ARTHRITIS & RHEUMATISM Vol. 40, No. 5 , May 1997, pp 859-864 0 1997, American College of Rheumatology 859

HENOCH-SCHONLEIN PURPURA IN ADULTHOOD AND CHILDHOOD

Two Different Expressions of the Same Syndrome

RICARDO BLANCO, VICTOR M. MARTINEZ-TABOADA, VICENTE RODRIGUEZ-VALVERDE, MIGUEL GARCIA-FUENTES, and MIGUEL A. GONZALEZ-GAY

Objective. To assess the possible differences be- tween children (120 years) and adults (>20 years) with Henoch-Schonlein purpura (HSP).

Methods. A retrospective study of an unselected population of patients with HSP who presented to our teaching hospital between 1975 and 1994. Patients were classified as having HSP according to the criteria proposed by Michel et al.

Results. Following the above-mentioned criteria, 162 white patients (113 male and 49 female) were classified as having HSP; 46 of the patients were adults (mean f SD age 53.2 f 16.9 years) and 116 were children (6.9 f 3.1 years). We were unable to identify any precipitating event in 72% of the adults and 66% of the children. The frequency of previous drug treatment, primarily antibiotics or analgesics, was similar in both groups, whereas previous upper respiratory tract infec- tion was more frequent among the children (P < 0.02). At symptom onset, cutaneous lesions were the main clinical manifestation in both groups. However, adults had a lower frequency of abdominal pain (P < 0.008) and fever (P < 0.01), and a higher frequency of joint symptoms (P < 0.001). During the clinical course, adults had more frequent (P < 0.001) and severe renal involvement. An increased erythrocyte sedimentation rate was also more frequent in the adults (P < 0.001). Adults required more aggressive therapy, consisting of steroids (P < 0.002) and/or cytotoxic agents (P < 0.001).

Ricardo Blanco, MD, Miguel A. Gonzalez-Gay, MD, PhD: Hospital Xeral-Calde, Lugo, Spain; Victor M. Martinez-Taboada, MD, Miguel Garcia-Fuentes, MD, Vicente Rodriguez-Valverde, MD: Hospital Universitario “Marques Valdecilla,” Universidad de Cant- abria, Santander, Spain.

Address reprint request to Vicente Rodriguez-Valverde, MD, Professor of Medicine and Chief, Rheumatology Division, Hospital Universitario “Marques Valdecilla,” Avenida Valdecilla s/n, 39008 Santander, Spain.

Submitted for publication June 19, 1996; accepted in revised form November 1, 1996.

The outcome was relatively good in both age groups, with complete recovery in 107 children (93.9%) and in 33 adults (89.2%) after a mean f SD followup of 19.4 2 27.7 (median 12) and 21.8 * 33.5 (median 15) months, respectively.

Conclusion. In adulthood, HSP, as defined by the criteria proposed by Michel et a], represents a more severe clinical syndrome, with a higher frequency of renal involvement. However, the final outcome of HSP is equally good in patients of both age groups.

Henoch-Schonlein Purpura (HSP) is an inflam- matory vascular disease characterized by involvement of the skin, joints, gastrointestinal tract, and kidneys. The main histopathologic features are infiltration of the small blood vessels with polymorphonuclear leukocytes and the presence of leukocytoclasia. HSP preferentially affects children between the ages of 5 and 15 years and is more common in boys than in girls (ma1e:female ratio 1.51). The pediatric form of the disease has been extensively studied, and it is generally considered a benign and self-limited disorder (1). Only a few reported studies have focused on the disease in adults, and they have generally found a worse outcome in this age group. The studies have employed various inclusion criteria and have evaluated a small series of selected patients with kidney dysfunction who were attending referral centers (2-5). It is therefore difficult to compare the clinical manifestations and outcomes of patients in these two age groups.

Classically, HSP has been considered a subgroup of hypersensitivity vasculitis (HSV) (6). However, in 1990, a subcommittee of the American College of Rheu- matology (ACR) delineated criteria for the classification of several vasculitides, defining HSV and HSP as two different entities (7,8). The ACR criteria were devel- oped by comparing HSP and HSV individually with all

860 BLANCO ET AL

other forms of vasculitis, rather than by specifically comparing the two entities. Since HSP and HSV share many clinicopathologic features, a high percentage of patients would be misdiagnosed. Therefore, in 1992, Michel et a1 (9) used the same database collected by the ACR Vasculitis Subcommittee to delineate new criteria for differentiating these two entities.

