: Sensitivity of amplifier T ells involved in the antibody response to type I11 pneumooal polysaharide to antilymphoyte serum. J Immunol 119: , Ammann AJ, Addiego J, Wara DW, Lubin B, Smith WB, Mentzer WC: Polyvalent pneumooal-polysaharide immunization of patients with sikle-ell anemia and patients with splenetomy. N Engl J Med 297:897-9, Ayvazian LF, Badger TL: Disseminated lupus erythematosus ourring among student nurses. N Engl J Med , 1948 Pratial Neurology, and Metabolism and Endorinology The University of Washington will hold a seminar in Pratial Neurology and one in Metabolism and Endorinology February 21-28, 1981 in Hawaii. For further information ontat Continuing Medial Eduation, University of Washington, Seattle, WA 98195, or all (26)