Plasmapheresis therapy of immunologic disease

Report of nine cases and review of the literature

Leonard H. Calabrese, D.O. J o h n D. Clough, M.D.

Department of Rheumatic and Immunologic Diseases Department of Immunopathology

Randa l l S. Krakauer , M.D.

Department of Rheumatic and Immunologic Diseases

Department of Immunology

Gerald A. Hoeltge, M.D. Department of Blood Banking and Hematology

T h e term plasmapheresis (removal of p lasma with or wi thout replacement with physiologic so-lutions) was first used in 1914 by Abel et al1 in their pape r "P lasma removal with re turn of corpuscles," which was an account of their a t t emp t to develop an artificial kidney. Modern experience with plas-mapheresis began in the early 1950s when the technique was used to remove a b n o r m a l p lasma protein in a pat ient with mul t ip le myeloma. 2 In the early 1960s, the procedure was successfully em-ployed to t reat the clinical manifestat ions of hyper-viscosity in a pat ient with Waldens t rom's macro-globulinemia.3

In the past decade, great advances have been m a d e in the technique of p lasma exchange, a n d the scope of diseases t reated with this me thod has broadened greatly. In theory, any disease in which a humora l phase is impor tan t in pathogenesis m a y be at least part ia l ly mit igated by removal of pa-tients' p lasma and subsequent replacement wi th another physiologic solution. Th is the rapy might benefit pa t ients with either of two types of immu-nologic disease: tha t media ted by an t ibody (either blocking or cytotoxic) or that media ted by circulat-ing i m m u n e complexes (CIC) or both . W e report our experience in t reat ing nine pat ients with a n u m b e r of different disease states, all of whom had

53

54 Cleveland Clinic Quarter ly

elevated CIC levels. Included are dy-namic da ta concerning the effects of plasma exchange on levels of CIC.

Methods

Assays

1. CICs were determined by Clq binding as described by Zubler et al.4

Results are expressed in units (1 unit = amount of Clq bound by 0.1 fig aggre-gated IgG). T h e upper limit of normal for the assay is 120 uni ts /ml . This value is the mean Clq binding plus two stan-dard deviations of sera from 20 normal volunteers.

2. Rheumatoid factor (RF) was de-termined by nephelometric assay (LAS-R, Hyland) (normal, < 10 uni ts /ml) .

3. Plasma volume was calculated by using established normal values for total blood volume (expressed in ml/kg) mi-nus the patient 's red cell volume deter-mined by hematocrit immediately be-fore plasmapheresis. Example:

Normal (male) total blood volume (TBV) - 66 to 100 ml /kg

Normal (female) T B V - 63 to 85 m l / kg-

For a 70-kg male with hematocrit , 40%, estimated plasma volume:

T B V (range) X weight - T B V (range) X hematocrit

(66 to 100) ml /kg X 70 kg - (66 to 100) ml /kg X 40%

(4620 to 7000) ml - (2640 to 4000) ml = 2000 to 3000 ml.

4. Clearance of CIC (actual). T h e clearance of CIC following the first plas-mapheresis was calculated by the for-mula :

estimated plasma volume (ml) X (CIC concentration [preexchange] uni ts /ml — CIC concentration [postexchange] units /ml)

5. Clearance of CIC (theoretical).

Vol. 47, No. 1

T h e clearance of a given substance (e.g., CIC) via plasmapheresis, when consid-ered as a function of volume alone, would logically depend on the fraction of plasma volume removed per ex-change. T h e fractional rate of exchange can be calculated using the following equation:

volume exchange/hour r =

plasma volume

• (equation 1)

If the plasma volume is considered a closed system from which a known vol-ume of fluid is removed simultaneous with replacement by the same volume of fluid lacking immune complexes, the concentration of C I C remaining (x) after a given volume of exchange is given by the equation:

x = xoe~" (equation 2)

where xo is the original concentration of CIC, r is the fractional rate of exchange and t is the durat ion of the exchange in hours. From this expression, a family of curves can be generated predicting the effect of a given volume of plasma ex-changed on the C I C level of a patient with any given plasma volume.

Procedure

All patients studied had significantly elevated CIC levels. Each plasma ex-change consisted of removal of 2 L of the patient 's plasma and simultaneous replacement with an equal volume of solution consisting of 50% purified pro-tein fraction and 50% normal saline with acid citrate dextrose solution. Seven of the nine patients received three daily plasma exchanges, one received two daily exchanges, and one received one exchange (Table I). Wherever pos-sible, blood was obtained immediately before and af ter each plasma exchange

Plasmapheresis therapy in immunologic disease 55 Summer 1980

for determination of CIC and RF. Con-comitant therapy and postplasmapher-esis therapy are outlined in Table 2.

Results

1. Effect of plasmapheresis on CIC. In the eight patients treated with two or more plasma exchanges, CIC levels fell from a mean of 970 ± 178 uni ts /ml (SEM) to a mean level of 190 ± 44 uni ts /ml (Fig. I). Follow-up da ta were available for seven of these eight pa-tients. At 16 weeks, postexchange da ta were available on five patients (1, 2, 5, 6, 9) (Table 1). Only patient 9, who was treated with cyclophosphamide, dem-onstrated sustained suppression of CIC. In patient 1, treated with low-dose methotrexate weekly, CIC rose from the normal range to 50% of the pretreat-ment CIC level at 16 weeks. At 12 weeks,

pat ient 3, treated with postexchange in-travenous methylprednisolone (IVMP) and then low-dose prednisone had re-lapsed to pretreatment CIC levels. At 2 weeks postexchange, patient 4, the only patient undergoing one plasmapheresis, and patient 7, treated with only conven-tional high-dose prednisone and plas-mapheresis, had experienced a prompt rebound of CIC levels.

2. Clearance rates of CIC. T o com-pare the theoretical rate of clearance of CIC based solely upon the fraction of plasma removed versus the actual amount of CIC cleared, it was necessary to generate a family of curves represent-ing percent C I C remaining for a given volume of plasma exchange utilizing equation 2 in the methods section. Since the volume of plasma exchange was con-stant in each patient, and since individ-ual plasma volume could be estimated

Table 1. Effects of plasmapheresis on CIC levels Dynamics of C I C and R F with plasmapher-

esis, units/ml Postplasmapheresis

Pa- Ex-I II III

units /ml

Pa- Ex-tient Age, sex Diagnosis change Pre Post Pre Post Pre Post 2 wk 4 wk 16 wk

1 64, F R A C I C 801 452 2 8 8 110 164 111 110 111 4 0 0

R F 153 126 128 111 111 9 8

2 62, F R A C I C 2 1 8 166 168 108 105 104 . . . - 165

R F 107 61 67 27 67 24 104

3 60, F R V C I C 8 4 4 2 0 6 527 110 179 105 155 155

R F 317 291 2 5 9 138 2 1 6 135

4 62, F R V C I C R F

7922 2 0 2 3 5 8 1 2

5 33, F R V C I C R F

1090 3 0 8 4 2 3 122 . . . 1082

6 54, M R A w i t h Fe l ty ' s syn-d r o m e

C I C R F

1228 196

651 6 5 6 384 144

4 5 9 129

. . . 1042

7 61, M N e c r o t i z i n g vascul i t i s

C I C R F

1007 672 581 2 5 0 700

8 71, F N e c r o t i z i n g C I C 1989 1261 1236 756 1071 2 7 8 vascul i t i s R F 194 172 198 139 154 92

9 29, F S L E C I C R F

739 120 105 9 9 105 104

R A = r h e u m a t o i d a r t h r i t i s , R V = r h e u m a t o i d vascu l i t i s , S L E = sys temic l u p u s e r y t h e m a t o s u s .

