A 72-year-old man with a purpuric rash

CASE CONTINUED: ARRIVING AT THE DIAGNOSIS

We start our patient on cyclophosphamide 175 mg daily in view of possible Wegener granulomatosis.

Even though purpura is extremely rare in primary antiglomerular basement membrane disease, this patient has life-threatening pulmonary hemorrhage, a complication seen in over 50% of these patients. Therefore, plasmapheresis is started empirically.

On the second day of cyclophosphamide treatment, tests for ANCA, glomerular basement membrane antibody, and antinuclear antibody are reported as negative, and complement levels are normal. Bronchoalveolar lavage shows no infection. Follow-up blood cultures are negative.

To summarize the findings so far, this patient has a purpuric skin rash, active urine sediment with red cell casts indicating glomerulonephritis, acute renal failure, and severe pulmonary hemorrhage requiring mechanical ventilation. Although one set of blood cultures showed gram-positive cocci, no source of infection, particularly endocarditis, could be identified.

Antiglomerular basement membrane disease would still be high on the list of suspected diagnoses, given his diffuse alveolar hemorrhage. As mentioned earlier, renal biopsy is imperative to making a diagnosis, because serologic tests have variable accuracy. And making the correct diagnosis has therapeutic implications.

Renal biopsy is performed and shows immune-complex mesangiopathic glomerulonephritis with positive immunofluorescent staining in the mesangium for IgA. Only one glomerulus shows fibrinoid necrosis.

Skin biopsy results obtained earlier showed positive direct immunofluorescence for IgA. Both renal and skin biopsies suggested Henoch-Schönlein purpura.

IgA deposition in the kidney and skin has been associated with liver cirrhosis, celiac disease, and infections with agents such as human immunodeficiency virus, cytomegalovirus, Haemophilus parainfluenzae, and Staphylococcus aureus. In a Japanese study,⁴ renal biopsy specimens from 116 patients with IgA nephropathy and from 122 patients with other types of kidney disease were examined for the presence of S aureus antigen in the glomeruli. Although antigen was not detected in non-IgA disease, 68% of specimens from patients with IgA nephropathy had S aureus cell envelope antigen together with IgA antibody in the glomeruli. However, no single antigen has been consistently identified, so it seems more probable that the development of IgA deposition in kidneys is a consequence of aberrant IgA immune response rather than the antigen itself.

HENOCH-SCHÖNLEIN PURPURA

Henoch-Schönlein purpura is a systemic vasculitis with a prominent cutaneous component. It is characterized by the tissue deposition of IgA-containing immune complexes. It is predominantly a disease of children but it can be seen in adults. A UK study found the prevalence to be 20 per 100,000 children, with the highest prevalence between ages 4 and 7 (70 per 100,000).⁵

The four cardinal clinical features of Henoch-Schönlein purpura are purpuric rash, abdominal pain, arthralgia, and renal involvement. Almost all patients have purpuric rash at some point in their disease course. Arthralgia with or without arthritis is typically migratory, oligoarticular, and nondeforming, usually affecting the large joints of the lower extremities; involvement of the upper extremities is less common.

Skin biopsy typically shows leukocytoclastic vasculitis in postcapillary venules with IgA deposition, and these findings are pathognomonic of Henoch-Schönlein purpura.

Gastrointestinal involvement can range from mild symptoms such as nausea, vomiting, abdominal pain, and paralytic ileus to severe disease such as gastrointestinal hemorrhage, bowel infarction, bowel perforation, and intussusception.

Renal involvement is common and is important, as it can in rare cases progress to end-stage renal disease. The urinalysis usually shows mild proteinuria with active sediment with red cell casts. Most patients have relatively mild disease, characterized by asymptomatic hematuria with a normal or slightly elevated creatinine. However, severe involvement may occur, with nephrotic syndrome, hypertension, and acute renal failure.

Different presentation in adults vs children

Adults with Henoch-Schönlein purpura only rarely present with bowel intussusception, whereas some studies have found that adults are more likely than children to develop significant renal involvement, including end-stage renal disease.^6,7

There is a general but not absolute correlation between the severity of clinical manifestations and the findings on renal biopsy. A poor prognosis (significant proteinuria, hypertension, renal insufficiency, or end-stage renal disease) is associated with crescent formation involving more than 50% of the glomeruli.⁸

Our current understanding of the longterm outcome of the renal disease in Henoch-Schönlein purpura is primarily derived from studies in children. In one study, complete recovery occurred in 94% of children and 89% of adults.⁷ A long-term study of 250 adults with Henoch-Schönlein purpura and renal involvement of sufficient severity to require biopsy reported that, at a median follow up of 15 years, 11% had become dialysis-dependent and 13% had severe renal failure (creatinine clearance < 30 mL/min).⁶ Recurrence is common, occurring in approximately one-third of patients, more likely in those with nephritis.⁸

The diagnosis of Henoch-Schönlein purpura is typically made on the basis of key clinical features. In patients such as ours who have an atypical presentation, biopsy of affected skin and renal biopsy can be essential in the diagnosis. Diffuse alveolar hemorrhage is exceedingly rare in Henoch-Schönlein purpura but can be seen, as in our patient.^9,10 In this setting, the findings of IgA deposits in skin and renal biopsy specimens, together with the absence of other clinical, serologic, or histologic features of other more-common potential causes, secured the diagnosis in this patient.

Henoch-Schönlein purpura is usually self-limited and requires no specific therapy. Evidence suggests that glucocorticoids enhance the rate of resolution of the arthritis and abdominal pain but do not appear to prevent recurrent disease or lessen the likelihood of progression of renal disease.⁸ Patients with severe renal involvement with renal function impairment may benefit from pulse intravenous corticosteroid therapy (methylprednisolone 250–1,000 mg per day for 3 days), followed by oral steroids for 3 months.¹¹

In anecdotal reports, renal function improved in 19 of 21 children with Henoch-Schönlein purpura and severe crescentic nephritis.¹² Studies have evaluated cyclophosphamide¹³ and plasmapheresis,¹⁴ but their role remains uncertain. Renal transplantation is an option in patients who progress to end-stage renal disease.