The aim of our study was to examine whether the age at onset of HSP reflects definable clinical character- istics of the disease in a large, unselected series of patients with HSP that was classified according to the criteria of Michel et al.

PATIENTS AND METHODS

Patient population. This was a retrospective study of 347 patients with small vessel cutaneous vasculitis who were seen in the rheumatology and pediatric divisions of a teaching hospital from January 1975 through December 1994. Cutane- ous vasculitis was diagnosed in 169 patients by a skin biopsy that showed characteristic histologic findings, such as neutro- phi1 infiltration, leukocytoclasia, and fibrinoid necrosis in the vessel walls of arterioles, capillaries, and postcapillary venules (10). The remaining 178 patients without skin biopsy had typical nonthrombocytopenic symmetric palpable purpura.

From among the initial group of 347 patients, 66 who had vasculitis secondary to other processes were excluded: 25 with rheumatoid arthritis ( l l) , 13 with systemic lupus erythem- atosus (12), 5 with Sjogren’s syndrome (13), 11 with essential mixed cryoglobulinemia (14), 4 with hematologic malignancies, 5 with major infections (4 with subacute bacterial endocarditis and 1 with meningitis), and another 3 with well-defined entities (1 with relapsing polychondritis, 1 with seronegative spondyl- arthropathy, and 1 with sarcoidosis). Four of the 25 patients with rheumatoid arthritis developed a hypersensitivity reaction to combined therapy with azathioprine and methotrexate; those patients have been described previously (15). From among the 281 patients with primary vasculitis, 18 with polyar- teritis nodosa (16), 4 with Wegener’s granulomatosis (17), and 2 with Churg-Strauss syndrome (18) were also excluded.

Of the remaining 257 patients with cutaneous vasculi- tis, 162 were classified as having HSP according to the criteria of Michel et a1 (9) (Table 1).

Patients older than 20 were considered adults, and those 20 years of age or younger were considered children. The cutoff age of 20 was chosen for two reasons: this age was proposed as a criterion for HSP by the ACR (age 520 at symptom onset) (8), and because this age best discriminated HSP from HSV in the study by Michel et a1 (9). When statistical analysis was performed using a cutoff age of 5 1 6 years, similar results were obtained (data not shown).

Clinical definitions. Nephropathy was categorized as mild or severe. Mild nephropathy was present if the patient had hematuria andlor proteinuria that was not in the nephrotic range. Severe nephropathy was present if the patient had nephrotic syndrome (i.e., plasma albumin of 525 gm/liter and either 1 gm of proteinuria/day/m* of body surface area or >3.5 gm of proteinurialday) with or without edema and/or acute

Table 1. Criteria for differentiating Henoch-Schonlein purpura from hypersensitivity vasculitis (traditional format)*

Criterion Definition

1. Palpable purpura Slightly elevated purpuric rash over 2 1 area of the skin that is not related to thrombocytopenia

meals, or bowel ischemia usually including bloody diarrhea

hematochezia, or positive result on test for occult blood in the stool

Gross hematuria or microhematuria (>1 per high-power field)

Development of first symptoms at 520 years

Absence of medications at disease onset that

2. Bowel angina Diffuse abdominal pain that is worse after

3. Gastrointestinal Gastrointestinal bleeding, including melena, bleeding

4. Hematuria

5. Age at onset 520 years

6. No medications might have been a precipitating factor

* The presence of 23 criteria yields a correct classification of Henoch- Schonlein purpura cases of 87.1%. The presence of 5 2 criteria yields a correct classification of hypersensitivity vasculitis cases of 74.2%. Reproduced, with permission, from ref. 9.

nephritic syndrome (i.e., hematuria with at least 2 of the following: hypertension, increased plasma urea or creatinine, and oliguria). Renal insufficiency was considered if the plasma creatinine concentration was >125% of the upper limit of normal.

Relapse was considered when a patient who was previously diagnosed as having HSP and who had been asymp- tomatic for at least 1 month presented with a new flare of cutaneous lesions or other systemic complications, mainly renal disease, related to HSP.