56 Cleveland Clinic Quarter ly Vol. 47, No. 1

Table 2. Clinical results Methyl-

Pa- prednisa-tient Concomitant therapy lone, 1 g Postexchange therapy Clinical outcome

1 Prednisone , x l P redn i sone , S u s t a i n e d remission f rom R A despi te pa r -7.5 m g / d a y 7.5 m g / d a y t ial serologic re lapse

Hydroxych loro- M e t h o t r e x a t e , q u i n e 7.5 m g / w k

2 Prednisone , 15 m g / d a y

Aspir in

x3 D-pen i c i l l amine T e m p o r a r y i m p r o v e m e n t fo l lowing t rea t -m e n t , b u t clinical a n d serologic re lapse by 3 weeks a n d n o response to penici l la-m i n e by 8 weeks

3 Prednisone , x l P redn i sone , I m m e d i a t e i m p r o v e m e n t in cen t ra l nervous 80 m g / d a y 40 m g / d a y system (CNS) s y m p t o m a t o l o g y , improve-

m e n t in pe r iphe ra l vasculi t is a n d second-a ry i schemia a n d sus ta ined remission in R A at 12 weeks

4 Predn isone , P redn isone , T r a n s i e n t increase in wh i t e b lood cell coun t 20 m g / d a y 20 m g / d a y ( W B C ) , wh ich subsequen t ly fell wi th re-

b o u n d of C I C levels. Progressive hea l ing of leg ulcers

5 Predn isone , P redn i sone , S low hea l ing of ulcers desp i te p r o m p t ser-15 m g / d a y 15 m g / d a y ologic re lapse

Hydroxych lo ro -q u i n e

6 Predn isone , P redn i sone , N o consis tent effect on W B C coun t , R A in 15 m g / d a y 15 m g / d a y remission before t h e r a p y

Aspir in 7 Prednisone , P redn isone , Pa t i en t was a l r eady on hemodia lys is a n d

8

80 m g / d a y 80 m g / d a y

Predn isone , 20 m g / d a y

m e c h a n i c a l ven t i la tor w h e n p l a s m a p h e r -esis was ins t i tu ted a n d desp i te p r o m p t serologic i m p r o v e m e n t , n o c h a n g e was no ted ; pa t i en t d ied 10 days la ter

N o i m m e d i a t e i m p r o v e m e n t in long-s tand-ing neurologic s y m p t o m s ; pa t i en t lost to fo l low-up

9 Prednisone , P redn isone , D r a m a t i c a n d sus ta ined i m p r o v e m e n t in 80 m g / d a y 60 m g / d a y l u p u s C N S s y m p t o m a t o l o g y a n d sus-

Cy toxan , C y t o x a n , t a i n e d remission of all serologic a b n o r -150 m g / d a y 150 m g / d a y mal i t ies ( C I C levels, c o m p l e m e n t levels,

a n t i - D N A a n t i b o d y levels)

based upon known weight, hematocrit , and established normograms for blood volume (see methods, 3), one can con-struct a graph representing percent CIC remaining for a 2-L plasma exchange versus any given plasma volume (Fig. 2). T h e calculated (actual) clearances based upon the mean of the upper and lower limit of estimated plasma volume are the points represented on the graph.

Clinical findings

Diagnoses of the nine patients treated are given in Table 1. Of these nine, six experienced some degree of clinical im-provement following plasma exchange. A summary of the clinical outcome is given in Table 2. Since all patients re-ceived corticosteroids in at least small doses and several patients received cy-

Summer 1980

totoxic drugs, it is difficult to separate the beneficial effects of plasmapheresis and other treatments in this small and nonrandomized study.

Case reports

Case 1. A 36-year-old white woman with a 5-year history of active (anatomic Stage III, functional Class III) seropositive rheu-matoid arthritis (RA) had failed to respond to several treatment programs, including gold and penicillamine. Four months prior to admission she had responded dramati-cally to a 1-g bolus of IVMP; however, the effect was temporary, lasting only 3 weeks after treatment. The duration of her morn-ing stiffness was then more than 2 hours, and

EFFECT OF PLASMAPHERES IS ON C Iq BINDING

« 1 9 8 9

14 -

10 -

CIQ

PRE POST

p<00l —

Fig. 1. C I C levels immed ia t e ly before and a f t e r two or m o r e p l a s m a exchanges .

o 100 f g < LlJ

Z t § < 2

^ 0

PLASMA VOLUME (L)

Fig. 2. S h a d e d area represents the pred ic ted c lea rance of C I C a f t e r a 2-L exchange for a pa t i en t wi th known p lasma vo lume. Black do t s represent ac tua l c learances for e ight pa t i en t s a f t e r t he first p l a s m a exchange .

on physical examination she had acute syn-ovitis of several joints. Treatment began with three 2-L plasma exchanges followed by 1 g of IVMP. The day after receiving a steroid bolus she noticed a virtual absence of morn-ing stiffness and her joints were much less painful. Methotrexate, 7.5 mg weekly, was started and she was discharged. Four weeks later she was still in both serologic and clin-ical remission, but after 8 weeks, her CIC level began to rise. The arthritis is still in remission at 16 weeks.

Comment. This patient's RA responded dramatically to therapy. The combination of IVMP and a low dose of methotrexate has seemingly helped to maintain the clinical remission and to delay the rapid rebound of CIC to pretreatment levels.

Case 2. A 62-year-old white woman had a 2-year history of progressive seropositive RA (anatomic Stage III, functional Class III). At the time of examination she had synovitis of most peripheral joints and 4 to 5 hours of morning stiffness. The only med-ications were small doses of aspirin and fre-quent injections of corticosteroid, which no longer provided relief. Because of her disa-bility and the acute nature of the disease, she was hospitalized for plasmapheresis and IVMP. Following therapy, prompt serologic and clinical improvement occurred. Treat-

Plasmapheresis therapy in immunologic disease 57

58 Cleve land Clinic Q u a r t e r l y

ment was begun with D-penicillamine. The symptoms recurred one week following ther-apy and by 6 weeks she had a total relapse.

