Can immunization precipitate connective tissue disease?Report of five cases of systemic lupus erythematosus and review of the literature

Seminars in

Arthritis and Rheumatism VOL 29, NO 3

DECEMBER 1999

Can Inlmunization Precipitate Connective Tissue Disease? Report of Five Cases o f Systemic Lupus Erythematosus and Review o f the Literature Steven A. Older, Daniel F. Battafarano, Raymond J. Enzenauer, and Arthur M. Krieg Objectives: To report a series of five patients who developed systemic lupus erythematosus (SLE) after immunization and review the literature on vaccineassociated connective tissue diseases and the theoretical mechanisms that could explain such an association. Methods: Uncontrolled retrospective analysis of cases identified sporadically over 7 years at three centers. Results: In our series of 5 patients, symptoms of SLE developed within 2 to 3 weeks after secondary immunization. All patients met American College of Rheumatology (ACR) criteria for the diagnosis of SLE. In most patients, symptoms have been persistent. Conclusion: Although a coincidental association between vaccination and the onset of SLE cannot be excluded, the temporal relationship with the development of symptoms makes it immunologically plausible that vaccination triggered systemic autoimmunity in these rare cases. We propose that epidemiological studies be performed to examine this potential association in more detail to quantitate the risk and identify possible genetic risk factors. Semin Arthritis Rheum 29:131-139. This is a US government work. There are no restrictions on its use.

INDEX WORDS: Immunization; vaccination; systemic lupus erythematosus.

T

HE PATHOGENESIS of autoimmune connective tissue diseases such as systemic lupus erythematosus (SLE) remains obscure despite intensive investigation. Microbial infection has been frequently hypothesized to be a trigger for the

initiation of autoantibody production, perhaps operating through mechanisms such as molecular mimicry. In theory, such a mechanism could also trigger autoantibody production after deliberate immunization with foreign proteins. In fact, even immuniza-

From the Rheumatology Service, Brooke Army Medical Center, and Veterans Affairs Medical Center and Department of Medicine, University of lowa. Steven A. Older, MD: Chief Rheumatology Service; Daniel F. Battafarano, DO: Staff, Rheumatology Service; Raymond J. Enzenauer, MD: Assistant Chief Rheumatology Service; Arthur M. Krieg, MD: Professor, Department of Medicine. No financial support was received for the preparation of this manuscript.

The opinions or assertions contained herein are those of the authors and do not necessarily reflect the views of the Department of the Army, Department of Defense, or the United States Government. Address reprint requests to Steven A. Older, MD, Rheumatology Service, Landstuhl Regional Medical Center, CMR 402, Box 79, APO AE 09180. This is a US government work. There are no restrictions on its use. 0049-0172/99/2903-000150.00/0

Seminars in Arthritis and Rheumatism, Vol 29, No 3 (December), 1999: pp 131-139

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tion with a self-antigen can induce the production of lupus-associated autoantibodies in various animal models (1-3). Immunization against infectious organisms is one of the most important advances of modern medicine. "With the exception of safe water, no other modality, not even antibiotics, has had such a major effect on mortality reduction and population growth" (4). Numerous studies have shown that immunizations are highly effective, with a low incidence of serious systemic adverse events. Although local reactions and mild self-limited constitutional symptoms are common, important complications are infrequent. Of the latter, neurological events are most prevalent, with autoimmune or rheumatic phenomena being rarely reported. In this article, we describe five cases of SLE that developed after immunization. Case 1

A previously healthy 31-year-old white man was activated from the Army Reserves for deployment to the Persian Gulf during Operation Desert Shield. At that time, he received a series of immunizations: typhoid, influenza, and meningococcal vaccines, tetanus toxoid, and immune serum globulin. As per military protocol, all vaccines were given intramuscularly into the fight arm, whereas the immune globulin was administered intramuscularly into both gluteals. On the day after immunization, he developed a tender "grapefruit-sized" erythematous reaction in his fight deltoid muscle at the site of the typhoid injection. One week later, he had developed fight upper extremity paresthesia, which was followed by nearly complete loss of motor function in that arm. Over the next several weeks he developed recurrent left-sided pleurific chest pain with pleural effusion, triphasic Raynaud's phenomenon, polyarthritis of wrists, elbows, and ankles, recurrent irregular violaceous rashes over both upper extremities, and acral edema with "red" urine. Musculoskeletal examination, performed 8 weeks after the immunizations were administered, showed bilateral wrist synovitis. His upper extremities showed Medical Research Council (MRC) (5) grade 3/5 strength of both proximal and distal muscle groups with associated atrophy. The lower extremity muscles showed MRC grade 4/5 strength. Deep tendon reflexes were absent in the upper extremities and weakly present in the lower extremi-

