Intermittent abdominal pain in IgA vasculitis

ABSTRACT Objective: To assess intermittent abdominal pain in IgA vasculitis patients and its relation to demographic data, clinical manifestations and treatments. Methods: A retrospective cohort study included 322 patients with IgA vasculitis (EULAR/PRINTO/PRES criteria) seen at the Pediatric Rheumatology Unit in the last 32 years. Sixteen patients were excluded due to incomplete data in medical charts. Intermittent abdominal pain was characterized by new abdominal pain after complete resolution in the first month of disease. Results: Intermittent abdominal pain was observed in 35/306 (11%) IgA vasculitis patients. The median time between first and second abdominal pain was 10 days (3–30 days). The main treatment of intermittent abdominal pain included glucocorticoid [n=26/35 (74%)] and/or ranitidine [n=22/35 (63%)]. Additional analysis showed that the frequency of intermittent purpura/petechiae (37 vs. 21%; p=0.027) and the median of purpura/petechiae duration [20 (3–90) vs. 14 (1–270) days; p=0.014] were significantly higher in IgA vasculitis patients with intermittent abdominal pain compared to those without. Gastrointestinal bleeding (49 vs. 13%; p<0.001), nephritis (71 vs. 45%; p=0.006), glucocorticoid (74 vs. 44%; p=0.001) and intravenous immunoglobulin use (6 vs. 0%; p=0.036) were also significantly higher in the former group. The frequency of ranitidine use was significantly higher in IgA vasculitis patients with intermittent abdominal pain versus without (63 vs. 28%; p<0.001), whereas the median of ranitidine duration was reduced in the former group [35 (2–90) vs. 60 (5–425) days; p=0.004]. Conclusions: Intermittent abdominal pain occurred in nearly a tenth of IgA vasculitis patients, in the first 30 days of disease, and was associated with other severe clinical features. Therefore, this study suggests that these patients should be followed strictly with clinical and laboratorial assessment, particularly during the first month of disease course.


INTRODUCTION
Immunoglobulin A (IgA) vasculitis, previously termed as Henoch-Schönlein purpura, is the most frequent primary vasculitis reported in children and adolescents' populations. [1][2][3][4][5] This vasculitis is characterized by skin, articular, renal and gastrointestinal involvements. [1][2][3][4][5][6] Acute onset of diffuse colicky abdominal pain has been described in up to 12% of IgA vasculitis patients at diagnosis. This gastrointestinal manifestation may be associated with serious complications, as bowel intussusception or gastrointestinal bleeding. 1,2 Of note, recurrent or intermittent colicky abdominal pain in IgA vasculitis were seldom described in previous case reports or case series. 1,2,[7][8][9][10][11] However, to our knowledge, additional analysis comparing patients with versus patients without intermittent abdominal pain in the first month of IgA vasculitis were not carried out.
Thus, the aim of the present study was to characterize intermittent colicky abdominal pain in the first month of children and adolescents with IgA vasculitis, and to assess the possible association of demographic data, clinical manifestations, laboratorial abnormalities and treatments in patients with and without this gastrointestinal manifestation.

METHOD
A retrospective cohort study was performed during a period of 32 years in a tertiary Pediatric Rheumatology Unit in São Paulo, Brazil. We analyzed 322 medical records. Of these, 16 were excluded due to lack of data. The remaining 306 patients fulfilled European League Against Rheumatism (EULAR), Paediatric Rheumatology International Trials Organisation (PRINTO) and Paediatric Rheumatology European Society (PRES) IgA vasculitis classification criteria. 6 This study was approved by the Local Ethics Committee.
Demographic data, such as age at diagnosis in years, gender and body mass index (BMI), were evaluated.
Abdominal pain was defined as diffuse colicky abdominal pain with acute onset assessed by medical history and physical exam. Severe abdominal pain was described as the presence of at least one of the subsequent: abdominal angina (severe postprandial diffuse colicky abdominal pain), 12 bowel intussusception or gastrointestinal bleeding. Intermittent abdominal pain was arbitrarily identified herein as a new episode of diffuse colicky abdominal ache after the complete resolution of the first event, both episodes occurring in the first month of disease. 10,11 Recurrent abdominal pain was defined as another flare of abdominal pain after the first month of disease. Abdominal Doppler ultrasound was performed in those IgA vasculitis patients with gastrointestinal bleeding. 1 The time between first and second diffuse colicky abdominal pain was also evaluated.
Intermittent purpura/petechiae were characterized as new skin lesions after total recovery of first episode, and persistent purpura/petechiae as cutaneous lesions lasting more than 30 days. The definition of arthritis was joint pain with limitation on movement or articular edema. Arthralgia was defined by articular pain without edema or limitation on motion. [1][2][3] Intermittent arthralgia/arthritis, as new onset articular inflammation after total resolution. [1][2][3] Orchitis was described as the presence of scrotal swelling and/or tenderness in physical exam and/or testicular Doppler ultrasound alterations. 2 The duration of orchitis was measured in days.
Nephritis was defined as hematuria >5 red blood cells/high power field or presence of red blood cells in the urinary sediment and/or proteinuria >0.1g/m 2 /day. Nephrotic syndrome was diagnosed according to edema, serum albumin <2.5g/L and proteinuria >1g/m 2 /day. 3 Acute kidney injury was characterized by increase in serum creatinine >2mg/dL 13 or according to modified RIFLE (Risk, Injury, Failure, Loss of renal function and End-stage renal disease) criteria. 14 Arterial hypertension was categorized as systolic and/or diastolic blood pressure ≥95 th percentile according to gender, age, and height on 3 or more occasions. 15 Neuropsychiatric involvement was characterized by the presence of at least one of the following manifestations: headache, impaired consciousness, seizures, hemiparesis and cortical blindness. 16 Current drugs were also recorded: prednisone/ prednisolone, intravenous methylprednisolone, ranitidine, intravenous immunoglobulin (IVIG), azathioprine, cyclosporine, intravenous cyclophosphamide (IVCYC) and plasmapheresis.
Patients with IgA vasculitis were divided into two groups: with and without intermittent abdominal pain in the first month of disease course.
Results were presented as median (range) or mean±standard deviation for continuous variables, and number (%) for categorical variables. Pearson's chi-square or Fisher's exact tests were used to compare categorical variables. Mann-Whitney test or Student's t-test were used to compare continuous variables. For all statistical tests, a p-value less than 0.05 was considered with statistical significance.