Comment. This patient with severe RA had the lowest levels of CIC in the pretreatment period. After a brief period of improvement, the disease was essentially unchanged from the pretreatment period.

Case 3. A 60-year-old white woman was transferred to the Cleveland Clinic because of gangrenous changes of the right foot. She had a 20-year history of seropositive deform-ing RA (anatomic Stage III, functional Class II) for which she was taking only aspirin. For several weeks before admission she had noted discoloration of the toes and pain in the right foot. On physical examination she had the stigmata of chronic destructive RA. Her right foot was cool with blistering and darkish discoloration of the skin from the midfoot distally (Fig. 3). Pulses were absent in the right foot but Doppler pressures were normal to the ankle.

Laboratory data included an extraordi-narily high RF of 837 units/ml (normal, < 10 units/ml), elevated CIC (Table / ) , positive antinuclear factor (ANF) (1:320), erythro-cyte sedimentation rate (Westergren) 110 mm/hr , normal serum viscosity, strongly positive cryoglobulins, and normal serum complement (total hemolytic complement).

During the first 48 hours, this patient became acutely psychotic. There were no focal neurologic symptoms. In light of the strongly positive laboratory profile, and the clinical signs and symptoms, the diagnosis of RA was made. A regimen of prednisone, 80 mg per day, was begun, and a series of three plasmaphereses were performed. After the first plasma exchange, there was dramatic improvement in her mental status. Unfor-tunately, irreversible tissue necrosis of the forefoot was present before plasmapheresis; however, no progression of the necrotic proc-ess occurred. After a stabilization period, a transmetatarsal amputation was successful. During the following 3 weeks, the arthritis was clinically inactive and rehabilitation was successful.

Comment. This patient had large vessel vas-culitis of the lower extremity and a psychosis

Vol . 47, No. 1

Fig. 3. Foot immed ia t e ly before p lasmapheres i s (pat ient 3).

that was possibly secondary to the arteritis. The central nervous system symptoms, which were new, promptly regressed with therapy. Unfortunately, irreversible necrosis was present and a transmetatarsal amputa-tion was performed. The rapid clearing of CIC is shown in Figure 4.

Case 4. A 54-year-old white woman had a long history of seropositive RA. During the 6-month period before admission, progres-sive vasculitic ulcerations of the lower ex-tremities had developed. She was treated with aggressive topical therapy followed by high-dose prednisone therapy (60 mg/day) without success. The physical examination showed multiple long-standingjoint deform-ities and, in addition, there were four ulcer-ated lesions on the legs that were necrotic with purulent drainage. Laboratory evalua-tion revealed a white blood cell count (WBC) of 2400/mm3 and markedly elevated RF and CIC (Table I). Splenomegaly was evident on liver-spleen scan. Because of failure to re-spond to conventional therapy and in light of the markedly elevated CIC, plasmapher-

S u m m e r 1980 P lasmapheres i s t he r apy in immuno log ic disease 59

l,200r

1,000

10 12 14 16 B 20 22 24 26 28 ' 14 APRIL MAY

I PLASMAPHERESIS f I gram METHYLPREDNISOLONE

Fig . 4. Ef fec t of t h e r a p y on C I C a n d R F ( p a t i e n t 3).

esis was initiated. A transient rise in the WBC was noted while CIC levels were fall-ing, and a subsequent fall in the WBC count was noted with rebound of CIC to pretreat-ment levels (Fig. 5). The ulcerated lesions healed over the next several months.

Comment. This patient's peripheral ulcers showed progressive healing following plasma exchange; exacerbations of these lesions re-quired two more exchanges, after which im-provement was noted and healing was com-plete.

Case 5. A 33-year-old white woman with seropositive RA and features of progressive systemic sclerosis had a history of recurrent painful vasculitic ulcers of the anterior as-pects of the lower legs. These ulcers failed to heal despite aggressive local therapy. In March 1978, she was admitted for more intensive topical ulcer therapy. After one month of bed rest and topical therapy the lesions were unchanged and increasingly higher doses of narcotics were required for relief of pain. Because of high CIC levels, low complement levels, and failure to re-spond to conventional therapy, two 2-L plasma exchanges were done. Within 10 days

of plasmapheresis treatment, granulation tis-sue began to appear in the ulcer sites and slow, progressive healing was observed dur-ing the next several months despite prompt serologic relapse (Table 1).

Comment. It is difficult to assess the efficacy of plasmapheresis in this patient since the clinical course extended over many months. Chronologically, the period of plasmapher-esis appeared to be a turning point in her condition. The brief period of serologic im-provement may have reflected a suppression of the immune response, allowing the con-ventional local therapies, which had failed to work in the past.

Case 6. A 54-year-old white man had a 7-year history of seropositive RA. The arthritis was in remission. He had no morning stiff-ness or painful joints. In March 1977, Felty's syndrome was diagnosed. The WBC count was 2500/mm3; however, there was no sign of infection. In January 1978, he had a respiratory infection with a temperature of 102 F; he was treated with penicillin and recovered uneventfully. In October 1978, his WBC count was 1650/mm3 with 27% poly-morphonuclear leukocytes. Splenomegaly was noted for the first time. The RA was still quiescent and he had no history of leg ulcer-

8,000

7,000

6,000

4,000

" a 3,000 ¡5

2,000

1,000

/I / 1

DIAGNOSIS: RHEUMATOID A R T H R I T I S VASCULIT IS FELTYS

8,000

6,000

4,000 S

2,000

:|NORMAL 4 8 12 16 20 24 28 k

MAY T PLASMAPHERESIS

PREDNISONE 20mq/DAY~

Fig . 5. Ef fec t of t h e r a p y on C I C a n d W B C (pa-t i en t 4).

60 Cleveland Clinic Quarterly Vol. 47, No. 1

ations. He was admitted to the hospital in November 1978 and underwent three 2-L plasma exchanges. Although the CIC levels fell promptly, there was no consistent change in the WBC count. In light of the paucity of symptoms associated with the lowered WBC count, observation rather than further treat-ment was planned.

He remains asymptomatic although the CIC has rebounded to pretreatment levels.

Comment. Plasmapheresis had no effect on the WBC count in this patient with Felty's syndrome. This is in distinction to patient 4, whose leukopenia improved transiently with plasma exchange therapy.

