IV Immunoglobulin Treatment of 4 Patients w/Juvenile Poly Arthritis Associated w/Parvovirus B19 Infection & Antiphospholipid Antibodies

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Intravenous Immunoglobulin Treatment of Four Patients With Juvenile

Polyarticular Arthritis Associated With Persistent Parvovirus B19

Infection and Antiphospholipid Antibodies

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Hartwig W Lehmann; Annelie Plentz; Philipp von Landenberg; Esther

Müller-Godeffroy; ne Modrow

Arthritis Res Ther 6(1):R1-R6, 2003. © 2003 BioMed Central, Ltd.

Copyright to this article is held by the author(s), licensee BioMed

Central Ltd. This is an Open Access article: verbatim copying and

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original citation.

Abstract

Children with rheumatic oligoarthritis and polyarthritis frequently

establish persistent parvovirus B19 infections that may be associated

with the production of antiphospholipid antibodies (anti-PL IgG). In

this study we analysed the influence of high-dose intravenous

immunoglobulin (IVIG) therapy on virus load, on the level of anti-PL IgG

and its potential capacity to improve the patients' clinical status.

Four juvenile patients with long-lasting polyarticular rheumatic

diseases and persistent parvovirus B19 infection, associated in three

cases with the presence of antibodies against ?2-glycoprotein I

(anti-?2GPI IgG), were treated with two cycles of IVIG on five

successive days (0.4 g/kg per day). Clinical parameters including scores

of disease activity, virus load and anti-PL IgG levels were determined

before, during and after treatment. Two patients showed a complete

remission that has lasted 15 months. During that period they showed

neither clinical nor laboratory signs of inflammation. Viral DNA was not

detectable in serum, and a decrease in anti-?2GPI IgG was observed. As

assessed by the Childhood Health Assessment Questionnaire and the

Health-related Quality of Life Questionnaire for Children, both patients

were no longer restricted in their activities of daily living and no

impact on the health-related quality of life was observed. In one

patient the therapy failed: there was no improvement of symptoms and no

decrease in virus load or inflammatory parameters. In the fourth

patient, clinical and laboratory parameters did not improve despite a

decrease in both viral load and anti-PL IgG. Our results show that the

use of IVIG to treat parvovirus B19-triggered polyarticular rheumatic

disease of childhood might offer an opportunity to improve this

disabling condition.

Introduction

Parvovirus B19 infection has been associated with a wide spectrum of

diseases. Besides acute infection resulting in anaemia and erythema

infectiosum (fifth disease), a rash illness of childhood, hydrops

fetalis in pregnant women and acute symmetrical polyarthropathy in

adults have been reported as clinical manifestations. Depending on the

haematological status of the host, B19 infection can be associated with

haematopoietic disorders such as anti-plastic crisis, thrombocytopenia

and pancytopenia. Hepatitis, myocarditis, myositis, neurological disease

and vasculitis can occur occasionally.[1] The relation of the infection

to acute arthritis–arthralgias in children is well known. Some of the

affected children develop chronic arthritis that is indistinguishable

from juvenile idiopathic arthritis.[2-5] In these patients parvovirus

B19 could frequently be detected in synovial fluid and serum samples. In

some of the affected children the infection persisted over months and

years. Furthermore we recently reported that in these children

persistent parvovirus B19 infection was frequently associated with the

presence of antiphospholipid antibodies (anti-PL IgG).[6]

During the past decade the treatment of various sequelae of chronic

parvovirus B19 infection with high-dose intravenous immunoglobulin

(IVIG) has emerged as a powerful tool to improve patient status or to

cure the disease. In most instances, immunosuppressed patients or

patients with haematopoietic disorders have been treated.[1] Solid

organs (such as kidney) have also been shown to become infected by

parvovirus B19 and to respond to immunoglobulin treatment.[7] Stahl and

colleagues reported a marked improvement after IVIG treatment in two of

three young patients with oligoarthritis and persistent infection with

parvovirus B19.[8] Here we show the results after treatment of four

adolescents having different polyarticular rheumatic diseases triggered

by parvovirus B19.