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ties. Pinprick and vibratory sensations were diminished in both upper and lower extremities. Skin examination showed urticaria and livido reticularis of both upper extremities. Pertinent laboratory findings included a white blood cell count of 3,100 cells/mm 3, hemoglobin 11.0 g/dL, and Westergren erythrocyte sedimentation rate of 80 mm/h. Urinalysis showed 300 mg/dL protein, 15 to 20 red blood cells per high-power field, and white blood cell and red blood cell casts. Chemistry profile showed normal serum electrolytes and renal and liver functions. Antinuclear antibodies were present at 1:1,280 titer in a speckled pattern, SS-B at 1:4 titer, anti-double-stranded DNA at 1,890 IU/mL (normal, 100 IU/mL), and rheumatoid factor at 1:80 titer. C3 was 65 mg/dL (normal, 85 to 193 mg/dL), and C4 was 7 mg/dL (normal, 15 to 45 mg/dL). Cerebral spinal fluid indicated 4 red blood cells/mm 3, 2 white blood cells/mm 3, protein of 139 mg/dL, glucose of 52 mg/dL, and immunoglobulin (Ig) G synthesis of 56.5 mg/24 hours (normal, <3.5 mg/24 hours); 5 oligoclonal bands were present. Further evaluation showed bilateral pleural effusions by chest radiograph, a small pericardial effusion by echocardiogram, polyradiculoneuropathy by electromyography and nerve conduction velocities, immunoglobulin and complement staining at the dermal-epidermal junction by skin punch biopsy of rash, and diffuse proliferative glomerulonephritis by renal biopsy. Seven years after diagnosis, despite initial therapy with high-dose corticosteroids and intravenous cyclophosphamide and ongoing treatment with hydroxychloroquine, azathioprine, and continued corticosteroids, he continues to suffer recurrent rashes, Raynaud's phenomenon, inflammatory arthritis, serositis, and cytopenias. He has residual neurological weakness, recurrent transient ischemic attacks, and chronic proteinuria. He has recently developed osteoporotic rib fractures. Case 2

A 23-year-old Hispanic woman, previously healthy and taking no medications, received a series of immunizations as a part of her Basic Training induction into the United States Army. By regulation, the following inoculations were performed: measles, mumps, rubella (MMR; given intramuscularly into the left arm), typhoid, influenza, and meningococcal vaccines and tetanus and

SLE FOLLOWING IMMUNIZATION

diphtheria toxoids (given intramuscularly into the fight arm). Additionally, she received an oral polio vaccination. Two days later, she complained of fever, nausea, vomiting, fatigue, and arthralgias that precipitated a 4-day hospitalization. No diagnosis was rendered at that time, and her symptoms waned. Two weeks after the immunizations, she developed another flu-like illness with a nonproductive cough, vomiting, diarrhea, fever, arthralgias, and a facial rash. Physical examination at that time indicated a temperature of 102°F, malar rash, occipital alopecia, oral ulcers, and decreased breath sounds at the left lung base. Laboratory studies included a white blood cell count of 2,700 cells/ mm 3 with 26% lymphocytes, hemoglobin 9.7 g/dL, and a Westergren erythrocyte sedimentation rate of 52 rnm/h. Antinuclear antibodies were present in a titer of 1:640. Also present were antibodies to SS-A, RNR and Sm antigens. Antibodies to doublestranded DNA were measured at 13 IU/mL (normal, < 10 IU/mL). C3 was 29 mg/dL (normal, 86 to 184 mg/dL), and C4 was < 8 mg/dL (normal, 15 to 45 rng/dL). Chest radiograph showed a left pleural effusion. Treatment with oral corticosteroids produced an incomplete clinical response. Shortly after discharge from the hospital, she was lost to follow-up. Her ,current condition is unknown. Case 3

