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Fc╨Ю╤Цriia polymorphism as a risk factor for invasive pneumococcal infections in systemic lupus erythematosus.

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1180
ARTHRITIS & RHEUMATISM
Vol. 40, No. 6, June 1997, pp 1180-1182
0 1997, American College of Rheumatology
CONCISE COMMUNICATIONS
FcyRIIA polymorphism as a risk factor for invasive
pneumococcal infections in systemic lupus
erythematosus
Patients with systemic lupus erythematosus (SLE) may
be at increased risk for severe Streptococcus pneumoniae
infections. In a report of the National Institutes of Health
cohort of 467 SLE patients, 9 individuals (1.9%) were identified as having had extrapulmonary or invasive pneumococcal
infections (1). A variety of invasive pneumococcal infections
in SLE patients has been previously reported, including bacteremia, spontaneous peritonitis, epiglottitis, cellulitis, and
fasciitis (1-4).
The native humoral immune response to pneumococcus is predominantly mediated by IgG2 subclass antibodies,
which appear to play a special role in host defense against
encapsulated organisms (5). Opsonization of bacteria by IgG2
enables efficient clearance of the contagion from the pulmonary air spaces by alveolar phagocytes. Pneumococci which are
not phagocytosed and killed may escape into the interstitial
tissue and the lymphatic drainage, resulting in bacteremic
dissemination (6).
This pivotal function of IgG2 in the defense against S
pneumoniae is intriguing in view of the observation that the
only human Fcy receptor (FcyR) which ligates IgG2 and clears
IgG2 immune complexes is the H131 variant of FcyRIIA (7,8).
This allelic variant has a histidine residue in the 131 position of
the second extracellular immunoglobulin-like domain, which is
involved in ligand binding. By contrast, the codominant R131
allelic variant possesses an arginine residue in that position and
has markedly lower affinity for IgG2. Other FcyR (i.e., FcyRI
and FcyRIII) also ligate IgG2 poorly. Consequently, in functional studies, phagocytes from individuals that are R131
homozygotes are less efficient than those from H131 homozygotes in internalizing IgG2-opsonized probes. R131/H131 heterozygote cells exhibit intermediate function.
Since IgG2 is a poor activator of complement, optimal
handling of IgG2-opsonized pneumococci is dependent upon
FcyRIIA genotype. We therefore hypothesize that this
FcyRlIA allelic polymorphism plays a role in the susceptibility
of SLE patients to fulminant pneumococcal infections.
From the cohort of 365 SLE patients in our Autoimmune Disease Registry and Repository computer database, 5
individuals with histories of invasive, culture-positive pneumococcal infections were identified (Table 1). All SLE patients
enrolled in this registry fulfilled the revised American College
of Rheumatology criteria for SLE (9). The number of pneumococcal infections identified is probably an underestimate
because infectious complications of SLE were not included in
primary data collection and could only be identified retrospectively from available medical records.
FcyRIIA genotyping was performed by polymerase
chain reaction amplification of genomic DNA from peripheral
blood leukocytes, using allele-specific primers as previously
described (10). Four of the 5 patients were determined to be
homozygous for the R131 allele, while the fifth (patient 5) was
an R131/H131 heterozygote. The gene frequency of FcyRIIAR131 in this group is thus 90%. Estimates of the gene
frequency of FcyRIIA-R131 in SLE have ranged from 52% to
65% and may differ between patient subsets depending on race
and organ involvement (refs. 10 and 11, and Salmon et al:
unpublished data). In non-SLE Caucasian American, African
American, and Hispanic American control populations, the
gene frequency of FcyRIIA-R131 is approximately 50% (refs.
10 and 11, and Salmon et al: unpublished data).
The patients were all young women (mean age 30;
range 24-38). None had received prior pneumococcal vaccination. Patients 3 and 4 had had quiescent disease for several
years, which was interrupted only by the acute pneumococcal
infection. SLE was diagnosed in patient 2 one month after
treatment of her pneumococcal pneumonia and lung abscess.
Patients 1 and 5 had had stable disease.
Clearly, many factors can contribute to the increased
susceptibility of SLE patients to pneumococcal infections.
Among the more obvious are corticosteroid and cytotoxic
therapy, hypocomplementemia, leukopenias, and hyposplenism. Concurrent immunosuppressive therapy probably
plays a relatively small role in our series of patients. None were
taking cytotoxic agents, and the maximum daily dose of
prednisone was 15 mg. Many of the soft tissue pneumococcal
infections in SLE reported by DiNubile and colleagues (3,4)
occurred in the setting of little or no corticosteroid therapy.