Materials and Methods

Patients

For IVIG treatment we selected four patients with juvenile idiopathic

arthritis that had lasted for between 23 and 125 months and persistent

B19 infection. Patients were classified according to International

League of Associations for Rheumatology criteria (Table 1).

Patient 1, a 12-year-old HLA-B27-negative girl, had

rheumatoid-factor-positive polyarthritis (negative for antinuclear

antibodies [ANA] and double-stranded DNA). Parvovirus B19-specific IgG

and IgM antibodies were initially detected 4 months after the onset of

symptoms and remained detectable during the whole observation time. At

the beginning of the disease the cervical spine, one ankle and one

metacarpophalangeal I joint were affected. Treatment was established

with methotrexate (MTX) (subcutaneous, 12 mg/m2 body surface per week)

in combination with an intravenous prednisolone pulse. Despite a

therapeutic regimen with combined applications of non-steroidal

anti-inflammatory drugs (NSAID), MTX and oral prednisolone, multiple

relapses occurred in small and large joints. First erosions (signal

cysts) were seen. Multiple treatments with arthrocentesis and

intra-articularly injected crystalline glucocorticosteroids

(triamcinolone hexaacetonid; TCHA) were performed. B19 DNA was

repeatedly amplified from synovial fluid and serum samples and

anti-?2GPI IgGs were detected (Table 1).

Patient 2, an HLA-B27-positive 17-year-old girl, had psoriatic arthritis

with daktylitis and multiple psoriatic efflorescences. Disease started

at the age of 9 years and activity was mild. After 7 years, mutilations

of metatarsophalangeal V and erosions of metatarsophalangeal IV and

metacarpophalangeal II joints was observed by X-ray. Frequent relapses

occurred subsequently, requiring subcutaneous MTX (up to 20 mg/week),

NSAID and multiple TCHA injections into small and large joints. X-ray

examinations showed slow progression of the erosions. IgG against

parvovirus B19 proteins VP1 and VP2, low titres of VP2-specific IgM and

viral genomes were detected during the first serological screening

performed at the age of 16 years. IgM antibodies and parvovirus DNA

remained detectable, together with anti-?2GPI IgG in subsequent serum

and in all synovial fluid samples (Table 1).

Patient 3, an HLA-B27-negative 16-year-old boy, had psoriatic arthritis

with psoriatic efflorescences at the scalp, starting with recurrent

monoarthritis of the right knee at the age of 12 years. The patient was

treated with low-dose prednisolone and repeated arthrocentesis of the

knee. After a relapse affecting the right knee and the wrist, oral MTX

was prescribed. During a relapse of the wrist and arthritis of the left

elbow, both joints were treated with TCHA. Despite a weekly

administration of 20 mg of subcutaneous MTX, he developed massive

effusions of multiple large joints requiring TCHA. Parvovirus B19 DNA

was detected in four different synovial fluid samples from the right

knee, both hips and the left elbow, and in two serum samples obtained

during the 6 months before the study (Table 1).

Patient 4, a 12-year-old girl, developed an effusion of the right knee

at the age of 21 months. Because of the transitory presence of

B19-specific IgM antibodies, parvovirus-associated reactive arthritis

was diagnosed. Initially the patient was treated with NSAID, low-dose

prednisone and chloroquine, which was subsequently replaced by

sulphasalazine. Despite this treatment regimen the patient developed

recurrent arthritis of both knees requiring multiple TCHA treatment, and

arthroscopic synovectomy of the right knee was performed. After a

long-lasting remission period NSAID treatment was stopped. Subsequently

relapses of both knees occurred. At this time point, nearly 10 years

after the initial detection of parvovirus B19-specific IgM, anti-?2GPI

IgG was detected and B19 DNA was amplified from serum. During a further

flare (4 months before the study), B19 DNA was found in serum and in the

synovial fluid of the left knee. The IVIG treatment was started after a

relapse occurred in the left knee, both ankles and the calcaneocuboid

and talonavicular joints.