Case 7. A 61-year-old white man was admitted for evaluation of advancing renal failure. He had been well until approxi-mately 4 weeks before admission when he began to experience flu-like symptoms with a nonproductive cough. Physical examina-tion on admission revealed that he was mildly short of breath but not in acute dis-tress. Aside from bilateral, coarse inspiratory rales, the examination was unremarkable. A chest roentgenogram revealed five-lobe in-terstitial-alveolar infiltrates. On the 12th hospital day, he was transferred to the med-ical intensive care unit because of increasing respiratory difficulty. Serum creatinine level had risen from 3.5 mg/dl on admission to 6.1 mg/dl. During the next several days, mechanical ventilation was required and he-modialysis was begun. An open lung biopsy revealed an acute pneumonia superimposed upon chronic interstitial pneumonitis. All cultures for bacteria, fungi, and opportunis-tic organisms were negative. On the basis of markedly elevated CIC levels and severely depressed serum complement (total hemo-lytic complement, 44 units/ml; normal, 70 to 190 units/ml), a regimen of high-dose prednisone, 80 mg daily, and a course of plasmapheresis were begun. Reduction of CIC levels and normalization of serum com-plement were observed during therapy. However, no change was noted in his pro-gressively downhill course. Prompt rebound-ing of the CIC levels was observed after plasmapheresis (Fig. 6). He died 10 days later.

Comment. Autopsy revealed a healing wide-spread arteritis. Plasmapheresis had no effect on the clinical course of this patient, but both respiratory and renal failure were well established before treatment. Our experience and that of others suggest the need for early institution of therapy in immunologically mediated renal disease.

Case 8. A 71-year-old white woman was admitted to the hospital for treatment of immune complex-mediated vasculitis. The principal manifestation of disease was mon-oneuritis multiplex with glove and stocking paresthesias and a right-sided carpal tunnel syndrome. Neurologic symptoms had pro-gressed during the preceding 8 months. She had lost considerable weight. On physical examination, she was cachectic with severe atrophy of the right thenar eminences. Sen-sory examination revealed decreased pin, temperature, and vibratory sensation in the lower extremities. She was treated with three 2-L plasma exchanges followed by IVMP. Prompt serologic improvement was noted; however, there was no change in her neuro-logic symptoms. She was discharged from the hospital with a return appointment in 2 weeks but has since been lost to follow-up.

Comment. This patient had no clinical im-provement in the immediate post-therapy period; however, it is possible that the neurologic damage was irreversible. Al-ternatively, since she has been lost to follow-up, delayed improvement would not have been detected.

Case 9. A 29-year-old white woman was referred for evaluation of systemic lupus erythematosus (SLE). In the past year she had experienced constant migratory arthral-gias and recently began to experience pho-tosensitivity and Raynaud's phenomenon. She described a recent episode of pleurisy. She had taken no medication.

Physical examination revealed some patchy alopecia and a faint erythematous rash over the malar area. The remainder of the examination was unremarkable. Labo-ratory tests revealed a hemoglobin of 11.4 g/ dl; WBC, 9300/mm3; ANF, 1:320; DNA binding, 50%; Clq binding capacity, 315 units (normal < 120 units); total hemolytic

S u m m e r 1980 P lasmapheres i s t he r apy in immuno log ic disease 61

1200

1000

600

200

COMPLEMENT \

DIAGNOSIS : ARTERITIS GLOMERULONEPHRITIS-PULMONARY INFILTRATES

N°\ N C ^ H

io o>

8 £

6 z

2 6 10 14 18 22 26 FEBRUARY

0 o

' 80 m g PREDNISONE

•-DECREASED N - N O R M A L I - P L A S M A P H E R I S I S

Fig . 6 . Ef fec t of t h e r a p y on C I C , c r e a t i n i n e a n d c o m p l e m e n t ( p a t i e n t 7).

complement (CH50), 45 units (normal 70 to 180 units); and negative rheumatoid factor. Urinalysis showed 3 to 5 red blood cells per high power field, creatinine level was nor-mal, and the 24-hour urine protein was 250 mg; no casts were seen.

One month later she came to the emer-gency room complaining of scintillating sco-toma followed by loss of vision in the right eye that morning, all of which lasted 20 minutes. Later that day, she experienced the same phenomenon, came again to the emer-gency room, and was admitted to the hos-pital. Physical examination was unremark-able except for some blurring of the right optic disc. The neurological consultant be-lieved that the attacks were consistent with either migraine or lupus cerebritis. Com-puted tomography (CT) of the head and lumbar puncture were performed and were unremarkable. A regimen of 40 mg of pred-nisone per day was begun. The patient's neurologic status remained unchanged, but she felt extremely weak until the fifth hos-pital day when she awoke feeling nauseated

and experienced diplopia, which was worse on left gaze. Cyclophosphamide (Cytoxan), 150 mg daily, was started and the prednisone was increased to 80 mg daily. Two-liter plasma exchanges were performed daily for 3 consecutive days. During this period minor symptoms, i.e., weakness, and dull headache continued, but beginning 2 days after plas-mapheresis and until discharge on the 20th hospital day, improvement continued and she felt stronger and free of neurologic symp-toms.

She has been seen twice in the outpatient department and has remained in complete serologic and clinical remission on a regimen of prednisone, 60 mg/day, and azathioprine, 150 mg daily.

Comment. The clearing of neurologic symp-toms and the prompt correction of serologic abnormalities soon after plasma exchange (Fig. 7) suggest that plasmapheresis was ben-eficial for this patient. Clinical and serologic remission has been maintained for 4 months following therapy with a combination of corticosteroid and cytotoxic drug (azathio-prine).

DIAGNOSIS SLE 5/11/79

o 400

•c3 P4 f"50

50 40

30 g a 2 0 *

10

0

f t t PLASMAPHERSIS

II 13 16 18 20 22 24 27 31 MAY JUNE

IS JULY

CYTOXAN 150 mg 0D

Fig . 7. Ef fec t of t h e r a p y o n C I C a n d a n t i - D N A a n t i b o d y ( p a t i e n t 9).

62 Cleveland Clinic Quarterly Vol. 47, No. 2

Discussion

We have treated nine patients with diseases associated with CIC with plas-mapheresis. Clinical improvement was observed in six of the nine. These pre-liminary da ta must be interpreted with caution because there was no control group and, in addition, each patient was also treated with some form of addi-tional immunotherapy. Even with these reservations, it can be argued from these da ta that plasmapheresis contributed to the clinical improvement. First, the ma-jority of patients treated had difficult therapeutic problems; t reatment with conventional therapy had failed, and symptomatic improvement was ob-served only after plasmapheresis was added to the therapeutic regimen. Sec-ond, the improvement in clinical pa-rameters followed the clearing of im-mune complexes, which presumably can be at t r ibuted to the effects of plasma-pheresis. Furthermore, in selected cases failure to respond to plasma exchange may be explained on an individual basis. For example, patient 7 had well-established renal failure before plasma-pheresis was instituted. Since that time, in a similar report, Lockwood et al have shown that p rompt initiation of plas-mapheresis is necessary if improvement of immunologically mediated renal dis-ease is to be expected. Alternatively, it may be argued tha t a l though immune complexes are present in all patients, they may not be of pr imary pathogenic importance.

