Intravenous immunoglobulins in Henoch-Schönlein purpura with severe gastrointestinal involvement. Case report and review of the literature

Abstract

Henoch-Schönlein purpura (HSP) is the most common systemic vasculitis in children. It often follows a viral infection. Although it is a self-limiting disease, various acute, and chronic complications can occur. We describe a case of a 6-year-old boy presenting with HSP and secondary multi-organ involvement. Because of diffuse purpura and arthralgia associated with acute abdominal pain, oral corticosteroid was administered but with no clinical improvement. Despite steroid treatment, the child developed hematemesis and massive intestinal hemorrhage, so he was treated with one dose of intravenous immunoglobulin (IVIG). This produced significant improvement in the gastrointestinal, cutaneous, and articular symptoms. Our case report demonstrates that IVIG may be useful in the treatment of complicated HSP with gastrointestinal involvement, but more structured research and guidelines are necessary for a correct therapeutic approach.

Introduction

Henoch Schönlein purpura (HSP), also known as Immunoglobulin A vasculitis (IgAV), is an acute IgA-mediated multi-organ vasculitis involving the small vessels of the skin, joints, gastrointestinal tract, and kidneys. Although rarely seen, it can also affect the central nervous system and the lungs. ¹

The first to describe this disorder was the English physician William Heberden in the early 1800s, but Dr. Johann Schönlein and his student Eduard Henoch were the first to identify the association between joint pain and purpura, and gastrointestinal and renal involvement and purpura, respectively. ²

Although HSP is most often self-limiting with an average duration of up to 4 weeks and it usually requires only supportive care, several acute, and chronic complications can occur. The most frequent acute complications are those related to the gastrointestinal system, including intussusception, bowel perforation, and massive bleeding. However, renal sequelae are the most serious chronic complications and the main cause of morbidity and mortality among children. ³

HSP is the most common systemic vasculitis of childhood with an incidence of 326.7 cases per 100,000. ⁴ This disease can affect individuals from 6 months to adulthood; in about 75% of cases, the onset occurs before the age of 8 and in 90% before the age of 10. HSP seems to predominate in males, with a ratio of 2:1 compared to females. ⁵ The pathogenesis is still unknown, but it is likely caused by immunologic, genetic, and environmental factors. Some genomic studies have found an association with the HLA-DQA1 and DQB1 haplotypes. Many patients report a preceding infection. ¹

In the vast majority of cases, the onset of purpura is preceded or is concomitant with an infectious episode, mainly regarding the upper respiratory tract, and for this reason it is much more frequent in the winter. However, many patients may also have an antecedent gastrointestinal or pharyngeal infection. Numerous pathogens have been suspected as triggers, including Group A Streptococcus pyogenes, herpes virus, parvovirus B19, coxsackie virus, adenovirus, and Bartonella. ⁶

The main typically presenting signs of HSP in children are palpable purpura without thrombocytopenia or coagulopathy; arthritis and arthralgia; abdominal pain, sometimes associated with bleeding; and renal disease showing with proteinuria. ⁷ The prognosis of HSP is generally good. Prompt and accurate diagnosis is important for appropriate management and timely treatment of complications. Although HSP is a common vasculitis in pediatric practice, well-designed controlled studies are lacking. ¹

Case presentation

A 6-year-old boy with no significant past medical history presented purpuric rash, polyarticular arthritis and arthralgias, orchitis and abdominal pain. He was assessed and subsequently admitted to the local hospital with a diagnosis of HSP. A throat culture isolated Group A Streptococcus pyogenes, treated with oral amoxicillin. Due to a deterioration of abdominal pain after 5 days, therapy with oral prednisone was started (2 mg/kg/dose) and the patient was transferred to our hospital for further management.

On admission, the patient presented with no fever and normal vital signs. On physical examination, there was a purpuric rash involving both upper and lower extremities, with non-pitting pedal edema (Figures 1 and 2).

Figure 1.

HSP of the hand.

Figure 2.

Purpuric hemorrhagic rash of the leg.