Treatment Regimen and Monitoring of the Patients

IVIG (commercially available immunoglobulin preparations previously

shown to contain large amounts of IgG against the viral capsid proteins

VP1 and VP2 and to be free of contaminating B19 DNA; Varitect CP;

Biotest, Dreieich, Germany) were administered at 0.4 g/kg body weight

per day for 5 days. A second cycle of treatment was applied 4 weeks

after the end of the first cycle. Patients were examined before each

treatment cycle, 1 and 9 months after the end of the second cycle and

subsequently at intervals of 3 months. Erythrocyte sedimentation rate

(ESR), complete blood count, C-reactive protein (CRP), alkaline

phosphatase, transaminases and ?-glutamyltransferase, creatine kinase,

lactate dihydrokinase, protein electrophoresis, urinalysis, ANA,

extractable nuclear antigens (ENA) and rheumatoid factor were

determined. To exclude other infections with arthritis-associated

infectious agents, various antibody titres were determined (for example

Borrelia, Yersinia, Campylobacter, Chlamydia, Salmonella and

streptolysin O). To estimate the clinical course, the number of affected

joints were counted at each presentation. The affected joints were

classified as active arthritis according to the American Rheumatism

Association criteria.

Detection of B19-Specific Antibodies, Immunocomplexes, Genomes and

Anti-Pl Igg

Patient samples were analysed for IgG and IgM against the structural and

nonstructural proteins of parvovirus B19 by Western blotting and ELISA

assays (RecomBlot and RecomWell; Mikrogen GmbH, Munich, Germany). The

total IgG content of these samples was determined by nephelometry. The

amounts of immunocomplexed virus, of B19 DNA and of anti-PL IgG were

determined as described.[3,6]

Global Assessment and Disease Impact on Activities of Daily Living

In addition to the doctor's global assessment, both parent's global

assessments were recorded on a visual analogue scale ranging from 0

(healthy) to 10 (severely affected). Restrictions in activities of daily

living and the impact on the health-related quality of life were

estimated by using the Childhood Health Assessment Questionnaire and the

Health-related Quality of Life Questionnaire for Children (KINDL) as

described.[2] Informed consent was obtained from the parents as well as

from the patients.

Results

Apart from elevated inflammatory parameters, no gross abnormalities in

the routine laboratory analysis were seen, except elevated

concentrations of total IgG at the ends of both treatment cycles and 4

weeks after the second cycle in all patients. VP1-specific and

VP2-specific reactions were obtained in all samples diluted 1:105 to

1:106. A slight anaemia and an elevated creatine kinase (CK) was

observed in patient 2. ANA were not detected in patients 1, 2 and 3.

Patient 4 showed a titre of 1:1600 in all samples. ENA were not

detectable (Table 2).

Patient 1 responded well to IVIG treatment. At the end of the cycles,

viral genomes could not be detected and anti-PL IgG declined. X-ray

examinations showed regression of the erosions. Oral steroid and NSAID

therapy were gradually decreased to zero. MTX application was continued.

During a post-treatment observation period of 15 months, no relapse

occurred and the patient was free from disease (visual analogue scale =

1; Table 2). The disability index decreased from 0.13 to 0. The

health-related quality of life increased from 75 to 83.3.

Patient 2 did not benefit from IVIG, although the elevated CK (103 U/l)

normalized during the first treatment cycle and the number of joints

affected with arthritis was reduced from four to two. The elevated ESR

and CRP increased slightly. Virus load and the level of anti-PL IgG

declined, but the patient still has recurrent pain in her lower back,

wrists, hips and knees. Nine months after treatment the left ankle was

swollen, the left wrist was painful and the range of motion was

decreased. The disability index increased during the observation period

from 0.63 to 1.25 (range: 0, no restrictions; 3, extreme restrictions).

The summary score of the KINDL decreased slightly from 62.5 to 59.4.