Thus, while the effects of corticosteroids can not be discounted, low doses probably do not have strong inhibitory
effects on phagocyte function in SLE (12). Four patients were
hypocomplementemic, but only 1 (patient 5) had C3 and C4
levels 4 0 % of normal. It is interesting that this was the only
patient who was an R131/H131 heterozygote. None was neutropenic, and only 1 was mildly leukopenic (patient 2).
Low serum IgG2 titers have been reported in some
SLE patients (13) and may explain the dampened antibody
response to pneumococcal vaccination in this population (1 4).
However, all of our patients had normal levels of serum IgG2,
as measured by radial immunodiffusion assays (Binding Site,
San Diego, CA).
Our findings suggest that the FcyRIIA-R131 genotype
is an additional risk factor for the development of complicated
pneumococcal infections, presumably from impaired clearance
of IgG2-opsonized pneumococci. This defect may allow bacterial dissemination from the lung into the bloodstream and may
have even more profound effects on hepatic and splenic
clearance mechanisms. In SLE, wherein functional asplenism
is estimated to occur in 4.6-7.1% of all patients (15), the role
of the IgGZFcyRIIA axis becomes even more critical because
removal of the bacteria becomes dependent on the less efficient hepatic clearance alone (16). Of 13 cases of functional
asplenism in SLE reviewed recently (17), 6 individuals developed pneumococcal sepsis, and another developed Salmonella
sepsis. Interestingly, histories of invasive or unusual infections,
including the encapsulated organisms Staphylococcus aureus
and Salmonella, were noted in 4 of our patients.
The increased gene frequency of FcyRIIA-R131 in
SLE (and particularly in lupus nephritis, in which the allelic
frequency is up to 65%) defines these patients as a population
with an inherently increased predilection for invasive pneumococcal infections (10). This independent risk may act synergistically with other concomitant conditions, such as splenic
dysfunction, hypocomplementemia, and immunosuppression,
to potentiate propensity for infections by encapsulated organisms like Spneumoniae. Support for this model is derived from
CONCISE COMMUNICATION
1181
Table 1. Fcy receptor IIA (FcyRIIA) genotype of systemic lupus erythematosus patients with invasive pneumococcal infections
Patienti
agelsexi
race*
Pneumococcal
infection
Disease
duration
FcyRIlA
genotype
1124iFiA
Pneumonia,
sinusitis,
periorhital
cellulitis,
hacteremia,
septic arthritis
9 years
R131iR131
2138lFlC
Pneumonia,
lung abscess
R131lR131
3134lFlC
Spontaneous
peritonitis
Pneumonia,
bacteremia
Preceded
diagnosis
by 1 month
16 years
12 years
R131lR13 1
2 years
R131iH131
4/30/F/H
5127iFlH
*A
=
Pneumonia,
bacteremia
African American; C
=
R131iR131
Caucasian American; H
=
Past infections
Concurrent therapy
Serum IgG2
(normal
1.55-5.54
mglliter)
Chronic sinusitis,
gonococcal septic
hip prosthesis,
staphylococcal septic
hip prosthesis,
recurrent
staphylococcal skin
abscesses
None
Prednisone 15 mglday
1.58
Normal
None
3.06
C3iC4 >50%
normal
Prednisone 10 mgiday,
hydroxychloroquine
Prednisolone
2 mdday,
hydroxychloroquine
Prednisone 10 mgiday
1.69
C3iC4 >50%
normal
C3lC4 >50%
normal
Salmonella tuboovarian
abscess
Escherichia coli
pyelonephritis and
bacteremia
Recurrent
staphylococcal skin
abscesses
3.93
4.08
Complement
131C4 <50%
normal
Hispanic American.
the observation that the FcyRIIA-R131 homozygous state is
associated with fulminant meningococcal infection in patients
with congenital complement deficiencies (18).
Recognition that SLE patients are prone to S pneum o n k infections requires a comprehensive approach to this
problem. None of the individuals identified in this study had
received previous pneumococcal vaccination. Since pneumococcal vaccinations are effective and safe in SLE patients (1),
we agree with universal vaccination of SLE patients and raise
the possibility that more frequent vaccine boosters may be
useful. Distinct benefit from vaccination may also result from
an enhanced IgGl humoral immune response ( 5 ) , which can
minimize the defect associated with the FcyRIIA-R131 phenotype. Moreover, because of the greater prevalence of antibiotic resistance in S pneumoniae, current knowledge of local
resistance patterns is important for effective containment of
infection. Lastly, increased susceptibility may be compounded
by a relative or absolute deficiency in IgG2 or other IgG
subclasses in the setting of SLE (13) which may be amenable to
gamma globulin therapy.