Statistical analysis. Data were first reviewed and then analyzed to compare the following aspects in the adults and the children: etiologic, clinical, and laboratory findings, as well as treatment and prognosis. Statistical analysis was carried out using the chi-square test for categorical variables and Student’s 2-tailed t-test for continuous variables. Statistical significance was defined as P 5 0.05. Data management and computations were performed with the Statistica software package.

RESULTS

Patient characteristics and etiologic factors. Of the 162 white patients classified as having HSP, 116 were children and 46 were adults. The main demo- graphic and etiologic data are shown in Table 2. Among all patients, the disease was more frequent in males and was somewhat less frequent during the summer. At clinical onset, 16% of children and 15% of adults (P not significant [NS]) were taking medications, most of which were for an upper respiratory tract infection. p-lactam antibiotics were the most common drugs prescribed. Hepatitis virus infection was found in 1 child (type B) and in 3 adults (2 with type B and 1 with type C). One

HSP IN ADULTS AND CHILDREN

Table 2. Demographic data and etiologic factors in children (520 years) and adults (>20 years) with Henoch-Schonlein purpura*

Children Adults (n = 116) (n = 46)

Age, mean 2 SD years Sex, no. males/females Seasonal pattern, no. (%)

Spring Winter Fall Summer

Unknown Infections

URTI Hepatitis

P-lactam antibiotics AnalgesicsDISAIDs Others

Etiologic factors, no. (%)

Drugs at disease onset, no. (%)

6.9 ? 3.1 76/40

39 (34) 30 (26) 28 (24) 19 (16)

77 (66)

35 (30)

18 (16) 13 (11)

1(1)

2 (2) 3 (3)

53.2 If: 16.9 3719

14 (30) 13 (28) 11 (24) 7 (15)

33 (72)

6 (13)t 3 (7)t 7 (15) 3 (7) 1 (2) 3 (7)

* URTI = upper respiratory tract infection; NSAIDs = nonsteroidal antiinflammatory drugs. t P 5 0.05.

of these adults was an intravenous drug user (negative for human immunodeficiency virus).

Clinical features. The main clinical features are summarized in Figure 1. Disease onset in adults was characterized by a lower frequency of abdominal pain and fever, and a higher frequency of joint symptoms and kidney involvement.

During the clinical course, cutaneous lesions were

861

present in all patients. Palpable purpura was observed in 98.3% of the children and in 93.5% of the adults (P = NS). Other skin lesions, usually a maculopapular rash, were present in 29.3% of the children and in 28.3% of the adults (P = NS). Skin lesions were more frequent on the lower extremities, although the upper extremities (35.3% of children versus 39.1% of adults; P = NS) and trunk (44.8% versus 52.2%; P = NS) were also affected. The duration of the skin lesions was 11.0 ? 9.2 days (median 8 days) in the children and 11.9 ? 7.5 days (median 9 days) in the adults (P = NS).

A skin biopsy was performed in 39 adults but only in 13 children. Although the adults had earlier joint manifestations (arthralgia and/or arthritis), when HSP was completely manifested, joint involvement occurred in 80.2% of the children and in 82.6% of the adults. On physical examination, however, arthritis was only ob- served in 31.9% of the children and in 37.0% of the adults (P = NS). The most frequent pattern observed was oligoarthritis affecting the ankles and/or knees.

Gastrointestinal involvement was present in 63.8% of the children and 56.5% of the adults (P = NS). The main symptom was the typical colicky abdominal pain. Melena was present in 5 children and in 11 adults (P < 0.001). The stool guaiac test showed positive results in 28.3% (15 of 53) of the children and in 59.1% (13 of 22) of the adults (P = 0.01). The classic clinical triad of HSP consisting of palpable purpura, joint symptoms, and

7%

100

ao

0 children

adults %

100

80

60

40

6 0

4 0

20 2 0

n 0 " skin joint GI # kidney fever I skin joint GI # kidney fever

Figure 1. Main clinical features of 116 children (520 years) and 46 adults (>20 years) with Henoch-Schonlein purpura, at disease onset (A) and during the clinical course (B). GI = gastrointestinal. * = P 5 0.05.