The abdominal examination was significant for diffuse tenderness; there was no rebound tenderness or muscle rigidity. The remainder of the physical examination was normal. We immediately performed an abdominal ultrasound examination that showed minimal ascites in the subhepatic region and pelvic cavity without intussusception. The subsequent X-ray examination excluded obstruction and perforation. Pediatric surgeons also evaluated the patient, suggesting that we continue the medical treatment. Laboratory tests performed on the second day of hospitalization revealed normal values of blood cell count, hemoglobin, platelet count, kidney function, total proteins, albumin, and serum electrolytes. There was no alteration in C3, C4, or autoimmunity screening (anti-nuclear antibodies—ANA, anti-Saccharomyces cerevisiae antibodies—ASCAs, and anti-neutrophil cytoplasmic antibodies—ANCA), and immunoglobulin levels (especially total immunoglobulin A—IgA—174 mg/dL, normal values for age 41–315 mg/dL). Blood tests showed a mild increase in acute inflammatory proteins (C-reactive protein—CRP—10.4 mg/L, erythrocyte sedimentation rate—ESR—41 mm/h) and transaminases (AST—aspartate transaminase—66 U/L, ALT—alanine transaminase—83 U/L). Urine analysis showed proteinuria, in no significant range, and no hematuria. In addition, the fecal occult blood test was positive.

We decided to continue steroid therapy at the same dosage (2 mg/kg/dose) in a single daily dose, plus proton pump inhibitors and symptomatic treatment with acetaminophen. A single dose of intravenous morphine was administered for better pain control, with benefit. Close monitoring of vital signs and daily bedside urine analysis were continued in the following days. The patient had an initial response to glucocorticoid, but after 9 days, he had worsening abdominal pain with hematatemesis and gross hematochezia (Figure 3).

Figure 3.

Significant intestinal bleeding.

Abdominal ultrasound with color Doppler (USCD), repeated after the relapse of gastrointestinal symptoms, showed thickening of the intestinal wall, significant fluid, bowel distention and minimal ascites between intestinal loops and in the pelvis. Furthermore, an abdominal computed tomography was performed, revealing no signs of bowel intussusception or perforation but small bowel wall thickening. Hence, a single dose of IVIG 2 g/kg was administered after 9 days of oral glucocorticoid had failed. Within 24 h, the patient had significant improvement of abdominal, cutaneous, and articular manifestations.

On the 19th day of his illness, an abdominal ultrasound showed bowel edema and ascites had completely resolved, as had the arthritis and purpura. On that date, before discharge, blood and urine tests were performed and found to be in the normal range. In this improved condition, for differential diagnosis with chronic intestinal diseases, a fecal calprotectin test was also performed, which was found to be in the normal range. The patient’s steroid dose was tapered over 4 weeks. On follow-up at 2 and 4 weeks, he remained well with normal blood and urine tests, but at the 5th month, he developed microscopic hematuria, for which he is followed by his nephrologist.

Discussion

HSP is a small vessel vasculitis with IgA-dominant immune deposits that typically involves the skin, gut and kidney, and is associated with arthralgia and/or arthritis. Rarely, other organs may be affected by the vasculitic process, in particular the central nervous system, scrotum, heart, lungs, and gall bladder.^8,9

During the 2005 Vienna Consensus Conference, organized by the European League Against Rheumatism (EULAR) and the Paediatric Rheumatology European Society (PReS), with collaboration from the American College of Rheumatology (ACR) and the European Society for Paediatric Nephrology (ESPN), the diagnostic criteria for all pediatric vasculitides were revised, including those for Henoch-Schönlein purpura (HSP). ⁷ Subsequently, at the 2008 Ankara Consensus Conference, supported by EULAR, the Paediatric Rheumatology International Trials Organisation (PRINTO), and PReS, the previously proposed classification criteria for pediatric vasculitides were validated with high sensitivity and specificity. Palpable non-thrombocytopenic purpura or petechiae, with lower limb predominance, is a mandatory criterion, in the presence of at least one of the following four features: diffuse abdominal pain, biopsy showing predominant IgA deposition, arthritis, or arthralgia, renal involvement (hematuria and/or proteinuria). ⁸

Although purpura is the key element of the disease, it is not always present at onset, and early signs of HSP may involve other systems, making early diagnosis difficult until the classical skin signs occur. ⁹ Patients can present initially with diffuse abdominal colicky pain, mimicking intussusception or gastrointestinal bleeding. If a biopsy is performed, histopathological examination typically reveals leucocytoclastic vasculitis or proliferative glomerulonephritis with predominant IgA deposits. A frequent presentation is acute arthritis, defined as joint swelling or pain with limitation of motion. Renal involvement may be present at any time. It could be characterized by proteinuria >0.3 g/24 h, urine albumin/creatinine ratio >30 mmol/mg on a spot morning sample, hematuria or red blood cell casts: >5 red blood cells per high-power field, red blood cell casts in the urine. ⁸