Arthur M. F. Yee, MD, PhD
Sonia C. Ng, A B
Rachcl E. Sobel, A B
Jane E. Salmon, M D
Hospital for Special Surgery
New York, NY
1. Klippel JH, Karsh J, Stahl NI, Decker JL, Steinberg AD, Schiffman G: A controlled study of pneumococcal polysaccharide vaccine in systemic lupus erythematosus. Arthritis Rheum 22:13211325, 1979
2. Lipsky PE, Hardin JA, Schour L, Plotz P: Spontaneous peritonitis
and systcmic lupus erythematosus. JAMA 232929-931, 1975
3. DiNubile MJ, Albornoz MA, Stumacher RJ, van Uitert BL,
Paluzzi SA, Bush LM, Nelson SL, Myers AR: Pneumococcal
soft-tissue infections: possible association with connective tissue
diseases. J Infect Dis 163:897-900, 1991
4. Patel M, Ahrens JC, Moyer DV, DiNubile MJ: Pneumococcal
soft-tissue infections: a problem deserving more recognition. Clin
Infect Dis 19:149-151, 1994
5. Sarvas H, Rautonen N, Sipinen S, Makela 0: IgG subclasses of
pneumococcal antibodies-effect of allotype G2m(n). Scand J Immunol 29:229-237, 1989
6. Bruyn GAW, Zegers BJM, van Furth R: Mechanisms of host
defense against infection with Streptococcus pneumoniae. Clin
Infect Dis 14:251-262, 1992
7. Warmerdam PAM, van de Winkel JGJ, Gosselin EJ, Capel PJA:
Molecular basis for a polymorphism of human Fcy receptor I1
(CD32). J Exp Med 172:19-25, 1990
8. Salmon JE, Edberg JC, Brogle NL, Kimberly RP: Allelic polymorphisms of human Fcy receptor IIA and human Fcy receptor IIIB:
independent mechanisms for differences in human phagocyte
function. J Clin Invest 89:1274-1281, 19Y2
9. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield
NF, Schaller JG, Tala1 N, Winchester RJ: The 1982 revised criteria
for the classification of systemic lupus erythematosus. Arthritis
Rheum 25:1271-1277, 1982
10. Salmon JE, Millard S, Schacter LA, Arnett FC, Ginzler EM,
Gourley MF, Ramsey-Goldrnan R, Peterson MGE, Kimberly RP:
FcyRIIA alleles are heritable risk factors for lupus nephritis in
African Americans. J Clin Invest 97:1348-1354, 1996
11. Duits AJ, Bootsma H, Derksen RHWM, Spronk PE, Kater L,
Kallenberg CGM, Capel PJA, Westerdaal NAC, Spierenburg GT,
Gmeling-Meyling FHJ, van de Winkel JGJ: Skewed distribution of
IgG Fc receptor IIa (CD32) polymorphism is associated with renal
disease in systemic lupus erythematosus patients. Arthritis Rheum
38:1832-1836, 1995
12. Boghossian SH, Isenberg DA, Wright G, Snaith ML, Segal AW:
Effect of high-dose methylprednisolone on phagocyte function in
systemic lupus erythematosus. Ann Rheum Dis 43541-550, 1984
13. Oxelius VA: Immunoglobulin G subclasses and human disease.
Am J Med 76 (suppl 3A):1-18, 1984
14. Jarrett MP, Schiffnian G, Barland P, Grayzel AI: Impaired
response to pneumococcal vaccine in systemic lupus erythematosus. Arthritis Rheum 23:1287-1293, 1980
15. Dillon AM, Stein HB, English RA: Splenic atrophy in systemic
lupus erythematosus. Ann Intern Med 9640-43, 1982
16. Hosea SW, Brown EJ, Hamburger MI, Frank MM: Opsonic
CONCISE COMMUNICATION
1182
requirements for intravascular clearance after splenectomy.
N Engl J Med 304:245-250, 1981
17. Scerpella EG: Functional asplenia and pneumococcal sepsis in
patients with systemic lupus erythematosus. Clin Infect Dis 20:
194-196, 1995
18. Fijen CAP, Bredius RGM, Kuiper EJ: Polymorphism of IgG Fc
receptors in meningococcal disease (letter). Ann Intern Med
119:636, 1993
Table 1. Number of pediatric rheumatologists in each US medical
school*
Pediatric rheumatology: status of the subspecialty in
United States medical schools
* Values are the no. of medical schools.
As we approach the twenty-first century, major
changes are taking place in the manner by which medical care
is delivered in the US. In planning for the future care of
children with rheumatic diseases in this country, several types
of information are needed, such as the population distribution
of these children (urban versus rural), frequency of the various
rheumatic diseases, academic needs of training institutions,
and outcome of the different approaches to care. This report
deals with the current representation of pediatric rheumatology in academic medical centers in the US.