DISCUSSION
To our knowledge, this was the first study that demonstrated intermittent abdominal pain in the first month of disease as a rare manifestation of IgA vasculitis patients and was associated with skin manifestations, nephritis and severe gastrointestinal involvement. In addition, recurrent abdominal pain was rarely observed in IgA vasculitis patients.
The advantage of the present study was the selection of this population followed in a tertiary center in Latin America with predominance of complex patients. 17 Furthermore, all subjects fulfilled the validated EULAR/PRINTO/PRES classification criteria 6 and were systematically assessed according to our standardized database, as previously reported. 1,2 At disease onset, approximately three quarters of our IgA vasculitis patients with intermittent abdominal pain had nephritis, suggesting a severe and periodic systemic involvement of this vasculitis. Indeed, nephritis is also commonly associated with IgA vasculitis flares, as reported in a study with Finland population. 18 Additionally, intermittent abdominal pain occurred in the first 30 days of IgA vasculitis patients. Therefore, these patients should be followed strictly with clinical and laboratorial assessment, particularly during the first month of disease course.
Regarding treatment, ranitidine showed to be effective in gastrointestinal manifestations in IgA vasculitis patients, decreasing duration and severity of gastrointestinal pain and bleeding as described in a Turkish research. 19 Our study demonstrated that, in spite of a higher use of ranitidine in IgA vasculitis patients with intermittent abdominal pain, the ranitidine use duration was reduced, suggesting that this H2-receptor antagonist seem to be a protective factor for this periodic abdominal pain.
Of note, recently US Food and Drug Administration alerts to healthcare professionals that ranitidine contains low levels of nitrosamine impurity called N-nitrosodimethylamine (NDMA). 20 This substance is identified as a probable human carcinogen, and the risk and benefit should be individually considered for each patient. 21 Further studies will be necessary to clarify this issue.
Moreover, glucocorticoid use is indicated for severe and complicated abdominal pain in IgA vasculitis patients. 22 Our study demonstrated that IgA vasculitis patients with intermittent abdominal pain required this medication more frequently and for a longer period.
The median time between the first and second episode of intermittent diffuse colicky abdominal pain was short, and the vast majority of patients associated with new cutaneous lesions, indicating that this pain etiology was probably due to disease activity. The diagnosis of abdominal pain in IgA vasculitis is usually easy and rarely requires a differential diagnosis with esophagitis, gastritis or gastric ulcer.
The main limitation observed in the present study was the retrospective analysis, with potential missing data. We also did not assess the serum galactose-deficient IgA1, a well-known biomarker of IgA vasculitis associated with severe abnormalities at diagnosis. 23 Abdominal Doppler ultrasound was only assessed in those IgA vasculitis patients with gastrointestinal bleeding. Results are presented as median (minimum value -maximum value) or n (%). *In the first month of disease; **azathioprine, cyclosporine or intravenous cyclophosphamide.
In conclusion, intermittent abdominal pain occurred in nearly a tenth of IgA vasculitis patients, in the first 30 days of disease, and was associated with other severe clinical features. Therefore, our study suggests that these patients should be followed strictly with clinical and laboratorial assessment, particularly during the first month of disease course.