European Journal of

Pediatrics Europ. J. Pediat. 125, 15--20 (1977)

�9 by Springer-Verlag 1977

Systemic Lupus Erythematosus in a Boy with a Review of the Japanese Literature

Yoshiko Fujii/, Yohnosuke KobayashF, Hajime Fujii 1, Tsuyoshi Higaki l, Hiroshi Hara 2, and Tomofusa Usuil

1 The Departments of Pediatrics and 2 Pathology, Hiroshima University School of Medicine, Hiroshima 734, Japan

Abstract. A 3-year-old boy with systemic lupus erythematosus (SLE) with no skin rash whatever throughout the course of the disease is described, and the possibility of occurrence without skin rash is stressed. Seventeen cases of SLE in male children were collected from the Japanese literature and reviewed. Death occurred in 4 patients. Not only renal but also pancreatic involvement was found to be of significance in causing death in childhood SLE.

Key words: SLE in male children - SLE without skin rash.

Introduction

Systemic lupus erythematosus (SLE) is most frequently encountered in adoles- cence, and the sex distribution indicates a definite female preponderance, with about 80% in girls compared with 20% in boys. The occurrence of the disease in young children, however, is rather uncommon and occupies only a small portion of childhood cases.

The purpose of this article is to present the case of a 3-year-old boy with SLE without characteristic skin rash and to give a brief review of the male children with SLE in Japan.

Report of a Case

The patient was a 3-year-7-month-old boy who was admitted to the Department of Pediatrics of Hiroshima University Hospital for further evaluation and treatment of proteinuria, anemia, and hepatosplenomegaly. Family history was negative for allergic or autoimmune diseases.

The patient had been well until 2 years of age, when he developed numerous purpura on the soles of the feet which were not associated with any constitutional symptoms and which disappeared within a few weeks. A year later he experienced another episode of purpura,

Address for offprint requests: Yohnosuke Kobayashi, M.D., Department of Pediatrics, Hiroshima University School of Medicine, Kasumi 1-2-3, Hiroshima 734, Japan

16 Y. Fujii et al.

increased in number, on the soles. Medical services were not sought until the child was 3 years and 2 months old when he had a gingival bleeding of one week's duration, fever, general weakness, and edema and petechiae on the face and feet. Pertinent physical findings on admission to another hospital were edema and petechiae on the face, hands, and legs, stomatitis, swelling of the lymph nodes in the cervical, axiUary, and inguinal regions, hepatomegaly of 5 cm, and a splenomegaly of 3 cm. Laboratory studies showed the following values: RBC, 364 x 104/cmm: a hemoglobin, 9.3 g/100 ml: platelet, 5.1 x 104/cmm: WBC, 7400/cmm with a normal differential count. Bleeding time was over 10 min. An ESR was 108 mm/hr (Wester- gren) and CRP was positive. Urinary protein was 30 mg/100 ml, and an RBC count in the sediment was 7 /HPF. Immunoglobulin determination gave 2500 mg/100 ml of IgG, 270 mg of IgM, and 200 mg of IgA. An RA test was negative. A chest roentgenogram showed findings compatible with pleurisy, which cleared in 3 weeks. Histological examination of the cervical lymph nodes obtained by biopsy was interpreted to show reticulosis. With administration of steroid hormone, cyclophosphamide, and antibiotics, the general condition markedly improved and lymphadenopathy completely disappeared. However, hepatosplenomegaly, proteinuria, anemia, and elevated IgG level remained almost unchanged. Three weeks after admission he developed arthralgia of bilateral knees and hip joints for two weeks. LE preparations, which were initially negative, showed a positive value 4 months later.

