Procainamide-Induced Serologic Changes in Asymptomatic Patients

By JAVIER MOLINA, M.D., EDMUND L. DUBOIS, M.D., MICHAEL BILITCH, M.D., STEPHEN L. BLAND, M.D., AND GEORGE J. FFUOU, M.D.

Serologic findings in cardiac patients who had no manifestations of drug- in- duced lupus and who had been taking procainamide for 6 weeks or more were compared to a similar group receiving quinidine, and a series of age- and sex- matched controls. Significant changes oc- curred only in the group of 22 patients

ADD IN 1962 first described a case of L procainamide-induced systemic lupus erythematosus (SLE).l During the past 5 years an additional 49 cases have been re- ported.2-1S The entity has now become a well-recognized form of chemically induced SLE. Our experience with 6 additional cases suggested that the syndrome may be far more common than realized and that serologic abnormalities might occur in asymptomatic patients. The first patient tested by one of us (E. L. D.) had a strongly positive LE cell test without symp- toms (Table 1). The aim of this study was to review a group of asymptomatic patients receiving procainamide to determine the incidence of antinuclear antibodies (ANA).l6 Two control groups of patients were evaluated: one a quinidine-treated series of comparable sex and age who were taking medication for essentially the same

treated with procainamide (p < 0.01). LE cell tests were positive in 12 (55 per cent). Antidesoxyribonucleoprotein (anti- DNP) tests were positive in 15 (68 per cent) and anti-DNA in 8 (36 per cent). A positive LE cell test, anti-DNP, or anti- DNA reaction was found in 17 (77 per cent).

disorder as the procainamide group, and a second group of similar age and sex with miscellaneous disorders who were receiving neither drug.

MATEFUALS AND METHODS All available asymptomatic patients (those who

had no manifestations suggestive of drug-induced lupus ) receiving procainamide or quinidine were included in the study. A series of 90 controls taking neither drug was also studied. Those with inflammatory and connective tissue diseases were excluded. The patients were otherwise selected as randomly as possible from among hospitalized medical patients until an appropriate number were obtained in each sex and decade. The majority suffered from degenerative cardiovascular disease. The following tests were done: rotary and rotary- washed clot LE cell preparations in the drug- treated groups,l7 immunofluorescent tests for ANA using as substrates calf thymus nucleoprotein and calf thymus DNA spots,ls total complement,lU and rheumatoid factor.20 Tests for ANA reacting with nuclei in rat liver sections18 were done on all

JAVIER MOLINA, M,D.: Fellow in Rheumutology, Uniuersity of Southern California School of Medi- cine, Los Angeles, California. EDMUND L. D ~ O I S , M.D.: Associate Clinical Professor of Medicine, Section of Rheumatic &are and Immunology, University of Southern California School of Medi- cine, Los Angeles, California. MICHAEL BILITCH, M.D.: Assistant Professor of Medicine, Section of Cardidogy; University of Southem California School of Medicine, Los Angeles, California.

STEPHEN L. BLAND, M.D.: FeUow in Rheumetd- ogy, University of Suuthern California School of Medicine, Los Angeles, Cdifornia. GEORGE J. FRIOU, M.D.: Professor of Medicine, and Dinectol; Section of Rhmmntic Disease and Immunology, University of Southern California School of Me&- cine, Lus Angeks, California.

Reprint requests should be d r e s s e d to Or. Dub& at the USC School of Medicine, 2025 Zonal Avenue, Los Angeles, California 90033.