There are no pathognomonic tests: the most frequent laboratory abnormalities are high ESR (57%), elevated serum IgA (37%), and proteinuria (42%). A child with obvious purpura may need little laboratory testing beyond a urine analysis acutely and during follow-up. A complete blood count with platelets and screening for coagulation defects may be helpful. Other useful tests may include an abdominal ultrasound and a throat culture for Group A Streptococcus. ⁹

HSP tends to be self-limiting, and the prognosis is generally good, so treatment is generally supportive and symptomatic, like pain control with analgesics and sometimes non-steroidal anti-inflammatory drugs, as long as the kidneys are not involved. HSP exhibits a variable and often relapsing course, in which children may experience symptoms for up to 2–3 weeks, and symptom recurrence can occur even 4 months after onset. It can also occur in adults with more severe manifestations than in children. ¹⁰

Significant morbidity and mortality are associated with gastrointestinal tract manifestations and renal involvement. ¹¹ It has been reported that 31–66.7% of patients present with gastrointestinal symptoms, such as abdominal pain, vomiting and diarrhea, but some patients may even progress to severe complications, such as intussusception, intestinal perforation, and hemorrhagic enteritis. Moreover, approximately 20–60% of patients with kidney involvement develop HSP nephritis (HSPN). ¹² A meta-analysis showed that abdominal pain and gastrointestinal bleeding in HSP are potential risk factors of HSPN. ¹³ Although there are no clear guidelines on the indication for the use of corticosteroids in HSP, abdominal pain remains the most common reason why corticosteroids are prescribed. Typically, as reported in the SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) recommendation with level D evidence, a single short course of steroids, such as prednisone, at 1–2 mg/kg/day for 1 week, rarely causes significant side effects. ⁴

In 2021, an expert consensus on recommendations for the diagnosis and treatment of IgAV was published in Egypt, based on the best available evidence and expert opinion. For gastrointestinal manifestations, oral or intravenous steroids are recommended in complicated cases, after ruling out intestinal intussusception. ¹⁴ New guidelines have recently been written in the United Kingdom confirming the use of steroids for severe abdominal involvement and/or gastrointestinal bleeding, once intestinal invagination has been ruled out. ¹⁴

Some retrospective analyses and case reports suggest that corticosteroids are associated with faster reduction and resolution of mild-to-moderate abdominal symptoms, such as pain, melena, and intestinal bleeding.^15–17 Weiss et al., following a meta-analysis, suggest that early corticosteroid use for children with HSP is associated with a statistically significant increase in the likelihood of resolution of abdominal pain within 24 h and a reduction in the likelihood of evolution and persistence of renal disease. They also conclude that prompt use of these drugs may also reduce the need for surgery and eventual recurrence of HSP. ¹⁸

In contrast, other smaller studies have shown that early use of glucocorticoids is helpful in controlling gastrointestinal symptoms but does not appear to have a significant impact on the clinical course.^19,20 Some studies have even suggested that corticosteroids may increase the risk of intestinal perforation by leading to increased secretion of gastric acid and pepsin and reducing the resistance of the gastrointestinal mucosa, which could be an additional risk factor for the development of gastrointestinal bleeding and perforation.^21,22 In addition, there is still a proportion of patients with refractory gastrointestinal symptoms who fail to achieve recovery even with the use of glucocorticoids. There is currently no consensus or high-quality guidelines or evidence on the management of steroid-resistant or steroid-dependent HSP with refractory gastrointestinal symptoms. ¹³

The literature, including small case series, adult studies and anecdotal reports, suggests that refractory HSP has been effectively treated with a variety of disease-modifying immunomodulatory therapies without the use of corticosteroids, among them IVIG (intravenous immunoglobulin), colchicine, cyclosporine, methotrexate, cyclophosphamide, mycophenolate mofetil (MMF), and azathioprine. ²³ Chinese guidelines published in 2013 stated that IVIG could have beneficial effects on severe symptoms during the acute phase, though with a weak degree of evidence. ²⁴ In fact, according to numerous reports, compared with steroids and other immunosuppressive agents, IVIG is free of long-term side effects, and in some centers, they are safely used in patients with steroid-resistant or steroid-dependent gastrointestinal complications. ¹³

IVIG is a type of blood product composed of human immunoglobulins from thousands of healthy donors, mainly containing IgG and a small amount of IgA and IgM. A high dose (1–2 g/kg) of IVIG has already been applied in other autoimmune and inflammatory diseases, such as in Kawasaki disease, idiopathic thrombocytopenic purpura, and Guillain-Barré syndrome. IVIG could act as an immune modulator on various cells of the innate and adaptive immune system, resulting in downregulation of antibody synthesis, facilitation of autoantibody clearance, inhibition of the complement pathway and cellular damage, and enhancement of corticosteroid sensitivity.^25,26