At the 1976 Conference on the Rheumatic Diseascs of
Childhood, sponsored by the Pediatric Section of the American College of Rheumatology (ACR), the participants envisioned that a pediatric rheumatology service would be established in each medical school in this country. Rationales for
this goal were to ensure adequate teaching of all medical
students and house officers in this vital area of chronic illness
in children, and to provide a role model and standards of care
in this subspecialty for graduates of US medical schools (I). A
number of trends related to reimbursement for patient care
and the financing of departments of pediatrics have thwarted
realization of this goal.
A list of 178 pediatric rheumatologists in the US has
been compiled from the records of the American Board of
Pediatrics (ABP), the Rheumatology Section of the American
Academy of Pediatrics (AAP), and the Pediatric Section of the
ACR. Of this number, 121 were certified in pediatric rheumatology by the ABP, and 135 of these physicians were associated
with a medical school. In an effort to examine whether there
has been an adequate increase in the supply of pediatric
rheumatologists during the last 20 years, the number of
pediatric rheumatologists in academic centers in 1976 and
1986, the years of the first and second Conference on the
Rheumatic Diseases of Childhood, was compared with data
from 1996. The number of academic centers with at least 1
pediatric rheumatologist in 1976, 1986, and 1996 was 17, 71,
and 80, respectively. The total number of pediatric rheumatologists was 27, 103, and 178, respectively.
In 1996,45 of the current 125 US medical schools had
no representation in this important area of chronic illness in
children (Table I). Although it is gratifying that 35 academic
centers in 1996 had between 2 and 6 pediatric rheumatologists
each, 45 had only a single physician in this subspeciality. These
solo rheumatologists seem especially vulnerable academically
within the current environment of severe financial constraints
and cost containment.
Additional comparisons were performed of the number of pediatric rheumatologists in the 15 research-oriented
medical schools that received the largest amount of National
Institutes of Health funding (Division of Research Grants,
No. of pediatric rheumatologists
Year
0
1
2
3
4
5
6
1976
1986
1996
109
55
45
13
52
45
2
12
22
1
5
9
0
0
2
1
0
I
0
2
1
1994), and of the 40 medical schools that graduated the highest
percentage of students entering primary care (range 28-44%)
(2). In the research schools, 1 had no pediatric rheumatologist
and the other 14 had 1-5 each. In the primary care schools, 17
had no pediatric rheumatologist and 14 had only 1. Thus, the
training of primary care physicians in this subspecialty has
especially been imperiled by the lack of teaching of, and role
models for, pediatric rheumatology in these schools.
According to data from the ABP, during the 6-year
period 1990-1995, 7-21 first-time takers of the general certification examination in pediatrics planned on entering a pediatric rheumatology fellowship. Although the average has been
12 fellowships per year, there were only 7 in 1992 and 1995.
The number of fellows in training who could be expected to
replace current pediatric rheumatologists is an unknown number. A work-force survey by the ACR and AAP is currently being
completed. In view of the new Residency Review Committee’s
requirements for fellowship training in pediatric rheumatology,
probably no more than 20 centers will qualify for certification (19
have applied in 1996). How many programs will choose to train
fellows in the future, or be able to do so, is uncertain, since
funds have been severely limited in this area for some years.
Based on the available data summarized above, 2
major conclusions can be reached: 1) Approximately one-third
of our medical schools do not have on their faculty any physician
experienced in the medical care of children with rheumatic
diseases, and 2) this deficit is particularly significant for medical
schools that provide training for primary care physicians.
Challenges will abound for the smaller pediatric subspecialties in this era of cost containment and emphasis on
primary care. Let us, as a profession, affirm that a subspecialty
such as pediatric rheumatology saves medical care dollars in
the long run, and that excellence in training in primary care
and pediatrics cannot be ensured without adequate representation of specialties such as pediatric rheumatology in our
medical schools.
James T. Cassidy, MD
University of Missouri School of Medicine
Columbia, MO
Balu Athreya, MD
Thomas Jefferson University
Philadelphia, PA
and Alfied I. DuPont Institute
Wilmington, DE
1. Cassidy JT: Pediatric rheumatology: fellowship training requirements and survey of specialty needs. Rheum Dis Clin North Am
13:169-173, 1987
2. Association of American Medical Colleges: Graduate Medical
Education Tracking Census (1988, 1989, and 1990)
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factors, lupus, polymorphism, systemic, pneumococcal, erythematosus, цriia, infectious, risk, invasive
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