862 BLANCO ET AL

Table 3. Renal involvement in 116 children (520 years) and 46 adults (>20 vears) with Henoch-Schonlein purpura

Children Adults P

No. (%) of patients with nephropathy 29 (25) 39 (85) 0.00001 Type of nephropathy, no. (%)*

Mild 25 (22) 33 (72) 0.00001 Severe 4(3) 6(13) 0.002

No. (%) with renal insufficiencvt O(0) 6(13) 0.0001

* Mild nephropathy = hematuria and/or proteinuria not in the ne- phrotic range. Severe nephropathy = nephrotic syndrome (i.e., pro- teinuria of 1 gm/day/m2 of body surface area or >3.5 gm/day with plasma albumin 525 gmfliter), with or without edema and/or acute nephritic syndrome (i.e., hematuria with at least 2 of the following: hypertension, increased plasma urea or creatinine, and oliguria). t Plasma creatinine >125% of the upper limit of normal.

abdominal pain was equally frequent in both groups (49.1% of children and 47.8% of adults; P = NS).

Renal involvement was not only more common in adults but was also more severe (Table 3). In contrast to the relatively high frequency of renal insufficiency ob- served in adults, none of the children developed renal insufficiency.

Laboratory data. Routine laboratory tests were done on all patients at the time of diagnosis. Rheuma- toid factor, antinuclear antibodies, cryoglobulins, and levels of C3 and C4 were determined in most of the adults, but in only a few of the children (Table 4). In patients with cryoglobulins, the precipitate was scarce (1+/4+, or trace amounts), and none of them could be classified as having cryoglobulinemia according to pub- lished criteria (14). Antineutrophil cytoplasmic antibod- ies (ANCA) were sought in patients who had been diagnosed since 1992. ANCA were negative in the 17 patients tested (8 children and 9 adults).

Table 4. Routine and immunologic laboratory findings in 116 chil- dren (520 years) and 46 adults (>20 years) with Henoch-Schonlein purpura*

Children Adults

Leukocytosis Anemia Increased ESR Increased IgA Positive rheumatoid factor Positive antinuclear antibodies Cryoglobulins Low C3 and/or C4

34.5 6.0

40.5 7.7 (2/26) 3.7 (1/27) 0 (0/25)

35.7 (5/14) 4.2 (2/47)

21.7 4.3

76.lt 50 (418)t 4.9 (2/41) 6.8 (3/44)

17.9 (7/39) 9.3 (4/43)

~

* Values are percentages (no. positive/total no. tested). Leukocytosis was defined as a leukocyte count 211 X lO’iliter, anemia as hemo- globin 5110 gm/liter, and erythrocyte sedimentation rate (ESR) as 220 mm/hour. t P 5 0.05.

Table 5. Differences between children (520 years) and adults (>20 years) with Henoch-Schonlein purpura in the present series and in the ACR series*

ACR series Present series

Children Adults Children Adults (n = 60) (n = 25) (n = 116) (n = 46)

Medication at symptom 7 461 15 15 onset

Abdominal angina 61 29 t 64 57 4 24’F

21t 13t 78t

Creatinine >1.5 mg/dl 0 Hematuria (micro or gross) 47 74t 22 Palpable purpura 85 96 98 93

33t 0 Melena 8

Oligoarthritis 39 39 18 24 ~ ~~

*Values are percentages. See ref. 8 for the American College of Rheumatology (ACR) series. t P 5 0.05 versus adults.

Treatment and outcome. Adults required drug therapy more frequently than did children (63.0% versus 39.6%; P < 0.007). Furthermore, treatment in adult patients was more aggressive. Corticosteroids were pre- scribed because of persistent skin lesions or because of visceral involvement, such as severe abdominal pain, gastrointestinal bleeding, or severe nephropathy, in 43.5% of the adults and 19.8% of the children (P < 0.002). Cytotoxic drugs, prescribed either as corticosteroid- sparing agents or as additional therapy in patients with severe renal involvement, were given to 21.7% of the adults (azathioprine in 3 and cyclophosphamide in 7) and to none of the children (P < 0.001).

In 36% of the adults and 42.6% of the children (P = NS), there was a relapse of HSP. Two children and 8 adults were lost to followup; none of them had systemic involvement, and they had been discharged after a complete recovery. The outcome was relatively good in both age groups, with complete recovery in 107 children and in 33 adults (P = NS) after a mean 2 SD followup of 19.4 2 27.7 (median 12) and 21.8 2 33.5 (median 15) months, respectively. Persistent microhe- maturia was observed in 6 children, whereas persistent mild renal impairment was present in 4 adults (creati- nine 1.6-2.4 mg/dl), 1 of whom developed arterial hypertension. Because of severe ischemia, 1 child under- went amputation of 2 fingers. Two adults had infections secondary to the therapy: one, who was being treated with oral corticosteroids and cyclophosphamide, died of pneumonia and septic shock produced by Klebsiella pneurnoniue, and the other developed bacterial pneumo- nia while he was being treated with corticosteroids and azathioprine.