608 ARTHRITIS AND RHEUMATISM, VOL. 12, No. 6 (DECEMBER, 1969)

PROCAJNAMIDE-INDUCED SEROLOGIC CHANGES 609

Table 1.Procainamide Therapy for Arteriosclerotic Heart Disease and Premature Ventricular Contractions'

Total Dose Duration, Rotary Clot Anti- Anti- Joint

Date Gm./bav mo. LE LE DNP DNA Symptoms Remarks

5-19-67 1.25 5 3+ 0 6-15-67 1.0 6 2+ 2+ 0 0

2+ 0 0 1:64 10-6-67 1.0 10 2+

12-8-67 1.0 12 4+ 4+ 1+ 0 0 Dose reduced to 0.75 Gm./day

1-5-68 0.5 13

2-2-68 0.25 14 3+ 3+ + 1:16

+ 1:4

since premature beats were less frequent

Dose reduced to 0.5 Gm./day; premature beats fewer

0

0

0 No symptoms of rheumatic dis- ease at any time

2+ 0 '+ 1:64 4-5-68 0 16 0

' I. G., 64-year-old Caucasian man. No family history of rheumatic disease.

sera from the drug-treated groups; only one was positive in this test and negative in the spot tests. All patients with positive LE cell, anti-DNP, or anti-DNA tests were seen and their medical his-

RESULTS

Table 1 summarizes the results obtained in case 1, which initiated our interest in

tory and findings reviewed. The data were compared to those obtained from

a series of 27 detailed cases of procainamide- induced IUDUS ervthematosus obtained from the

this investigation. Table 2 lists the groups of patients studied and the etiology of their

as age and duration Of as literature and 6 of our own patients.1-15.21 therapy.

Table 2.-Patient Groups Studied Duration of

Total Ages, rs. Medication mo No. M F Etiology* Range MeJan Mean Range Mediin Mean

Procainamide: Asymptomatic 22 12 10 ASHD = 15 36-79 62.5 67.0 1.5-34.0 11.5 12.8

RHD= 1 ? = 4

Mydys= 2

RHD= 7 ?= 9

Mydys= 2 Quinidine 19 10 9 ASHD= 8 31-70 58 57.2 2.0-120 20 31.8

RHD= 6 ?= 4

HCVD= 1

RHD= 0 Hypertension = 9

Misc. disorders = 45

Symptomatic 33 16 17 ASHD = 15 4-77 57.5 61.0 1.0-72 10 14.6

Controls 90 47 43 ASHD=36 50-80 64 64.0

My dys = myotonic dystrophy. RHD = rheumatic heart disease. ? = unknown. ASHD = Arterio- sclerotic heart disease. HCVD = hypertensive cardiovascular disease.

610 MOLINA ET AL.

The sex distribution in all groups was similar. The incidence of rheumatic heart disease in the symptomatic procainamide series from the literature (21 per cent) and quinidine control group (32 per cent) was higher than in the asymptomatic procaina- mide group (5 per cent). Comparison of the cardiac groups by age, sex, and type of arrythmias showed no significant differ- ences. Duration of treatment was similar in both procainamide series and longer in the quinidine group.

The range of daily procainamide dose was from 0.75 to 6.0 Gm. per day, but there was no relationship between total dose at the time of testing and occurrence of posi- tive tests.

The earliest changes appeared at 1% to 4 months in 4 patients who are of particular interest, since 3 had a background sugges- tive of rheumatic or “autoimmune” disease prior to procainamide therapy. One was a 62-year-old Caucasian woman with auric- ular fibrillation of unknown etiology and a history of thyroidectomy for hyperthyroid- ism in 1960. Prior to procainamide therapy she had antithyroid antibodies in a titer of 1:2048, positive anti-DNP and anti-DNA tests, and negative LE cell preparations. The LE cell test became positive 1% months after treatment with 1.5 Gm. per day, al- though no symptoms appeared. The second person, a 63-year-old Caucasian man with paroxysmal auricular tachycardia due to

arteriosclerotic heart disease, had a histo- logically proved rheumatoid nodule re- moved from the elbow in 1963 but never had joint symptoms until 2 months after procainamide, 2 Gm. per day, was begun. ( See Table 3. ) The third patient was a 48- year-old Caucasian woman with minimally active chronic rheumatoid arthritis of 11 years’ duration whose tests became positive 4 months after receiving 2 Gm. daily, and whose disease then exacerbated. Since these 3 had an antecedent history of rheumatic disease, the relationship of the procaina- mide therapy to the serologic abnormalities is difEcult to evaluate. It is interesting that these 3 were the only patients in the group with a medical background possibly pre- disposing to such abnormalities. The fourth was a 61-year-old woman with arterio- sclerotic heart disease who had a positive anti-DNP test 3 months after taking 2.5 Gm. per day, but no rheumatic symptoms.

