Granulomatosis with polyangiitis with intestinal involvement successfully treated with rituximab and surgery

Abstract

Intestinal perforation is a rare and life-threatening complication in granulomatosis with polyangiitis (GPA). A 55-year-old Japanese man who had been undergoing maintenance haemodialysis was diagnosed with GPA via a pathologically proven nasal granuloma and proteinase 3-antineutrophil cytoplasmic antibody-positive status. He was started on 60 mg prednisolone. Haematochezia was observed due to the colon ulcer after treatment initiation. Two doses of intravenous cyclophosphamide were administered every 2 weeks. Despite the treatment, there were two episodes of severe abdominal pain with peritonitis within a week. Perforation of descending colon and severe ischaemia of the ascending colon was observed during each emergency laparotomy, and ileostomy was performed. Vasculitis in the small vessels was confirmed. In conclusion, patient with severe intestinal involvement and who was unresponsive to conventional therapy was treated with surgery followed by rituximab administration, and remission was achieved.

Background

Granulomatosis with polyangiitis (GPA), a small-vessel vasculitis, is rare in Japan. The upper (84.9%) and lower (78.8%) respiratory tracts and kidneys (63.6%) are majorly affected.¹ Gastrointestinal involvement is less common, and severe intestinal involvement is even rarer. Perforation is one of the most severe and life-threatening complications of GPA. A combination of surgery and immunosuppressant therapy is crucial to control intestinal ischaemia due to vasculitis. Glucocorticoids and cyclophosphamide are commonly used to treat GPA; however, some patients are resistant to these standard therapies.² We present the case of a Japanese man who had been undergoing maintenance haemodialysis and who had two severe episodes of peritonitis despite standard therapy. He was successfully treated with surgery and rituximab.

Case presentation

A 55-year-old Japanese man was admitted to our hospital for the treatment of an ulcer and granuloma of the left nasal septum. He had a 1-year history of purpura in his lower limbs; his dermatologist had previously screened for proteinase 3-antineutrophil cytoplasmic antibody (PR3-ANCA) for which the patient tested positive. An ulcer and a granuloma were detected in his left nasal cavity, and diagnosed as necrotising vasculitis and granuloma, respectively. No lesion was observed in his lungs. He had been on maintenance dialysis for 20 years because of hypertensive nephropathy. Both kidneys were atrophic and were not suitable for renal biopsy.

Investigations

On admission, laboratory data indicated a white blood cell count of 9500/mm³, haemoglobin level of 64 g/L, platelet count of 28.1×10⁴/mm³ and C-reactive protein level of 0.64 mg/dL. The patient tested positive for PR3-ANCA (46.2 U/mL; normal level <3.5 U/mL) and negative for myeloperoxidase ANCA. He tested negative for antinuclear antibody (1:40), anti-double-stranded DNA immunoglobulin G and antismooth muscle antibody. Based on the clinical and laboratory findings, he was diagnosed with GPA. Renal anaemia and gastrointestinal bleeding were suspected; however, no bleeding site was detected through upper and lower intestinal endoscopy. Erythropoietin was periodically administered.

Treatment

Treatment was started with oral administration of 60 mg of prednisolone. Haematochezia was observed on the 37th hospital day. Total colon fibre revealed a punched-out ulcerative lesion in the caecum and a semicircular punched-out ulcerative lesion in the descending colon. Histopathological evaluation revealed non-specific, active chronic inflammation. Two doses of 500 mg of intravenous cyclophosphamide (IVCY) were administered every 2 weeks.

On the 45th hospital day, myalgia was observed in the lower limbs and high intensity was observed in T2-weighted magnetic resonance images of gastrocnemius muscle. However, muscle biopsy findings were normal. On the 47th hospital day, a cavity lesion was observed in the upper lobe of the right lung. Alveolar lavage was performed, and few Gram-negative organisms were identified. Pseudomonas aeruginosa was detected in the culture, and antibiotics were started. The cavity did not change markedly after antibiotic therapy was initiated. GPA was considered to have affected the lungs. On the 66th hospital day, the patient developed abdominal pain and signs of peritonitis. Laboratory analyses revealed a white blood cell count of 9200 /mm³ and C-reactive protein level of 4.34 mg/dL. Abdominal CT revealed free air, and perforation of the intestinal tract was suspected (figure 1). Emergency surgery was performed, and perforation of the descending colon was diagnosed. Partial resection of the colon was performed, and a colostomy was created in the transverse colon. On the 73rd hospital day, severe abdominal pain appeared again. Laparotomy was performed, and necrotising colitis in the ascending colon was diagnosed; right hemicolectomy was performed, and an ileostomy was created (figure 2). Vasculitis was confirmed in small vessels in the resected specimen (figure 3), and high fever persisted after surgery. Rituximab 375 mg/m² was administered on the 80th hospital day. CRP level decreased from 16.59 mg/dL on the 74th hospital day to 0.25 mg/dL on the 93rd hospital day. To measure disease activity, we used the Birmingham Vasculitis Activity Score (BVAS) (V.3). Prior to treatment, the BVAS score of the patient was 15 on the first operation day (66th hospital day), which is considered as severe disease. After the second surgery, the BVAS score was still as high as 12 on the 80th hospital day, before decreasing to 4 on the 93rd day after rituximab was administered. Oral intake was started again on the 90th hospital day.