On referral to us, physical examination was essentially negative except for a slight pallor of the face and hepatosplenomegaly. The skin was clear, and there were neither edema nor petechiae. Joints were intact. An RBC was 377 • 104/cmm and a hemoglobin 8.5 g/100 ml. The serum iron level was 156 micrograms/100 ml. The urinary protein and casts were negative, but Addis count indicated an RBC count of 132 x 104/cmm. Routine chemical studies and ESR yielded normal values. The following immunological evaluations were negative: LE cell preparations, antinuclear factor (ANF), and DNA antibody and Coombs test, both direct and indirect. Determination of immunoglobulins gave normal values, but ilia-globulin was 52mg/100 ml, which was found to be slightly decreased. Although the diagnosis of SLE was strongly suggested, it was not established with certainty because of the absence of characteristic butterfly rash and lack of other clinical and laboratory features of the disease. As such may have been modified by the foregoing steroid and anti-metabolite medications, all therapy was withdrawn to determine whether or not there would be a recurrence of the disease. About three weeks after cessation of treatment, cervical lymph nodes were palpable, proteinuria a n d hematuria were present, and an ESR was 98mm/hr and CRP was 2(+). Resurgence of immunological parameters was also evidenced by positive LE cell preparations, ANF • 160, positive cryoglobulin, a slight increase of IgG level, and 30mg/100ml of /~la-globulin. Histological findings of the kidney specimens taken by biopsy were consistent with moderate hyperplasia of basement membranes, and wire loop lesions and formation of hematoxylin bodies were not evident. The liver showed a picture of chronic hepatitis, and in the lymph nodes, reticulosis was present. With the diagnosis of lupus sine lupo, prednisone, 2mg/kg, was resumed with a resultant improvement of the constitutional symptoms and the above immunological indices. Cyclophosphamide was started in the eighth week with a tapering dose of the steroid hormone. The patient's general condition was satisfactory, but the hepato- splenomegaly was not favorably affected,

Immunological survey of the family members and relatives was grossly normal except for slightly lower levels of IgG in an elder brother (580rag/100 ml) and in a maternal uncle (480 mg/100 ml).

Intercurrent measles and primary atypical pneumonia at 4 years and 2 months, and 4 years and 3 months, respectively, were without any untoward consequences. Otitis media, pneumonia, and abscess formation of the gingiva at 4 years and 6 months of age, however, were accompanied by the exacerbation of the underlying disease as was reflected in markedly decreased CHs0 level of 9 u/ml, positive LE cell preparations. Antibiotics and temporarily increased steroid hormone successfully controlled the above infection, followed by negative LE cells and a normalized CHs0 value. During a 3 years' follow-up in the out-patient clinic, the patient was maintained on an alternate day regimen of daily prednisolone of 10 mg and has been entirely asymptomatic. The hepatosplenomegaly gradually regressed.

SLE in Boys 17

Review of the Literature

A total number of 20 males under 15 years of age was collected from Japanese literature based upon a survey of Japana Centra Revuo Medicina extending over a period from 1954 to 1975. Concurrently 73 female children were similarly summarized for comparison for age and sex distribution, the details of which will be reported elsewhere. Among 20 cases, 3 cases were omitted because of an inadequate description, and the remaining 17, who fulfilled preliminary ARA(1) criteria for SLE, formed the basis of this review. Age at onset of the disease was estimated from the appearance of the first symptom of the disease which logically could be due to SLE, as advocated by Dubois and Tuffanelli [3]. Age at diagnosis was the time of specific diagnosis. Table 1 lists the pertinent clinical and laboratory data, and outcome of these 17 patients. The time interval between the age at onset and at diagnosis extended f r o m a few weeks to as long as 3 years and 8 months. Fever and nephropathy were almost constantly observed, and facial erythema was recognized in all but two cases, 1 and 13. Hapato- and /o r splenomegaly was encountered in as high as 73.3%. Positive LE cells were detected in about 70% of the cases examined. Death occurred in 4 patients: by renal failure 1 year and a half after the onset of the disease (Case 17), by renal failure and necrotic pancreas by 1 year and 6 months (Case 11), by steroid- induced pancreatitis after 7 months (Case 8), and by unspecified cause (Case 6). As is evident from the Table 1, the present patient (Case 1) was the youngest ever reported in the present series.

Comment

Like other autoimmune disorders, SLE in children is most commonly seen in adolescent girls, and its occurrence in the younger age group is rather rare. For instance, in a large series of 520 patients of Dubois and Tuffanelli [3] covering all the age groups, patients under 9 years of age occupied only 3.5% compared with 23.0% in the group 10--19 years of age. As to sex distribution in children with SLE, Kornreich et al. [6] enumerated the figures of 81% girls and 19% boys in a series of 54 children. Meislin and Rothfield [8] also noted a similar distribution in 42 patients, and in 37 children studied by Cook et al. [2], 34 (92%) were girls. It is also seen in Japan as evidenced by our present study which indicates a female predominance of 77.8%. In addition to a difference in sex incidence of the disease, other features deserve some comment when analyzed for the age at onset. In a study of 54 children Kornreich et al. [6], noted a significant difference as noted below: 20 females and 9 males in the group of less than 12 years of age, compared to 24 females and only one male in the adolescent onset group. Maddock [7] and also Meislin and Rothfield [6], however, observed that the age of onset among male patients, both adults and children, was constant for all decades and that there was no preferential age group such as was noted in a peak incidence during adolescence for girls. According to Dubois and Tuffanelli [3], female pre- ponderance was less pronounced in the younger group. The small number of patients in the group in the present study made it difficult to assess an accurate

18 Y. Fujii et al.

Table 1. A summary of SLE in male

Case No.