Though IVIG has a global safety profile, we sometimes see severe adverse events, such as anaphylaxis, hemodynamic shock, respiratory/renal failure, thrombosis, blood count alteration, and aseptic meningitis. These are documented but infrequent. Theoretically, IVIG administration does not appear to immunosuppress and has a generally favorable tolerability. However, this blood-derived product inherently carries a potential for infectious agent transmission. Additionally, consistent availability, affordability, and sustained efficacy remain challenges associated with IVIG therapy. ²⁶

Morotti et al. reported two children with HSP characterized by severe gastrointestinal symptoms refractory to high-dose oral or intravenous corticosteroids, who instead demonstrated a rapid clinical response to IVIG administration. ²⁵

Similarly, a French retrospective study reported on eight children with HSP and severe gastrointestinal manifestations. All were initially treated with oral steroids as first-line therapy but required IVIG as second-line treatment. Of these, six experienced symptom resolution within 7 days, while the remaining two required a second IVIG dose with subsequent benefit. The authors concluded that IVIG could be a viable alternative for severe gastrointestinal forms of HSP. ²⁶

Oner et al. in 2023 conducted a retrospective study in which 12 patients required IVIG; of these, 5 experienced marked clinical improvement, while the remaining required additional therapies (e.g. cyclophosphamide or plasma exchange). The authors noted that cases with a prompt response to IVIG had lower levels of CRP and ESR, similar to our patient. ²⁷

In our clinical case, due to the absence of established protocols and following a thorough literature review, taking into account the well-documented adverse effects associated with steroid treatment (such as hyperglycemia, hypertension, weight gain, acne, and immunosuppression) along with the clinical experience at our center, we decided to use the same regimen of 2 g/kg in a single administration, exactly as widely used in the better-known Kawasaki disease. In most cases reported in the literature, as well as in our patient, remission of gastrointestinal symptoms was recorded within the next 24–48 h after IVIG infusion.

Among the second-line therapies, the use of immunosuppressive drugs such as cyclophosphamide or MMF has been reported for some patients with steroid-resistant gastrointestinal involvement. ²⁸ MMF, which suppresses lymphocyte proliferation, is very effective in many autoimmune diseases even in pediatric age, such as systemic lupus erythematosus, and seems to be a relatively safe and effective drug for the treatment of HSP. Gicchino et al. proposed the use of MMF in cases of severe steroid side effects, dependence, or ineffectiveness of steroids. ¹⁰

Hemoperfusion is an extracorporeal blood purification modality. The procedure selectively eliminates abnormal cells, components and cytokines (IL-6, TNF-α) in the blood due to an excessive inflammatory process. ²⁹ In their study, Zhang et al., concluded that hemoperfusion treatment combined with corticosteroids was more effective in eliminating serum immune mediators than corticosteroid alone in HSP, resulting in marked improvement of gastrointestinal symptoms and reduction of HSP recurrence. ¹³

Crayne et al., following a retrospective analysis of eight children, proposed rituximab (RTX) as a viable therapeutic alternative for steroid-dependent HSP. ²³ RTX is a monoclonal antibody that binds to CD20, expressed on human B cells and expressed at a low level on a small subset of T cells.^29–31 After binding to CD20, it induces B-cell depletion through complement and antibody-mediated cytotoxicity. Via this mechanism, the decrease in circulating IgA levels is induced, contributing to the reduction of pathology in HSP. ³² RTX appears to reduce the number of hospitalizations, the oral corticosteroid burden in children with less severe refractory HSP, and the achievement of clinical remission of pathology. ²³

Conclusions

Although HSP is a common vasculitis in pediatric practice, well-designed controlled studies regarding its treatment and management are lacking. This is partially due to the usual self-limiting progress of the disease. ⁴ A key challenge is an early, prompt and accurate diagnosis in order to instigate appropriate management, timely treatment of complications, and close follow-up. ³³

Because experience on the use of IVIG in HSP-related gastrointestinal vasculitis is still limited, further studies and perhaps a controlled trial versus corticosteroids are needed before considering IVIG as standard therapy in patients with HSP and refractory gastrointestinal disease.

Finally, we reiterate the urgent need for therapeutic trials investigating novel agents that promote corticosteroid sparing. This is of paramount importance in the pediatric population, given the significant concerns surrounding glucocorticoid toxicity. ³⁴