It is difficult to interpret with confi-dence the clinical effects of plasmapher-esis in our study group, but the ability of plasma exchange to lower CIC levels was dramatic. Those patients receiving two or more exchanges had prompt low-ering of CIC levels from a mean of 970 uni ts /ml to a level of 190 uni t s /ml (Ta-

ble J). In five of these eight patients, CIC levels became normal (<140 uni t s / ml) following plasma exchange alone, and in the remaining three patients (pa-tients 6 through 8), CIC levels were reduced but not to normal levels. It is interesting that the three patients in whom the CIC levels did not become normal were the same three who expe-rienced the least clinical improvement from the treatment regimen. Factors that might contribute to the failure of plasmapheresis to normalize CIC levels in these patients include rapid resyn-thesis of CIC or decreased endogenous clearance mechanisms, i.e., reticuloen-dothelial blockade or both. With regard to the dynamic effect of plasma ex-change upon ongoing immune complex disease, the results of our study are in accord with the experimental work of others in that plasma exchange alone is ineffective and is routinely followed by a rebound of CIC. 6 , 7 This effect was not blocked by steroids as can be seen graph-ically in Figure 6. In those patients fol-lowed up 16 weeks, only patient 9, who was treated with full-dose cytotoxic therapy, sustained normalization of CIC levels. I V M P , low-dose methotrexate, and conventional doses of oral cortico-steroids had a delaying effect, at best, in affecting the rebound of CIC levels.

We at tempted to compare the actual clearance rate of CIC with a calculated value based upon equation 2.

T o apply these results to clinical prac-tice, certain conditions must be met; these constitute the assumptions im-plicit in the use of this calculation.

1. Synthesis and endogenous clear-ance of CIC must be slow com-pared to the rate of exchange.

2. Exchange between intravascular and extravascular immune com-plex pools must be slow compared to the rate of plasma exchange.

Summer 1980 Plasmapheresis therapy in immunologic disease 63

3. Concentrat ion of the CIC must not affect their physical properties in such a way that the efficiency of their detection might be reduced.

4. There must be instantaneous mix-ing of the replacement fluid throughout the intravascular pool.

5. Plasma volume must be accurately determined.

It is clear that not all of these assump-tions may be valid; moreover, assump-tions that may be valid in one clinical setting, e.g., low rate of endogenous complex formation and clearance, may be invalid in another. Even with these reservations, Figure 2 shows that with the exception of patient 2, the clearance rates of the remaining patients equaled or exceeded the predicted rates in every case. Several explanations of this phe-nomenon are possible. First, the dilu-tional effect of the replacement fluid (immunoglobulin-free, complement-free plasma protein fraction) may alter the physical properties of the remaining CIC, reducing the efficiency of their detection. This explanation is probable in at least some instances since we have found that when diluted, CIC from dif-ferent patients will react with different Clq binding than would be predicted from undiluted sera (unpublished data). This phenomenon is independent from protein concentration and is being in-vestigated in our laboratory. A second explanation is that plasmapheresis en-hances endogenous clearance mecha-nisms possibly by "unblocking" the re-ticuloendothelial system. Results of re-cent studies have indicated that such a "block" exists in several immune com-plex disease states;8 Lockwood et al9

have demonstrated that plasmapheresis can potentially unblock this system.

Review of literature

Technique. The proliferation of stud-

ies utilizing plasmapheresis can be at-t r ibuted in large part to the advances in technique dur ing the past decade. In early experience, plasma exchange was performed manually by wi thdrawing a unit of blood, separating the cells f rom plasma by centrifugation, and re turning the red blood cells to the donor. Since the late 1960s, plasma exchange has been more commonly performed by one of an increasing number of models of cell separators.10 ,11 These machines can now separate plasma, red cells, white cells, and platelets in large volumes. T h e technique is rapid, replaces u p to 4 L of plasma in a 2-hour period and causes little discomfort or risk to the pat ient who requires only percutaneous venous cannulat ion. At these high rates of ex-change, it is necessary to replace the patient 's plasma with an isooncotic so-lution such as fresh frozen plasma, pu-rified protein fraction or a lbumin to avoid a hypooncotic state with subse-quent edema formation.1 2 T h e proce-dure can be performed with few short-or long-term adverse effects. Prolonged (one year or more) intensive plasma-pheresis of normal volunteers had no detectable effect on delayed hypersen-sitivity as assayed by lymphocyte count, skin testing, and mitogen stimulation, but did significantly reduce the serum concentration of immunoglobulin, C3, and albumin.1 3

Rationale. T h e procedure of remov-ing a patient 's plasma and replacing it with another physiologic solution could be potentially beneficial in any condi-tion in which a humoral phase would be important in pathogenesis. In theory, two broad categories of immunologic injury would be most responsive to such therapy: those that mediated by anti-body or those that mediated by CIC.

Disease states mediated by circulating ant ibody may be subclassified into two

64 Cleveland Clinic Quarterly Vol. 47, No. 2

categories: cytotoxic and blocking. Cy-totoxic antibodies generally involve the combination of IgG or IgM ant ibody with an antigenic determinant on a cell membrane or other surface. These an-tibodies frequently fix complement leading to cell lysis or immunologic damage of the target surface in the case of a noncellular antigen, i.e., glomerular basement membrane (GBM). Examples of this type of reaction are listed in Table 3. Blocking ant ibody is a second type of antibody-mediated process. In general these antibodies do not fix complement and do not lead to immunologic damage of their targets, but rather lead to an alteration in their function. Either sup-pression or stimulation can be observed, depending on the conditions. An exam-ple of stimulation resulting from anti-body is Graves' disease22 in which im-munoglobulins capable of displacing thyrotropin have been identified. Dis-eases in which ant ibody brings about inhibition of biologic function include insulin-resistant diabetes with anti-in-sulin receptor immunoglobulins2 3 and myasthenia gravis with antiacetylcho-line receptor antibody.24 Other exam-ples of this type of reaction are listed in Table 3.