A 25-year-old healthy black man received a series of vaccinations as a part of his Basic Training induction (see case 2). Three days after immunization, he developed low-grade fevers, myalgias, arthralgias, and malaise. Approximately 2 weeks later, he noted the onset of painful swelling in the joints of both hands and wrists, scattered pruritic rashes, diffuse lymphadenopathy, and painful breast enlargement, in addition to persistent fevers and malaise. He soon developed left pleuritic chest pain and dyspnea on exertion. Physical examination showed fever, symmetrical inflammatory arthritis, bibasilar pulmonary crackles, lymphadenopathy, splenomegaly, and tender gynecomastia. Laboratory studies were remarkable for 17,000 white blood cells/mm 3, hemoglobin of 10.0 g/dL, Westergren erythrocyte sedimentation rate of 52 ram/h, creatinine kinase of 1,410 U/L (normal range, 21 to 232 U/L), and mild transaminase elevations. A direct Coomb's was positive, but other serologies were negative. A chest radiograph showed an

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enlarged cardiac silhouette and bibasilar infiltrates. Echocardiogram showed a posterior pericardial effusion. Lymph node biopsy was interpreted as "reactive," without evidence for infection or malignancy. Additional testing indicated the presence of antinuclear antibodies in a titer of 1:640 and anti-double-stranded DNA at 193 IU/mL (normal, <100 IU/mL). Serum estradiol was 73.5 pg/mL (normal range for males, <35 pg/mL). Computed tomography of the chest indicated a left lower lobe infiltrate, a small left pleural effusion, and symmetrical gynecomastia. Treatment with oral corticosteroids resulted in rapid resolution of clinical symptoms, but recurrent inflammatory arthritis and serositis during steroid taper required the institution of hydroxychloroquine and azathioprine. Two years after initial diagnosis, his disease continues to be active. Methotrexate has been added to his treatment regimen, and he continues to require moderate to high-dose corticosteroids.

Case 4

A 28-year-old black woman received typhoid and hepatitis A immunizations as a part of the routine soldier immunization program. Three weeks later, she noted lower extremity muscle pain and weakness while riding her bicycle. Within 2 months she had developed recurrent oral ulcers, alopecia, and inflammatory polyarthritis of the small joints of her hands, ankles, knees, and elbows. Past medical history was remarkable for the onset of Raynaud's phenomenon 3 years earlier, at which time serum antinuclear antibody testing, the only laboratory test ordered, was negative. Other medical problems included essential hypertension, cold-induced asthma, and migraine headaches. Medications included nifedipine and naproxen regularly, and Midrin (Carnrick Laboratories, Cedar Knolls, NJ), Fiorinal (Novartis, Summit, NJ), and an albuterol inhaler as needed. At the time of the rheumatology evaluation, physical examination was significant only for scattered dilated capillary loops on nailfold capillary microscopy and MRC grade 4/5 weakness at the right hip flexors. Laboratory studies showed a serum creatine kinase of 764 IU/L (normal range, 20 to 271 IU/L), and the presence of anti-Sm, anti-RNR and antinuclear antibodies (1:2,560 titer, speckled pattern). Complete blood count, urinalysis, chemistry profile, complement levels (C3 and

1~34

C4), and double-stranded DNA were all normal or negative. She was diagnosed with SLE and treated with oral corticosteroids and hydroxychtoroquine, which resulted in prompt resolution of her symptoms. However, now, 14 months after diagnosis, she continues to suffer from recurrent oral ulcers, alopecia, Raynaud's phenomenon, myositis, and inflammatory polyarthritis. Methotrexate has been added to her treatment regimen.