Study of the number of positive tests and their relationship to duration of therapy and daily dosage at the time of the test showed that 13 of 14 taking 1.25 Gm. per day or more had one or more positive tests, versus only 4 of 8 taking 1.0 Gm. daily or less. The one patient with no positive tests in the higher dose group was supposedly taking 2.0 Gm. per day for 1.5 months, but her reliability is doubtful. This suggests that the average daily dose is a critical factor as well as presence of an underlying

Table 3.-Procainamide Therapy for Artzriosclerotic Heart Disease and Paroxysmal Auricular Tachycardia’

Total Dose, Duration, Rotary Clot Anti- Anti-

Date Gm./day mo. LE LE DNP DNA Remarks

10-4-67 3 1 wk. 0 0 0 0 Rheumatoid factor, $1: 1280; no joint symptoms 11-28-67 3 2 1+ 1+ 1+ 0 Arthralgia and a.m. stiffness for first time; PIP

1-24-68 3 4 RHBf 2+ + + Joint changes persist; CBC, UA normal 2-7-68 3 4 0 1+ 1$ 1+ Joint changes persist; CBC, UA normal 5-22-68 3 7 2f 4+ + 0 Increasingly active rheumatoid arthritis

joints puffy, unable to extend right elbow

OI.M., 63-year-old Caucasian man with rheumatoid nodule removed in 1963. Family and past

t RHB = round hematoxylin bodies. history negative for rheumatic disease.

PROCAINAMIDE-INDUCED SEROLOGIC CHANGES 611

rheumatic background. There was no rela- tionship between total dose or duration of therapy and positive tests. The daily dose, total dose, and duration of procainamide treatment were comparable to those of symptomatic cases reported in the litera-

Autopsy data are available on one asymptomatic patient who committed sui- cide 1 month after having positive LE cell and anti-DNP tests. He was a 55-year-old Caucasian with no family history of rheu- matic disease, and had taken procainamide, 4 Gm. daily, for 19 months to control recur- rent ventricular tachycardia due to arterio- sclerotic heart disease with myocardial infarction. At autopsy there was evidence only of arteriosclerotic heart disease and elevated barbiturate levels. Careful review of histologic material, including spleen and kidney sections, revealed no findings sug- gestive of SLE.

The percentage of abnormalities is shown graphically in Fig. 1. Half the asympto- matic procainamide group, 22 cases, had positive LE cell tests versus only 1 of 19 in the quinidine control series ( P < 0.01) .22

Anti-DNP was present in 15 patients in the procainamide group (68 per cent) versus

only 2 in the quinidine controls (11 per cent) ( P < 0.01). Eight in the procaina- mide series had anti-DNA antibodies (36 per cent) and none in the 19 quinidine con- trols ( P < 0.01). One or more of the ANA tests (LE cell, anti-DNP, or anti- DNA) was positive in 17 of the 22 pro- cainamide cases (77 per cent) versus only 3 of 19 quinidine controls (16 per cent) (P < 0.01). Total complement was normal in 17 of 18 procainamide-treated cases studied and was reduced in one. Similar data were obtained in the quinidine group. Rheumatoid factor was positive in 4 of 21 cases in the procainamide group and in none of 16 tested in the quinidine series.