HSP IN ADULTS AND CHILDREN 863

DISCUSSION

We studied an unselected group of patients with HSP that was classified according to the criteria pro- posed by Michel et a1 (9). Most rheumatic diseases, including vasculitis, lack pathognomonic features. Be- cause of this, the ACR has long had an interest in the classification of rheumatic diseases in order to improve communication among physicians and to permit more direct and uniform comparisons of research studies (19). In this regard, the present patient series cannot be compared with others because 1) many of the previous series were selected populations, usually with kidney dysfunction (2-4); 2) the ACR criteria for the classifi- cation of vasculitis have only been available since 1990, with previous studies basing patient selection on various inclusion criteria (e.g., the presence of nonthrombocy- topenic purpura only [20]); and 3) in other studies, such as the largest reported series of HSP in adults (5), several data suggest that the study populations repre- sented a mixture of several types of cutaneous vasculitis and that some patients had an underlying disease. Thus, in the other studies (2-4), a worse outcome might well have been found. However, our study yielded results similar to those reported by Michel et a1 (9), in which HSP in adulthood was associated with a significantly higher proportion of melena and hematuria, more fre- quent renal function impairment, cutaneous ulcers, and a higher frequency of previous drug therapy. Our results confirm an increased frequency of nephropathy and melena in adults, but we did not find differences in cutaneous ulcers and medication intake (Table 5).

Although in clinical practice, a skin biopsy is rarely needed in order to diagnose HSP in children, it may be necessary in adults. In fact, in the ACR report (8), the biopsy findings were able to exclude >50% of the non-HSP patients who had palpable purpura and were over age 20 at symptom onset. In a previous study of cutaneous vasculitis, a wide spectrum of clinical associations were observed in adult patients, but only either HSP or HSV was found in the children (21).

IgA seems to play a pathogenic role in HSP, as supported for example by its presence in cryoprecipi- tates (22) and the finding of an increased number of circulating IgA-secreting cells in patients with active HSP (23,24). Moreover, IgA-dominant immune deposits can be observed in most patients with HSP (25), and its presence has been included in the definition adopted by the Consensus Conference on the Nomenclature of Systemic Vasculitides (26). Recently, Helander et a1 (27) have critically assessed the diagnostic utility of vascular

deposits of IgA. Those authors found that although IgA deposits are nonspecific, when combined with selected clinical data, their presence improves the diagnostic accuracy for HSP. Further prospective studies are nec- essary to confirm Helander’s proposal. At present, there is no “gold standard” for the diagnosis of HSP. We believe that arguments can be made in favor of any selection criteria. Thus, we have followed a set of differential criteria derived from the database collected in the multicenter prospective study of the ACR Sub- committee on classification of Vasculitis. IgA deposits in tissues were not examined in the ACR study (8,9), and therefore, we did not assess them.

The design of the present study does not allow conclusions to be drawn about the therapeutic approach to HSP; such conclusions should be made from the findings of prospective controlled trials. The efficacy of corticosteroids and cytotoxic agents in the treatment of HSP is a subject of controversy. In our series, cortico- steroids were used in patients with refractory skin le- sions, abdominal pain with gastrointestinal bleeding, or severe nephropathy, and cytotoxic agents were used as corticosteroid-sparing agents or as additional therapy in patients with severe renal involvement. Despite the presence of a more severe syndrome in the adults in our series, the final outcome did not differ significantly from that in the children. It is possible that the good outcome achieved in our adult patients may be somewhat due to a more aggressive therapeutic approach.

In summary, we report a large, unselected popu- lation of patients with HSP that was classified according to strict criteria. In adults, HSP represented a more severe clinical syndrome with a higher frequency of renal involvement. However, the outcome in both age groups was similar, with complete recovery from the disease in the majority of the patients.

ACKNOWLEDGMENT

We thank Dr. Gene G. Hunder for his critical review and interesting suggestions.

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