Case 5

A 29-year-old active-duty black woman was immunized with anthrax vaccine in her right arm before and during deployment to Saudi Arabia. Twelve days after the second immunization into her left arm, she developed potyarthritis, followed within 1 week by the emergence of malar rash, oral ulcers, alopecia, and fever up to 102°R Evaluation in a Saudi Arabian hospital confirmed the physical findings. A third anthrax vaccination was given 2 days after the onset of arthritis, but the remaining three doses in the series of six were canceled. Laboratory studies indicated a white blood cell count of 2,300 cells/mm 3, a hemoglobin of t 0 g/dL, and a Westergren sedimentation rate of 42 mm/h. Urinalysis showed 3 + proteinuria and microscopic hematuria. Further evaluation at a United States medical center showed a 24-hour urine collection of 1,433 mg protein and a creatinine clearance of 104 mL/min. Renal biopsy showed mesangial lupus nephritis with occasional subepithelial deposits seen by electron microscopy. Antinuclear antibody was present in a titer of 1:640. Antibodies to double-stranded DNA were measured at 148 IU/mL (normal, < 7 IU/mL). Also detected were a positive Coomb's test and an IgG anticardiolipin antibody measured at 19.9 GPL (N < 12.3 GPL). She was hypocomplementemic with a C3 of 59 mg/dL (83 to 177) and C4 less than 10 mg/dL (t5 to 45). Treatment with oral corticosteroids and hydroxychtoroquine resulted in marked improvement of arthritis and resolution of the rash and fevers. However, after 8 months, she continues to experience recurrent inflammatory arthritis and oral ulcers, and she has persistent microscopic hematttria. Serum obtained on entry into the US Army 4 years earlier was available for analysis from the Department Of Defense Serum Repository. After written permission, we studied this serum for the presence

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of antinuclear antibody, which was found in a titer of 1:320. DISCUSSION

Most adverse effects resulting from immunization are minor and self-limited. Symptoms such as local swelling, low-grade fevers, arthralgias, myalgias, and malaise are generally thought to be due to reactions to the noxious components of the vaccine itself. Neurological complications are not infrequent and have been divided into those due to infection by live-attenuated viral vaccines and those that have been termed "allergic," such as polyradiculoneuropathy, Guillain-Barr6 syndrome, acute transverse myelitis, and optic neuritis(6). Some reactions, such as the arthritis associated with the rubella vaccine (7,8) and idiopathic thrombocytopenic purpura associated with the MMR immunization (9), mimic manifestations of the native infection. Also described after immunization are rheumatic conditions, which are self-limited and neither mimic the native infection nor relate to a particular type of vaccine. Examples include reactive arthritis (10-13), Henoch-Sch6nlein purpura (14-17), and small vessel vasculitis (18). The development of chronic connective tissue disease after immunization has been rarely reported in the medical literature. We describe the onset of SLE in five soldiers who received commonly administered immunizations as a part of either predeployment preparation (cases 1, 5), basic training induction (cases 2, 3), or routine soldier immunization (case 4). All five cases met American College of Rheumatology criteria for SLE (19). The interval between immunization and the onset of symptoms in each of the cases was similar to that described in serum sickness; however, contrary to serum sickness, the manifestations did not resolve. Two of the five patients were male, contrary to the marked female predominance of idiopathic SLE. None of the subjects had been exposed to drugs known to induce lupus, nor did they relate a family history of connective tissue disease. No subject described signs or symptoms of connective tissue disease before their vaccinations (except the history of Raynand's in case 4). To our knowledge, the first report of SLE after immunization was described by Fox in 1943 (20). He presented the case of a 17-year-old girl who developed signs and symptoms of SLE 1 week after receiving anti-tetanus sertun. Her condition progres-

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sively deteriorated over more than 4 months, culminating in death. Her diagnosis of SLE was confirmed at autopsy and was manifested by malar rash, polyarthritis, serositis, glomerulonephritis, and Libman-Sacks endocarditis. In 1948 Ayvazian and Badger (21) published the case histories of 3 young nursing students who had received repeated typhoid-paratyphoid (diphtheria) and streptococcus toxin (scarlet fever) immunizations (21). Within months of these immunizations, each student developed manifestations of fulminant and fatal SLE. In all three cases, the diagnoses were confirmed at autopsy. More recently, Tudela et al (22) and Guiserix (23) reported separate cases of SLE within 2 weeks of the first dose of recombinant hepatitis B vaccine. Other chronic connective tissue diseases also