1 2 3 4 5 6 7 8

Age at onset 2y 4y 2y8m 4y8m 7y 6y2m 12y Age at diagnosis 3y2m 4yl lrn 5y 5y5m 7y 7y 7y8m 12y Fever + + + + + + + + Facial rash - + + + + + + Edema + + + + + + + Joint symptoms + + + - + + + - Hepatomegaly + + + + + + + + Splenomegaly + + + - + + Purpura + + + - - - Nephropathy + + + + + + + +

Anemia a + - + _ + - + - Leucopeniab . . . . . . . + Platelet (x 104) 9.8 7.2 14 7.5 20.6 N ESR (mm/hr) 20 102 80 93 48 84 30 STS . . . . . . RAT + + + V-Glob. (g/100 ml) 1.35 2.0 1.91 2.04 IgG (mg/100 ml) 1200 4650 LE cells + + + + + - - - ANF • 160 + x 128 CHs0 (u./ml) fl 1 a-glob. 52

(rag/100 ml)

Outcome Alive Alive Alive Alive Alive Dead Alive Dead

a Hemoglobin less than 10 g/100 ml. b WBCC less than 400/cmm. N: Normal

age d i s t r i bu t ion , f o r an e x p l a n a t i o n o f wh ich a l a rge r n u m b e r o f pa t i en t s wil l be

r equ i r ed .

O n e o f the c l in ica l pecu l ia r i t i e s w i th this pa t i en t was the absence o f

c h a r a c t e r i s t i c fac ia l o r o t h e r sk in r a sh f r o m the onset . T h e p r e sen t case even tua l l y

fu l f i l led 5 o f t he p r e l i m i n a r y A R A cr i te r ia fo r SLE(1) , i.e., o r a l u l ce r a t i on ,

a r thr i t i s , p o s i t i v e L E cell, p leur i t i s , and t h r o m b o c y t o p e n i a . In a d d i t i o n , fever ,

e d e m a , g e n e r a l i z e d l y m p h a d e n o p a t h y a n d h e p a t o s p l e n o m e g a l y , a n d l a b o r a t o r y

f ind ings , such as pos i t i ve A N F , a n t i - D N A a n t i b o d y , a n d dep res sed c o m p l e m e n t leve l were a lso o f a id in a r r i v ing a t t he co r r ec t d iagnos is . In the beg inn ing ,

h o w e v e r , t he l ack o f fac ia l bu t t e r f l y r a sh o r o t h e r sk in les ion was qu i t e

bewi lde r i ng , w h i c h o n e m a y o f t en t e n d to accep t as a c l in ica l sine q u a n o n fo r

S L E . T h e p re sen t r ev i ew d i sc losed on ly one such case o f " l u p u s sine l u p o " (Tab le

1, Case 13). Based o n a s tudy o f la rge g r o u p s o f pa t i en t s i n c l u d i n g b o t h adu l t s

and ch i ld ren , the i n c i d e n c e o f t he fac ia l e r y t h e m a seems to be h i g h e r in J a p a n ,

i.e., 70% in F u k a s e ' s 532 pa t i en t s [4] ve r sus 56.7% in 520 pa t i en t s by D u b o i s and Tu f f ane l l i [3]. I t is n o t ce r ta in , h o w e v e r , w h e t h e r o r n o t these f igures ref lec t the

ac tua l inc idence . A n u m b e r o f cases m a y h a v e e scaped cl inical r e c o g n i t i o n s imply

due to the u n a w a r e n e s s o f l ack o f sk in rash. T h e sk in rash, i n c l u d i n g n o t on ly a

SLE in Boys

children under 15 years of age in Japan

19

9 10 11 12 13 14 15 16 17

9y 12y8m +

+

13y 12yllm l ly l lm 14y 14y 12yl0m 13y3m 12yllm 13y 13y2m 13y8m 14y 14y2m 14y3m 13y9m + + + - - + + + +

+ + + + + + +

+ + + - - + + + +

+ + - - + + + +

- - + + - - _ +

- + + - - _ +

+ + + - - _ + +

+ + + + + + + +

+

33.4 40 +

1300 +

x 32 34

+ + + + + + + - -

+ + + + - _

0.5 1.8 11 19 21.8 N 7.7 20 30 139 63 35 116 86

_ _ + - - + +

1.55 2.34 3200 1700 520

+ - - + + + + +

x 32 + + 12 43

Alive Alive Dead Alive Alive Alive Alive Alive Dead

characteristic facial one but also rashes of other types, appears to be more frequently encountered in children, i.e., 83.7% in the report of Cook et al. [2] and 88% in the present male series, than in adult patients. When 73 girls were included for an analysis of frequency of the skin manifestations, the incidence reached as high as 98% and, as far as could be determined, there have been only these two male patients, in whom skin rash was lacking. Although it may be coincidental that cases with lupus sine lupo were boys, an awareness of and a search for such atypical cases with this fact in mind will certainly lead to a discovery of many more such patients and give a clue to the positive conclusion of age and sex distribution of the disease in childhood.