During the second IVIG treatment cycle and afterwards, patient 3

developed large effusions of the right and left hip followed by

recurrent massive effusions of the right knee requiring treatment with

TCHA. B19 DNA (103 genome equivalents/ml) was amplified from both serum

and synovial fluid. One serum sample obtained at the end of the second

cycle contained anti-PL IgG (Table 2). ESR (34 mm/h) and CRP (0.9 mg/dl)

were moderately increased, but antibody titres against various

arthritis-associated infectious agents were unrevealing. Oral

prednisolone was increased from 3 mg/day to 25 mg/day (subdivided in two

doses of 20 mg in the morning and 5 mg in the evening of each day);

treatment with MTX was unchanged. Despite this regimen, two further

flares at the right knee occurred and arthroscopic synovectomy was

performed. Histology revealed an acute synovitis with massive

infiltrations of plasma cells, and B19 DNA was amplifiable from the

tissue specimen. After a further massive effusion at the right knee,

cyclosporin A was added to the therapeutic regimen (3.5 mg/kg body

weight). After two subsequent relapses (left elbow, right hip) the

patient reached a disease-free interval lasting 12 months. The

disability index before treatment was 0.13; this decreased to 0 after

the various therapeutic interventions. The KINDL summary score increased

from 62.5 to 75.0.

In patient 4 the effusions of five large joints decreased and painful

joint motion disappeared during the first IVIG treatment cycle. No

concomitant therapy except continuing naproxen (10 mg/kg body weight)

was applied. After the second IVIG cycle only a diminished range of

motion of the left calcaneocuboid and talonavicular joints was observed,

which further normalized. Virus DNA was not detectable and anti-PL IgG

declined, despite a slight increase observed 9 months after IVIG

treatment without reappearance of symptoms (Table 2). Fourteen months

after the first treatment cycle, naproxen treatment was reduced to 5

mg/kg body weight without disease recurrence. The disability index

normalized from 0.25 (minor disabilities) to 0. All activities of daily

living were performed without any restrictions. The summary score of the

KINDL increased from 78.1 to 86.5. At 15 months after treatment the

child was still in full remission.

Discussion

The therapeutic trial with intravenous application of high-dose

immunoglobulins resulted in an obvious improvement of symptoms in two of

four adolescents with long-lasting, severe polyarticular rheumatic

diseases. Previously all patients had failed to respond to intensive

immunosuppressive therapy. Despite the development and presence of

B19-specific immune reactions, they showed a prolonged state of viraemia

or viral persistence in synovial fluid and were incapable of eliminating

the virus. This might have been due to an inadequate immune reaction

against the viral capsid proteins VP1 and VP2, which have been shown to

contain epitopes that induce the production of B19-neutralizing

antibodies.[9,10] No defects in the elicitation of either VP1-specific

or VP2-specific IgG were observed in any of our patients. However, it is

possible that the inability to eliminate B19 virus might be associated

with decreased antibody affinities. None of our patients had diseases

related to impaired T-cell function. All showed normal immune response

to parvovirus B19 proteins as well as to other infectious agents and had

normal or elevated immunoglobulin levels, excluding general B-cell

dysfunctions. However, the possibility cannot be excluded that the

impaired elimination of parvovirus B19 was caused by treatment of the

patients with immunosuppressive drugs like MTX or oral steroids over

long periods.

In patients 1 and 4 IVIG therapy was capable of eliminating the virus

from the peripheral blood. In patient 4 a polyarticular relapse was

cured without any concomitant therapy. A similar result had been

reported previously for a patient with parvovirus B19-associated anaemia

persisting for 10 years.[10] These observations point to subtle defects

in specific antibody production and rule out a defect in the T cell

immune response. Furthermore, several mechanisms have been proposed to

explain the immunomodulatory effects of IVIG. These include modulation

of cytokine production and the neutralization of circulating

autoantibodies.[11] In addition, we observed a decrease in anti-PL IgG

together with a control of B19 viraemia in patients 1 and 4. The

benefits of using anti-PL IgG in IVIG therapy in mice have been

described previously.[12,13] It might therefore be proposed that in

patients 1 and 4 the improvement observed by IVIG was due to the

combination of the decrease in both B19 viraemia and anti-PL IgG. It is

not clear whether the therapy is capable of inducing a definite cure.