A detailed discussion of immune com-plex disease is beyond the scope of this paper, but it has been the subject of several recent reviews.26"28 With regard to the therapeutic potential of plasma exchange in disease mediated by CIC, several points deserve consideration. T h e mere presence of C I C in the circu-lation does not necessarily bring about immunologically mediated disease. A complex interaction of many factors must exist before immunologic damage is observed. These factors include the rat io of antibody to antigen, ability of the CIC to fix complement, presence of

Table 3. Conditions characterized by circulating ant ibody

Cyto tox ic a n t i b o d y I m m u n e hemoly t ic a n e m i a 1 4

I m m u n e t h r o m b o c y t o p e n i a 1 5

I m m u n e neu t ropen ia , Fel ty ' s 1 6 , 1 7

I m m u n e l y m p h o p e n i a 1 8 ' 1 9

A n t i - G B M disease2 0 '2 1

Blocking a n t i b o d y Graves ' disease2 2

Insul in resistant d iabetes 2 3

M y a s t h e n i a gravis2 4

M a l i g n a n c y wi th "b lock ing fac to r s" 2 5

vasoactive amines to enhance vascular permiability, and localization of CIC to the target organ. Aside from the above factors that primarily affect the deposi-tion of CIC, other factors important in C I C formation and elimination, such as the nature and t iming of the antigenic exposure and the integrity of the retic-uloendothelial system, are critical in de-termining the extent of the resultant immunologic disease. T h e mere elimi-nation of a given quanti ty of CIC is no assurance that clinical benefit will re-sult. Furthermore, plasmapheresis could theoretically have deleterious effects on immune complex-mediated disease by such mechanisms as adversely altering the ratio of antibody to antigen or by causing release of vasoactive amines by a similar mechanism as has been dem-onstrated dur ing hemodialysis.29

Plasma exchange is not in itself help-ful in most immunologic disease states for which it has been employed, as dem-onstrated by experiments in both ani-mals and man. Bystryn et al6 showed that removal of specific ant ibody by plasma exchange invariably resulted in a rapid rebound of ant ibody to levels above those in the pretreatment period. In further experiments, it was demon-strated that this rebound could be

Summer 1980 Plasmapheresis therapy in immunologic disease 65

blocked by the administrat ion of cyclo-phosphamide.3 0 When humans undergo plasmapheresis without concomitant immunosuppression, a similar rebound in antibody levels has been described. Examples of this phenomenon include insulin-resistant diabetes31 with anti-in-sulin receptor antibodies and severe Rh disease in women.32 Plasmapheresis combined with adjuvant corticosteroid and cytotoxic therapy have been suc-cessful in suppressing levels of anti-G B M antibodies in patients with Good-pasture's syndrome. Furthermore, re-bound of antibody to pretreatment lev-els was observed in one patient when cytotoxic therapy was discontinued.33 In certain situations, plasma exchange alone may be sufficient to eliminate an ' unwanted antibody. Branda et al7 have demonstrated in immunized dogs that plasmapheresis may permanent ly sup-press antibody produced by a secondary but not a primary immunizat ion. Ac-cordingly, they recommended that plas-mapheresis alone be considered only for patients in whom multiple intermittent stimulations leading to unwanted anti-body are suspected. This concept would theoretically apply to any condition in which pathogenic ant ibody is stimu-lated in a secondary fashion, i.e., hem-ophilia with anti-Factor VIII antibod-ies. However, adjunctive corticosteroid or cytotoxic therapy or both have tra-ditionally been employed to control such an immunologic response.34 '35

Plasmapheresis has also been applied in disease states characterized by CIC and hypocomplementemia. Several in-teresting questions regarding the kinet-ics of immune complex formation and removal have been raised. Jones et al36

in treating patients with acute SLE pos-tulated that plasma exchange, in addi-tion to removing immune complexes on

a purely volume basis, somehow en-hanced endogenous reticuloendothelial function, a t tempt ing to explain a dis-proportionate fall in serum anticomple-mentary activity, which was observed in several patients. Recently, in a detailed study of splenic function in patients with various conditions characterized by CIC, Lockwood et al5 '9 demonstrated impaired reticuloendothelial function that was "unblocked" by plasma ex-change. This is in agreement with our da ta that actual clearance rates equaled or exceeded predicted rates in all but one patient. Additional explanations of the potential benefit of plasmapheresis in immune complex-mediated disease include depletion of mediators, such as complement and coagulation factors brought about by the substitution of purified protein fraction (PPF) (immu-noglobulin-free, complement-free) for plasma.

Treatment

Plasmapheresis in antibody-mediated disease

Myasthenia gravis. Strong evidence exists of pathogenic antibody activity in this condition. Antiacetylcholine recep-tor antibodies have been identified in 87% of pat ients with myasthenia gravis, but not in patients with other neurologic or au to immune diseases.24 This anti-body crosses the placenta and is believed responsible for the appearance of tran-sient neonatal myasthenia gravis. Fur-thermore, a disease similar to myas-thenia can be produced in animals by immunizat ion with acetylcholine recep-tor.37

Tradit ionally, patients who fail to re-spond to medications that directly facil-itate neuromuscular transmission have

66 Cleveland Clinic Quarterly Vol. 47, No. 2

been treated by some form of immuno-logic intervention such as steroid, cyto-toxic drugs, or thymectomy. Plasma-pheresis has been reported to be success-ful in the t reatment of myasthenia gravis.38,39 Studies by Dau et al40 have shown the increased strength of patients treated with plasma exchange to be con-current with falling titers of acetylcho-line receptor antibody; moreover, clini-cal relapses were associated with a re-bound in titer.

Antiglomerular basement membrane disease. Goodpasture 's syndrome is a combination of glomerulonephritis and pulmonary hemorrhage, which is be-lieved to be mediated by ant ibody di-rected against glomerular and alveolar basement membranes. T h e natural course is characterized by progressive deterioration culminat ing in death from intractable pulmonary hemorrhage or renal failure.41 Trea tment with steroids or immunosuppressive drugs or both has met with varying success. Nephrectomy has been considered to be of benefit in some patients with life-threatening pul-monary hemorrhage;4 2 however, the re-sults have not been consistent.21

In 1976, Lockwood et al33 described seven patients with anti-GBM-induced Goodpasture's syndrome, treated with plasmapheresis and immunosuppressive therapy. Since then, additional reports of such therapy have appeared.43"49 Re-cent review of the literature concluded that plasmapheresis and immunosup-pressive therapy may reverse the renal lesion in some patients with Goodpas-ture's syndrome.49 In the 24 cases of ant i -GBM disease reported by Lock-wood et al,5 they emphasized the need for early institution of therapy.

Rh disease. Plasmapheresis via the cell separator combined with intrauter-ine transfusion has been claimed by sev-

eral workers to improve fetal survival in women immunized by the Rh isoanti-gen.12,29, -50,51 Trea tment must be started early and frequent large volume ex-changes appear necessary.