Figure 1.

Abdominal CT scan prior to the first surgery. Free air was detected in front of the liver (left panel) and in the retroperitoneal space adjacent to the descending colon (white allow head in the right panel).

Figure 2.

Gross appearance of the resected specimen in the second surgery: * indicates the lesion of mucosal prolapse.

Figure 3.

Microscopic appearance of the submucosal layer in the ascending colon resected in the second surgery (H&E staining: ×400): Inflammatory cell infiltration was observed in the small vessel wall (arteriole and venule).

Outcome and follow-up

On the 103rd hospital day, there was increased discharge (1500–3196 mL/day of watery stool) from his ileostomy along with abdominal pain. His diet resulted in worsened small intestinal ischaemia, and reabsorption capacity of the small intestine deteriorated; accordingly, the patient underwent fasting. The BVAS/GPA score increased to 15 on the 103rd hospital day. Rituximab was administered trice weekly. Remission was achieved, and oral intake was started again.

Discussion

We herein present the case of a patient on maintenance haemodialysis who was diagnosed with GPA on biopsy and who experienced two episodes of severe peritonitis, requiring emergency surgical intervention. The average annual incidence of GPA is 2.1/million individuals and 14.3/million individuals in Japan and the UK, respectively.³ Intestinal involvement in GPA is rare in Japanese. The patient met the diagnostic criteria of GPA published by Watts et al, who concluded that there should be histological confirmation of the disease in at least one of the three principal sites (upper and lower airways and kidneys) to establish the diagnosis.⁴ No signs or symptoms of malignancy, inflammatory bowel disease, hepatitis B antigenaemia or eosinophilia were observed. A lung cavity appeared during the disease course, and antibiotics were administered to prevent lung abscess development. The effect of GPA on his kidneys was unknown because he was on maintenance dialysis, and his kidneys were atrophic and unsuitable for renal biopsy. Severe intestinal involvement is a rare complication of GPA and is reported in 3%–25% of GPA/Wegener’s granuloma (WG) cases.^{1 5 6} This condition has only been reported in patients presenting with extensive involvement of other organs (lungs and kidneys). Severe intestinal manifestation in GPA, including perforation, ulcers and persistent bleeding, likely occurs within a short time of the diagnosis, and the commencement of immunosuppressive therapy has been reported for this.^7–12 In the present case, intestinal bleeding and perforation appeared within only two and a half months after treatment with glucocorticoids and IVCY. Biopsy specimens are typically obtained by colonoscopy from the mucosal layer, and it is difficult to obtain information from deeper layers (ie, submucosal layer, smooth muscle layer). Therefore, it is difficult to establish a diagnosis of vasculitis by means of endoscopy.

Our patient seemed to be resistant to standard therapy. Since the 1970s, administration of glucocorticoids and cyclophosphamide has constituted the standard treatment for WG¹³; however, for some patients, this approach may not be sufficient to achieve lasting disease remission or to prevent relapse. Rituximab is a chimeric monoclonal anti-CD20 antibody that achieves selective prolonged depletion of B lymphocytes. Evidence for the efficacy of rituximab treatment comes from the rituximab in ANCA-associated Vasculitis (RAVE) trial, which is multicentre, randomised, double-blind trial of rituximab compared with cyclophosphamide. In this trial, 197 ANCA-positive patients with either Wegener’s granulomatosis or microscopic polyangiitis were enrolled; of these, 64% of those treated with rituximab achieved remission without the use of prednisone at 6 months, where 53% of those treated with cyclophosphamide achieved remission; these data statistically met the criterion for non-inferiority.¹⁴ Furthermore, in a subanalysis of the RAVE trial, patients with PR3-ANCA associated vasculitis achieved remission significantly more often when treated with rituximab as opposed to cyclophosphamide/azathioprine (65% vs 48%).¹⁵ Moreover, Jillella et al measured the level of rituximab in blood before and after each haemodialysis session and reported that rituximab was not eliminated by haemodialysis, thus therapeutic levels of rituximab may be maintained in patients undergoing dialysis. The blood level of rituximab was maintained at similar level in a patient with normal renal function, and dosage adjustment may not be necessary.¹⁶ In total, four doses of rituximab were administered weekly in the present case, and no adverse effect was observed. Intestinal manifestation is one of the most severe complications of GPA and should be treated with the most intensive therapy available. Rituximab is effective and safe even for the patients on haemodialysis.

Patient’s perspective.

I still feel abdominal pain sometimes; however, I am eating a rice gruel diet, and do not feel severe abdominal pain. I hope to get well and go home soon.

Learning points.

• Intestinal involvement is one of the most severe complications of GPA.

• Full dose of rituximab (375 mg/m², four doses weekly) should be administered to achieve remission in patients unresponsive to conventional therapy.

• Rituximab is effective and safe even for the patients on haemodialysis.