have been described after immunization. In 1956, Robertson and Leonard (24)estimated the occurrence of "major delayed reactions" as 0.25% to 0.3% of approximately 200;000 military recruits receiving "various inoculations," including paratyphoid A and B (T.A.B.T.) (24). These reactions usually occurred 7 to t0 days after immunization and were described clinically as resembling acute rheumatic fever, rheumatoid arthritis (RA), polyarteritis nodosa (possibly Wegener's granulomatosis), thrombocytopenic purpura, and "disturbances of the reticuloendothelial system." Aside from this report, a total of 43 cases of chronic connective tissue disease arising after immunization have been adequately documented in the English language literature (20-37)(Table 1). Thirteen cases of inflammatory polyarthritis meeting 1987 American

Table 1: Connective ]issue Disease After Immunization Disorder

Vaccine

Systemic lupus erythematosus

Tetanus Typhoid/paratyphoid

Typhoid Smallpox

BCG*

14

M

12 10 6 13 60 66 46 48 45

M M F M M F M F M

Combination

Anthrax Tetanus Hepatitis 8

Reiter's syndrome Dermatomyositis

Diphtheria

Polyarteritis nodosa

DPT¢ Influenza

Pertussis *Bacille Calmette Guerin, t Diphtheria-pertussis-tetanus.

Gender

17 F 18 F 18 F t8 F 43 F 26 F 31 M 23 F 25 M 28 F 29 F 34 F [12 patients] 20 F 49 F [10 patients] 22 M 5 M

Hepatitis B

Rheumatoid arthritis

Age (yr)

Onset of Symptoms

Reference

7 days NA NA N.A 14 days 7 days 7 days 14 days 14 days 21 days t 2 days 21 days < 6 weeks 4 days 1 day 10-21 days 10 days 14 days 5-6 weeks 2-3 weeks 1 day 6 weeks 10 days 7 days 4 days 10 days 8 days 7 days

20 21 21 21 22 23 Present Present Present Present Present 25 26 27 28 29 30 31 32 32 33 33 33 34 34 35 36 37

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Rheumatism Association (ARA) criteria for RA have been reported after tetanus toxoid administration (25,26). Twelve cases of apparent RA also have been reported after recombinant hepatitis B vaccination (27-29). Two features of hepatitis B-induced RA are noteworthy. First, the development of inflammatory arthritis occurred 1 to 3 weeks after the second or third immunization. Second, most of these individuals had HLA class II genes expressing the RA shared motif, indicating that they were genetically susceptible to developing RA. One case of Reiter's syndrome was reported after a typhoid vaccination (30). Six cases of dermatomyositis following different immunizations have been reported in English (31-33). Systemic necrotizing vasculitis has been reported in five cases (34-37). In considering the reported cases of postimmunization connective tissue disease, a few observations may be made. The development of symptoms approximately 1 to 3 weeks after secondary immunizations is biologically plausible as resulting from vaccine-related autoimmunity, because this is the time during which the boosted immune response is at its peak. In contrast, very few of these reported cases had disease onset after an initial immunization or within the first 3 days of vaccination. This suggests that the mechanisms responsible for vaccine-related connective tissue disease may differ from those responsible for neurological sequelae. There are no evident associations with patient age or gender; however, unlike the generally female predominance of idiopathic connective tissue disease, the incidence of postimmunization connective tissue disease was similar for men and women (Table 1). Except for the limited association of tetanus toxoid (25,26) and hepatitis B vaccination (27-29) with the development of RA, the vaccine type and class (live or killed) seems to bear no correlation with the resultant rheumatic disease. Hyperimmunization was associated with five of the reports (21,25,33,37); however, large-scale studies have shown little risk of repeated intense immunization, even with large antigen doses (38,39). Most of our cases received multiple or combination vaccines, but single-agent vaccines also appear to be able to cause vaccine-associated rheumatic disease (Table 1). Administration of multiple or combination vaccines is not considered more likely to induce adverse effects than are single-agent vaccines (40).