Mortali ty in children with SLE is apparently higher than in adults. Half of the number of deaths in the present series was caused by renal failure, one of which was associated with pancreatic necrosis (Cases 11 and 17). According to Meislin and Rothfield [8], the presence of renal disease at diagnosis plays a decisive role in the duration of survival, and the mortali ty is higher in the subsequent order in the following groups: children with renal disease, children without renal disease, adults with renal disease, and adults without renal disease. One patient (Case 8) succumbed to the steroid-induced pancreatitis as early as 7 months after the onset

20 Y. Fujii et al.

of the disease, following a steroid therapy of about 2000 mg of prednisolone extending over the above period [5]. Riemenschneider et al. [9] reported six cases of glucocort icoid- induced pancreatitis in children, four of w h o m were patients with disseminated lupus erythematosus, and reviewed 21 children with this complicat ion. Of these 21, half had clinical a n d / o r pathological evidence of renal involvement, and it was also interesting that steroid-induced pancreatitis was more frequent in males, i.e., with a ratio of 12 males to 6 females (sex unspecified in 3) and that three were boys a m o n g 4 patients with DLE. This complicat ion of steroid therapy is relatively u n c o m m o n in children, compared with the other well recognized side effects. It is quite conceivable that SLE, the nature of which is mul t iorgan involvement, renders also the pancreas equally affected and sus- ceptible to the adverse reactions of the steroid hormone. As shown in Table l, renal involvement was found in almost all patients. This fact raised the possibility that steroid-induced pancreatitis could occur more frequently in these children than in those with other disorders. Therefore one should be on guard for the threatening symptoms of acute pancreatitis, regardless of the dura t ion of steroid therapy.

Acknowledgment. Miss M. Ohara, Kyoto University, assisted in the preparation of the manuscript.

References

1. Cohen, A. S., Reynolds, W. E., Franklin, E. C., Kulka, J. P., Ropes, M. W., Shulman, L. E., Wallace, S. 12.: Diagnostic and therapeutic criteria committee of the American Rheumatism Association. Preliminary criteria for the classification of systemic lupus erythematosus. Bull. Rheum. Dis. 21, 643--648 (1971)

2. Cook, C. D., Wedgwood, R. J. P., Craig, J. M., Hartman, J. R., Janeway, C. A.: Systemic lupus erythematosus, Description of 37 cases in children and a discussion of endocrine therapy in 32 of the cases. Pediatrics 26, 570--585 (1960)

3. Dubois, E. L., Tuffanelli, D. L.: Clinical manifestations of systemic lupus erythematosus, Computer analysis of 520 cases. J. Amer. Med. Assoc, 190, 104--111 (1964)

4. Fukase, M., Ofuji, T.: Symposium on autoimmune diseases. (1) Epidemiology of SLE, PSS and DM in the western part of the main Island and Shikoku Island in Japan. J. Jap, Soc. Intern. Med. 61, 571--575 (1972)

5. Kawamoto, K., Kobayashi, K., Toyota, S.: Pancreatic apoplexy during the course of steroid- therapy in a case of systemic lupus erythematosus. J. Hiroshima Med. Assoc. 20, 502--506 (1967)

6. Kornreich, H., Koster, K., Hanson, V.: Rheumatic diseases in adolescence. Pediatr. Clin. North Amer. 20, 911--931 (1973)

7. Maddock, R. K., Jr.: Incidence of systemic lupus erythematosus by age and sex. J. Amer. Med. Assoc. 191, 149--150 (1965)

8. Meislin, A. G., Rothfield, N.: Systemic lupus erythematosus in childhood, Analysis of 42 cases, with comparative data on 200 adult cases followed concurrently. Pediatrics 42, 37~49 (1968)

9. Riemenschneider, T. A., Wilson, J. F., Vernier, R. L.: Glucocorticoid-induced pancreatitis in children. Pediatrics 41, 428--437 (1968)

Received April 21, 1976