Hematologic disease. A wide variety of hematologic conditions mediated by pathologic antibodies have been treated by plasma exchange. Anti-factor VIII antibodies develop in about 10% of clas-sic hemophiliac antibodies; this presents a major problem in management of these patients. Plasma exchange with or without immunosuppressive therapy has successfully extended the half-life of subsequently administered factor Y J J J 32, 34, 52

Posttransfusion purpura is a rare but serious condition that develops in per-sons who lack the P1A1 platelet antigen, or who have become immunized to it through pregnancy or blood transfusion. When these patients have received transfusions, profound thrombocyto-penia develops in approximately one week, occasionally associated with life-threatening hemorrhage. Plasma ex-change has been reported to be success-ful in the management of this condi-

53

tion. Idiopathic thrombocytopenic pur-

pu ra is mediated by a plasma antiplate-let factor widely believed to be an anti-body.15 Corticosteroids and immuno-suppressive drugs control the disorder in the majority of patients albeit after days or weeks. Plasmapheresis has been used successfully in several patients for whom conventional therapy was not satis-factory, either because of life-threat-ening hemorrhage or when such ther-apy was considered ineffective or dan-

s i , 52, 54 gerous. '

Branda5 5 has also reported plasma exchange to be effective in the t reatment of hemolytic anemia mediated by anti-

Summer 1980 Plasmapheresis therapy in immunologic disease 69

e antibody. Finally, Tursz et al56 have reported removal of anti-B-cell ant ibod-ies by plasmapheresis in a patient with hypogammaglobulinemia who had a subsequent rise in B-cell numbers; the effect was only transient.

Endocrine disorders. Muggeo et al31

have recently reported the success of plasmapheresis in treating an insulin-resistant diabetic who had autoant ibod-ies directed against the insulin receptor. In a highly provocative recent report, Dandona et al57 have treated a pat ient with Graves' disease who had acute pro-gressive exophthalmos and pretibial myxedema. Clinical improvement was noted after plasma exchange t reatment and was thought to coincide with de-creasing IgG and specific thyroid-stim-ulating immunoglobulin levels. T h e re-sults suggested that plasmapheresis may be useful in treating such conditions.

Skin conditions. Plasmapheresis as yet has had limited use in few skin conditions.58 ,59 T h e serum of patients with pemphigus contains an ant ibody directed against an antigen in the epi-dermal intercellular space. At present, the use of plasma exchange in this con-dition remains controversial.

Immune complex-mediated disease

Systemic lupus erythematosus. SLE is one of the prototypes of immune com-plex-mediated disease. M a n y of its clin-ical manifestations, especially renal in-volvement, appear to be directly related to immune complex-mediated in-jury.60"62 Accordingly, on theoretical grounds, active SLE should potentially benefit from removal of immune com-plexes via plasma exchange.

Jones et al,63 '64 in a preliminary re-port and recently in a series of 14 pa-tients, have presented evidence that

plasmapheresis is beneficial in the treat-ment of certain patients with SLE. Of their group of 14 patients, eight had evidence of either clinical improvement or clinical and serologic improvement at the t ime of plasmapheresis. Three pa-tients showed no improvement and the conditions of three patients were consid-ered unevaluable. Three patients with high levels of CIC preplasmapheresis had sudden falls in CIC levels greater than could be accounted for on the basis of amount removed. Jones et al ex-plained this observation on the basis of unblocking of the reticuloendothelial system, thus enhancing endogenous clearance. O u r one patient with SLE also had a sudden fall in CIC, in excess of tha t calculated on the basis of amount removed. Clinically, our one patient who was extremely active serologically (i.e., CIC ten times normal, depressed hemolytic complement and DNA bind-ing of 50%) had total clearing of central nervous system symptoms within 5 days of treatment. Several other reports have also suggested plasma exchange may be beneficial in t reatment of this disorder.36 '65

Vasculitis. Necrotizing arteritis is a final pathologic expression for a wide variety of pathogenic mechanisms. In recent years, many disease states be-lieved to be of widely differing etiologies have been thought to induce injury through an immune complex process. Some of the more clearly defined disease states in which immune complex-me-diated vasculitis plays a role include Hb s Ag positive arteritis, hypersensitiv-ity vasculitis, vasculitis associated with endocarditis, essential mixed cryoglob-ulinemia, vasculitis associated with some malignancies, rheumatoid vascu-litis, and serum sickness. I m m u n e com-plexes have also been identified in some

68 Cleveland Clinic Quarter ly Vol. 47, No. 2

cases of Wegener's granulomatosis; how-ever, their role in pathogenesis is not clear at this time.66

When vasculitis is not secondary to a treatable cause such as endocarditis, current conventional therapy has cen-tered about the use of steroids and cy-toxic drugs and has met with varying degrees of success.67,68 Therefore, when the success of plasmapheresis is exam-ined in combination with these modali-ties, it is difficult to evaluate the results without the benefit of any prospective randomly controlled trials. Lockwood et al9 have treated a large series of patients with nephritis secondary to polyarteritis and Wegener's granulomatosis with a combination of plasmapheresis and im-munosuppressive therapy and demon-strated considerable improvement in the majority of patients as shown by fall in serum creatinine levels and disappear-ance of CIC. Goldman et al69 have re-cently reported the successful use of lim-ited plasmapheresis in three of four pa-tients with rheumatoid vasculitis. T w o of their successfully treated patients re-ceived full-dose cytotoxic drugs in ad-dition to plasma exchange. T h e other two including the therapeutic failure received D-penacillamine. In the pres-ent study three patients with rheuma-toid vasculitis and two patients with necrotizing arteritis were treated. T h e results were interpreted as possibly ef-fective in the two RA patients with leg ulcerations and probably effective in the R A patient with ischemic gangrene of the forefoot. In patient 7 with necrotiz-ing arteritis, plasmapheresis had no ef-fect on established pulmonary renal in-sufficiency; furthermore, this patient had the dramat ic rebound of CIC levels (days) apparent ly unaffected by pred-nisone, 80 mg/day . Plasmapheresis has also been helpful in treating the im-

mune complex, mediated complications of subacute bacterial endocarditis7 0 and cryoglobulinemia.71

Rheumatoid arthritis. R A is a sys-temic disease in which immune com-plexes have long been thought respon-sible for many of the articular and non-articular manifestations. Recently, Wal-lace et al.72 have treated 12 patients with either plasmapheresis or lympho-pheresis or both. Ten of 12 patients had remission periods averaging 4 months. Clinical remissions appeared to be sus-tained even when serologic parameters such as immunoglobulins, sedimenta-tion rate, and CIC had returned to pre-pheresis levels. In the present study only two patients were treated for severe re-fractory RA. Both patients received dif-ferent postexchange t reatment regi-mens. One patient treated with metho-trexate has remained in remission more than 4 months; the patient treated with penicillamine relapsed in 2 weeks. Al-though additional studies are in prog-ress, the present experience is too limited to draw any conclusions.

Disease state of presumed immunologic origin

Thrombotic thrombocytopenic pur-pura (TTP). Bukowski et al73 '74 and later others75"77 have reported success in the treatment of T T P by plasmapheresis using fresh frozen plasma as a substitute. Although immune complex formation has been postulated as an etiologic mechanism, none has been identified for this disorder.