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Rare reports of SLE induction after immunization should not preclude routine immunization in patients with established SLE. The excess morbidity and mortality associated with infection in SLE (41) indicates the clear benefits of immunization in this patient population. The cases presented here raise an etiologic question distinctly separate from concerns regarding disease flares in SLE patients receiving routine immunization. Immunization of SLE patients with influenza vaccine (42-44) and recombinant hepatitis B vaccine (45) has been well tolerated. In a recent study involving 73 SLE patients receiving multiple vaccines simultaneously, only six patients (8%) developed a mild increase in SLE disease activity scores, with an equal number of patients improving postimmunization (46). These studies reinforce the safety of immunization in patients with known SLE. Immunization with microbial antigens or even self antigens is an established mechanism of inducing lupus-like disease in experimental animal models. For example, immunization with certain microbial DNA-binding proteins or even microbial DNA is sufficient to induce antibodies against doublestranded DNA (47-49) and other autoantigens (50). Experimental immunization with the polyomavirus BK induces anti-dsDNA antibody production in normal rabbits (51), as can primary infection in human children (52). Antibodies cross-reactive for microbial antigens and self double-stranded DNA can arise spontaneously after immunization (53), and they may have pathogenic potential (54). The evolution of the autoantibody response to chromatin likewise displays characteristics of a T celldependent immunization response (55). Among the other autoantibody responses that can be induced by infection or deliberate immunization are anti-Sm (1), anti-Ro (2), and anti-ribosomal (3). Immunization with a single self-epitope can drive an autoreactive response if the epitope is multimerized, indicating the important role for antigen structure (56). In these cases, repeated immunizations are required to raise autoreactive responses. The described cases of connective tissue disease after immunization are decidedly rare. Whether these cases represent a cause-and-effect relationship or merely coincidence remains conjectural. Because cases have been sporadically reported, there may be a tendency to assume coincidence rather than association. However, in these de-

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137

scribed cases, the temporal relationship between immunization and disease onset is surprisingly precise (approximately 1 to 3 weeks), reminiscent of a serum sickness-like reaction that could have been driven by the large amount of antigen. Nonetheless, serum sickness syndrome should have resolved spontaneously and should not give rise to the observed autoantibody production. The rapid dew~,lopment of a severe local reaction in case 1 is compatible with an Arthus-type reaction, which may have been precipitated by the simultaneous administration of antigen and immune globulin. Of course, an Arthus reaction could not directly explain the subsequent clinical course. We hypothesize that these patients may have had an unrecognized genetic predisposition to autoimmunity, which was triggered by immunization. If larger numbers of patients with vaccine-induced lupus can be identified, then studies to identify genetic risk factors should be performed to permit safer vaccination in the future. With such an understanding, it should become possible to develop safer ways for vaccinating patients who may be prone to developing autoimmune diseases. Of note, recent studies indicate that certain types of vaccination strategies may actually reduce the severity of lupus in genetically predisposed mice (57-59). Several categories of "environmental triggers" have been attributed to the precipitation of clinical SLE. Included among these are ultraviolet radiation, food, infection, and drugs (60,61). We propose that immunization be added to this list, at least until

epidemiological data can be gathered to quantify the frequency of this occurrence. Recognition of postimmunization connective tissue disease as an entity should not necessarily change current immunization practices, given the proven efficacy and safety profiles of the latter. Indeed, by reducing the incidence of infections, vaccination of individuals genetically prone to SLE would diminish their exposure to more potent immune-stimulating infections and thereby may reduce the risk of disease. Recognition of the potential role of vaccination as a trigger for autoimmunity may serve as a focus for further investigation into the etiopathogenesis of connective tissue diseases. Elucidation of association, risk, or causality will likely require a large multicenter study over a significant period. A critical issue in performing such a study will be the use of a stringent definition of vaccine-associated induction of SLE to minimize inclusion of coincidentally associated cases. Based on our experience and on previous reports of vaccine-associated connective tissue diseases, we propose that cases be considered as being possibly vaccine-related if symptoms develop within the first 3 weeks after a booster immunization, and that cases be considered less likely to be vaccine-related if symptoms develop after this time.

ACKNOWLEDGMENT The authors thank Drs Michael Fischbach and Augustin Escalante for their contribution of case 2.

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