The one patient in the quinidine group with a positive LE cell test was a 64-year- old Caucasian woman who had received quinidine for paroxysmal auricular tachy- cardia due to arteriosclerotic heart disease for 30 months, from June, 1965, to January, 1968. Rotary and clot LE cell tests were negative before quinidine therapy. Past history revealed a Coombs negative hemo- lytic anemia with negative LE cell prepara- tion and vague arthralgia since 1963. The spleen, removed in March, 1967, showed no evidence of SLE. Her anti-DNP and anti-

PROCAINAMOE

I 0 10 20 30 40 50 60 70 60

Ye POSITIVE

Fig. 1 .-Incidence of positive serologic tests in asymptomatic procainamide-treated patients, a comparable group of quinidine-treated patients, and age-matched controls receiving neither drug. Comparison of any single test or the combined tests in the pro- cainamide group with either quinidine or age-matched control group had a value of P < 0.01.

612 MOLINA ET AL.

DNA reactions were equivocal in undiluted serum.

Two other quinidine-treated patients had weakly positive anti-DNP with no evidence of rheumatic disease.

Within the procainamide-treated group there was no relationship between age and positive tests. Several patients in the pro- cainamide series were older than those in the quinidine group, but when the data were separated by age groups there was no difference in the incidence of positive re- sults. The one patient in the group of 90 controls with a positive anti-DNP was a 79-year-old man with arteriosclerotic heart disease and emphysema. None of the con- trols had positive anti-DNA tests.

DISCUSSION The mechanism through which procaina-

mide induces these serologic reactions is unknown. It appears to be dose related, since 13 of 14 patients taking 1.25 Gm. per day or more had such antibodies compared to only 4 of 8 receiving 1 Gm. daily or less. The majority of our patients were men with arteriosclerotic heart disease and its com- plications with no rheumatic history. The data suggest therefore that the response can be induced in almost all individuals by appropriate exposure to the drug. Pro- cainamide-induced lupus is similar to the idiopathic form of the disease, with the exception that no renal involvement has yet been reported in the 33 cases that we have reviewed or examined.21 In certain other clinical situations, including chronic active hepatitis, and in some patients with rheu- matoid arthritis, ANA also occur without association with nephritis. Many patients with idiopathic SLE never have overt renal damage, despite years of symptoms and positive ANA reactions or persistent posi- tive LE cell preparations. Procainamide- induced disease appears to resemble this more benign form of SLE. An additional difference between procainamide-induced

and classic SLE is found in the occurrence of anti-DNA in 8 of the asymptomatic pro- cainamide-treated patients in our series. Anti-DNA has been strongly associated with nephritis and acutely active disease in previous studies of SLE. In a recent report it has been shown that ANA in lupus pa- tients with nephritis is high in complement- fixing activity, while in other conditions, including the ANA induced by procaina- mide in these patients, the complement- fixing activity was Thus, although the serologic findings may precede lupus- like disease, there are interesting clinical and serologic differences from classic SLE.

Two individuals in our series eventually developed symptoms requiring cessation of the drug. One was a 64-year-old man whose only complaint was tiring easily after 8 months of procainamide therapy. At this point, his LE cell tests were strongly posi- tive. The following month, arthralgia ap- peared in shoulders and fingers. Sedimenta- tion rate (Wintrobe) was elevated. White blood cell count was 3800/mm.3 His symp- toms disappeared 2 weeks after cessation of procainamide without other therapy. More than 4 months passed before the serologic abnormalities reverted to normal. Such gradual regression of serologic abnor- malities is frequently observed in sympto- matic cases of procainamide The second patient was a 50-year-old woman who had myalgia after 15 months of re- ceiving 1.5 Gm. per day. Her LE cell and anti-DNP and anti-DNA tests were positive after 12 months of therapy and remained so 9 weeks after the medication was changed to quinidine. The myalgia sub- sided within a week after discontinuation of procainamide. Thus there are clear indica- tions that the serologic findings of ANA in these patients may herald the development of clinical disease.