Parvovirus B19 DNA has been shown to persist in synovial cells,

indicating a state of virus latency.[14] Therefore an occasional

reactivation of latent parvovirus B19 resulting in a new production

cycle cannot be excluded and might lead to new flares.

In both patients with psoriatic arthritis (patients 2 and 3), IVIG

treatment failed. It has to be assumed that the development of psoriatic

arthritis is influenced by multiple genetic and environmental factors,

including productive viral infections. Recently, parvovirus B19 proteins

have been shown in synovial tissue of patients with psoriatic

arthritis.[15] Even though we observed a decrease in virus load, IVIG

treatment was not sufficient to improve significantly the clinical

course in our two cases of long-lasting rheumatic diseases. This seems

not to be a general feature of psoriatic arthritis, because Gurmin and

colleagues report three patients with improvement of their arthritis

after a single course of IVIG (2 g/kg body weight).[16]

In patient 2 the symptoms of arthritis did improve; however, this

patient could not be cured even though parvovirus B19 DNA could not be

detected in the serum after the second treatment cycle. This might have

been due to a rheumatic disease lasting for more than 8 years, resulting

in major joint destructions. The reason for the severe relapse observed

in patient 3, with multiple effusions containing free and

immunocomplexed B19 particles, remains unclear. IVIG treatment might be

associated with an enhanced formation of immunoglobulin complexes,

resulting in the induction of complement and cytokines and in the

stimulation of inflammatory reactions. In addition, at the end of the

second treatment cycle the patient displayed anti-PL IgG in the serum

that might have been passively transmitted by the immunoglobulins and

might have led to enhanced inflammation.[17]

Stahl and colleagues reported successful IVIG treatment of parvovirus

B19-triggered oligoarthritis and monoarthritis.[8] We showed the

induction of a disease-free interval of 15 months in patients with

chronic erosive arthritis. Therefore IVIG treatment might be a

therapeutic option for juvenile patients with arthritis and persistent

parvovirus B19 production.

Abbreviation Notes

ANA, anti-nuclear antibodies; anti-PL IgG, antiphospholipid antibodies;

?2GPI, ?2-glycoprotein I; CK, creatine kinase; CRP, C-reactive protein;

ENA, extractable nuclear antigens; ESR, erythrocyte sedimentation rate;

IVIG, intravenous immunoglobulin; KINDL, Health-related Quality of Life

Questionnaire for Children; MTX, methotrexate; NSAID, non-steroidal

anti-inflammatory drugs; TCHA, triamcinolone hexaace-tonid; VP1, viral

protein 1; VP2, viral protein 2

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Competing Interests

None declared.

Correspondence Address

Professor ne Modrow, Institute for Medical Microbiology,

Universität Regensburg, Franz-f-Strauss Allee 11, 93053 Regensburg,

Germany. Tel: +49 941 944 6454; fax: +49 941 944 6402; e-mail:

susanne.modrow@...

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Acknowledgements

We thank Professor R Lissner (Biotest GmbH, Dreieich, Germany) for the

generous donation of Varitect CP immunoglobulin preparations; Mikrogen

GmbH (Munich, Germany) for the donation of Recom-Blot and Recom-Well

tests; and Karin Beckenlehner and ia Herrmann for excellent

technical assistance.

Funding Information

The work was supported by the European Community (EU contract

QLK2-CT-2001-0087).

Hartwig W Lehmann1, Annelie Plentz2, Philipp von Landenberg3, Esther

Müller-Godeffroy4 and ne Modrow2

1Rheumaklinik Bad Bramstedt, Bad Bramstedt, Germany

2Institute for Medical Microbiology, Universität Regensburg, Regensburg,

Germany

3Department for Clinical Chemistry and Laboratory Medicine, Universität

Mainz, Mainz, Germany

4Clinic of Pediatrics, Medizinische Universität Lübeck, Lübeck, Germany