Raynaud's disease. T h e pathogenesis of Raynaud 's disease is not well defined, but the frequent association of the phe-nomenon with a wide variety of connec-tive tissue disorders makes the proposi-tion of an immunologic etiology tempt-

Summer 1980 Plasmapheresis therapy in immunologic disease 69

ing. Talpos et al78 have reported treating five patients with severe Raynaud ' s dis-ease who were refractory to other ther-apy with plasmapheresis and claimed striking improvement in both clinical parameters and ultrasonic velocimetry of digital arteries.

Acute polyneuropathy. Evidence ex-ists for a myelinotoxic IgM antibody in the sera of patients with "acute infective polyneuritis."79 Controlled trials have demonstrated steroids to be ineffective.80

Brettle et al81 recently reported dra-mat ic results in the treatment of one patient with plasmapheresis.

Asthma. Ga r tmann et al82 have re-ported improvement in one pat ient with severe as thma treated with plasmapher-esis. Clinical improvement lasted several months only to relapse, but promptly responded to reinstitution of plasma-pheresis.

Transplantation. Plasmapheresis has been used in several areas in clinical organ transplantat ion. Cardella et al83

have successfully managed five of seven episodes of renal rejection with plasma-pheresis. Graze and Gale84 have re-ported unsuccessful a t tempts to treat several patients with chronic graft ver-sus host reactions following bone mar-row transplantat ion.

Paraproteinemia. T h e use of plasma exchange in removal of paraproteins was the earliest clinical experience with this tool.85 Although the hyperviscosity syndrome has been the most commonly treated complication, others have also been treated.86 Ibster et al87 have re-ported the success of plasma exchange in three patients with malignant para-proteinemia who developed hemostatic complications. Misiani et al88 have also recently reported excellent recovery of renal function in three patients in whom acute renal failure developed dur ing the

course of multiple myeloma. Plasmapheresis is an exciting new

therapeutic modality with great poten-tial in a wide variety of immunologic disorders. Early experience with this tool has been encouraging, with many re-ports demonstrat ing clinical and sero-logic improvement with little significant morbidity.

A word of caution must temper this optimism, for virtually all trials of this therapy to date have been uncontrolled. Since it is apparent that plasmapheresis alone is sufficient to control only a few immunologic disorders, the exact role of adjuvant immunotherapy needs to be defined. In addition, the beneficial ef-fects a t t r ibutable to the plasmapheresis itself as opposed to the associated im-munotherapy have not in many in-stances been clearly definable. Apart from these reservations, the cautious ap-plication of this modality adds a new dimension to the immunopharmacol -ogic a rmamentar ium.

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remova l w i th r e t u r n of corpuscles (p lasma-phaeresis) . J P h a r m a c o l E x p T h e r 5 : 6 2 5 - 6 4 1 , 1913-1914.

2. A d a m s W S , B lahd W H , Bassett S H : A m e t h o d of h u m a n p lasmapheres i s . P roc Soc E x p Biol M e d 80: 377-379 , 1952.

3. So lomon A, Fahey J L : P la smapheres i s ther -a p y in mac rog lobu l inemia . A n n I n t e r n M e d 58: 789-800, 1963.

4. Z u b l e r R H , L a n g e G, L a m b e r t P H , et al: De tec t ion of i m m u n e complexes in u n h e a t e d sera by a modi f i ed 1 2 5I-CIq b i n d i n g test; effect of h e a t i n g o n t h e b i n d i n g of C l q by i m m u n e complexes a n d app l i ca t ion of t h e test to sys-t emic lupus e ry thema tosus . J I m m u n o l 116: 232-235 , 1976.

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8. F r a n k M M , H a m b u r g e r M I , Lawley T J , et al: Defect ive re t iculoendothel ia l system Fc-re-cep to r func t ion in systemic lupus e r y t h e m a -tosus. N Engl J M e d 300: 518-523 , 1979.

9. Lockwood C M , Wor l l edge S, Nicholas A, et al: Reversal of i m p a i r e d splenic func t ion in pa t i en t s w i th nephr i t i s or vasculi t is (or bo th ) b y p l a s m a exchange . N Engl J M e d 300: 5 2 4 -530, 1979.

10. M c C u l l o u g h J , F o r t u n y IE, K e n n e d y BJ , et al: R a p i d p l a s m a exchange wi th the cont in -uous flow cell cen t r i fuge . T r a n s f u s i o n 13: 9 4 -99, 1973.

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18. Win f i e ld J B , Winches t e r R J , K u n k e l H G : Associat ion of cold-react ive a n t i l y m p h o c y t e an t ibod ies wi th l y m p h o p e n i a in systemic lu-p u s e ry thematosus . Ar thr i t i s R h e u m 18: 5 8 7 -594, 1975.

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20. Lerner RA, Glassock R J , Dixon FJ : T h e role

of an t i -g lomeru la r b a s e m e n t m e m b r a n e an t i -b o d y in the pa thogenes is of h u m a n g lomeru-lonephri t is . J E x p M e d 126: 989 -996 , 1967.

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22. M u k h t a r E D , S m i t h B R , Pyle G A , et al: Re la t i on of thyro id- s t i m u l a t i n g i m m u n o g l o b -ulins to thy ro id func t ion a n d effects of sur-gery, rad io iod ine , a n d an t i t hy ro id drugs . L a n -cet 1: 713-715, 1975.

23. K a h n C R , Flier J S , B a r R S , et a l . T h e syn-d romes of insul in resis tance a n d acan thos i s nigr icans; insul in- receptor disorders in m a n . N Engl J M e d 294: 739-745 , 1976.

24. L inds t rom J M , Seybold M E , L e n n o n V A , et al: A n t i b o d y to ace ty lchol ine receptor in myas then i a gravis; prevalence , cl inical corre-lates, a n d d iagnos t ic value. Neuro logy 26: 1054-1059, 1976.

25. He l l s t röm K E , Möl le r G : I m m u n o l o g i c a l a n d i m m u n o g e n e t i c aspects of t u m o r t r ansp lan -ta t ion . P rog Allergy 9: 158-245, 1965.

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29. C r a d d o c k P R , Feh r J , Da lmasso AP , et al: P u l m o n a r y vascular leukostasis resul t ing f r o m c o m p l e m e n t ac t iva t ion by dia lyzer ce l l ophane m e m b r a n e s . J Cl in Invest 59: 879 -888 , 1977.

30. Bystryn J C , Schenke in I, U h r J W : A mode l for regula t ion of a n t i b o d y synthesis by s e r u m an t i body . Progress in I m m u n o l o g y . A m o s B, ed. New York, A c a d e m i c Press, 1971, p 627.

31. M u g g e o M , Flier J S , A b r a m s RA, et a l : T r e a t -m e n t by p l a s m a e x c h a n g e of a pa t i en t w i th a u t o a n t i b o d i e s to the insul in receptor . N Engl J M e d 300: 477-480 , 1979.

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