Fakhro et al. reported 15 cases of sero- logic and clinical changes induced by pro- cainamide in a group of ‘less than 50

PROCAINAMIDE-INDUCED SEROLOGIC CHANGES 613

patient^."^ Four with serologic changes were asymptomatic. All 4 had positive anti- nuclear antibody tests, and 2 had positive LE cell tests.

Since our preliminary report of these data the observations have been confirmed by the recent paper by Blomgren et al?5 They prospectively studied 16 patients re- ceiving procainamide. Eight developed ANA within 9 months. LE cells were not observed. Two developed symptoms after their ANA tests were positive.

I t is important to follow the serologic status of the procainamide-treated patient, since insidious manifestations of the pro- cainamide lupus-like syndrome are often confused with cardiac complications, par- ticularly thrombophlebitis and pulmonary embolism.*l Joint manifestations or fever may be considered due to a complicating arthritis in older individuals. In procaina- mide-induced lupus, arthritis and arthralgia occurred in 91 per cent of 33 cases.2l Myalgia and calf tenderness were common. Fever was present in 39 per cent. Pleuritic pain occurred in 51.5 per cent. Pleural effusion was present in 33.3 per cent. Pul- monary infiltration occurred in 30 per cent and pericarditis in 18 per cent.

The only 2 patients who developed symp- toms in our series had strongly positive LE cell tests before lupoid manifestations ap- peared. Blomgren et a1.26 observed 2 similar cases. Therefore, it seems probable that serologic testing at the onset of therapy and at intervals of approximately 4 months may alert the physician as to which patients may be susceptible. If necessary, the patient can be changed to other antiarrhythmic agents,

such as quinidine, diphenylhydantoin, or propanolol.

Finally, the occurrence of ANA in un- treated aged individuals must be con- sidered in relation to the data reported here. According to a recent paper by Svec and Veit?* up to 25 per cent of female pa- tients in the 60-90 year age range have serum antinucleoprotein antibodies. Our patients cover a younger age range (45- 70), and in our laboratory only 1 of 90 untreated patients between ages 50-80 showed a positive reaction. Their data, therefore, relate to a substantially higher age range. In addition, there was a striking sex-related difference in the report of Svec and Veit, since their incidence in males was only 2.3 per cent, with an average for both sexes of 16 per cent. The incidence in our procainamide patients was the same in both sexes, a further point of difference be- tween procainamide-induced ANA and ANA occurring in aged populations.

ACKNOWLEDGMENT We are indebted to Dr. Robert F. Maronde,

Professor of Medicine, University of Southern California School of Medicine, for use of his computer program for obtaining a printout of all prescriptions written for quinidine and pro- cainamide in the Outpatient Department. Dr. John Weiner, Assistant Professor of Medicine, University of Southern California School of Medicine, statistically analyzed the data. Dr. Eliot Corday, Dr. Herbert Gold, and Dr.

Harold Bernstein referred patients from their pri- vate practice for this study.

This study was supported by grants from the Arthritis Foundation, National and Southern Cali- fornia Chapters; Public Health Service (Research Grant AM 09703); and the National Lupus Erythematosus Foundation.

SUMMARIO IN INTERLINGUA Le constatationes serologic in patientes cardiac qui monstrava nulle manifestationes

de lupus pharmacogene e qui habeva prendite procainamida durante 6 septimanas o plus esseva comparate con le constatationes serologic in un simile gruppo recipiente quinidina e con illos in un serie de subjectos de controllo appareate in etate e sexo. Alterationes significative occurreva solo in le gruppo de 22 patientes tractate con procainamida (p < 0,Ol). Tests pro cellulas LE esseva positive in 12 (55 pro cento).

MOLINA ET AL. 614

Test a anti-desoxyribonucleoproteina (anti-DNP) esseva positive in 15 (68 pro cento) e tests a anti-ADN in 8 (36 pro cento). Un positive test a cellulas LE, a anti-DNP, o a anti-ADN esseva trovate in 17 (77 pro cento).

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