A limited form of granulomatosis with polyangiitis in an ulcerative colitis patient receiving sulfasalazine

Discussion

Extra intestinal manifestations of UC occurs in approximately 25% of patients. There is an overlap between these manifestations and the complications of UC treatment. Sulfasalazine (SSZ) is widely used in the treatment of UC and it is known to cause many side effects, including a hypersensitivity reaction that resembles pulmonary eosinophilia, bronchiolitis, and interstitial lung infiltrates.⁴ Orbital pseudotumor has not been shown to be a side effect of this medication. Co-existence of SSZ treatment’s complications with other clinical conditions were recognized.

Miura et al⁵ reported a case of necrotizing glomerulonephritis with positive C-ANCA, PR-3, and eosinophilia after resuming treatment with sulfasalazine in a patient with UC. The question of SSZ causing ANCA associated vasculitis (AAV) is to be answered. Adverse events due to SSZ encompass n-acetyltransferase-2 slow acetylator phenotype, long duration of treatment, and high cumulative doses. Several studies have shown that SSZ promotes apoptosis and selectively blocks NF-^KB-dependent gene transcription in various cell types, including neutrophil apoptosis.⁶ The so called neutrophil priming leads to an auto antibody response and production of ANCA.⁶

In our case, the co-existence of GPA was supported by the presence of orbital pseudotumor, chronic sinusitis, epistaxis, and positive C-ANCA. The patient improved and achieved remission while on mesalazine, which made it unlikely to be the cause. The pathogenesis of UC was not clear, but it has been emphasized that it is due to immune system dysregulation. The association of UC and GPA with the presence of C-ANCA may indicate a common immunological background. Positive ANCA is present in 40-80% of UC patients, while (PR-3) ANCA is found to be positive in 6% of UC patients by ELISA.⁶

Previous case reports regarding the association of a limited form of GPA and UC were mainly in the form of pulmonary involvement in GPA. Yano et al⁷ reported a patient with bronchiolitis obliterans organizing pneumonitis-like variant in a UC patient. His P-ANCA and drug lymphocyte stimulation test (DLST) for mesalazine were positive and transbronchial biopsy was consistent with GPA. This was labelled as a limited form of GPA in a UC patient. Fayaz et al⁴ reported a case of a similar scenario with P-ANCA positive and negative C-ANCA and thoracoscopic lung biopsy was consistent with the eosinophilic variant of GPA. The DLST was not performed in this case like most similar reports. Kasuga et al³ described a young lady with UC who had multiple nodular infiltrates in the lungs and increased PR-3 ANCA. She was on mesalazine, which is known to cause pulmonary toxicity. She improved without treatment or discontinuation of mesalazine. The reported cases on the association of UC and GPA, the UC diagnosis preceded the occurrence of GPA by several years, and the GPA presentations were usually in the form of pulmonary involvement. Isse et al,² reported an elderly patient who was known to have GPA and was in remission then she developed exophthalmus and her radiological and histopathological investigation revealed orbital inflammatory pseudotumor which was treated with prednisolone.

Limited form of GPA that is not life threatning can be treated with MTX, rituximab, mycophenolate mofetil, leflunomide, and cyclosporine. Modifying treatment according to the severity of the disease often proved successful.⁸ Methotrexate was compared to cyclophosphamide (non-renal vasculitis alternatively treated with methotrexate trial) and although they were equally effective, there was a delay in remission in the MTX group compared to the cyclophosphamide group, especially in patients with extensive pulmonary involvement with a higher rate of relapse. In the treatment of vasculitis, the difficulty lies more in maintaining the remission rather than inducing it. There are several studies comparing different regimens in maintaining remission. In the WEGENT study, this trial directly compared AZA and MTX in the maintenance of remission after induction with cyclophosphamide. At 29 months, there was no difference in survival between the 2 arms. Rituximab has been approved to treat ANCA-associated vasculitis after the good outcome from different studies that proved its efficacy compared with the standard therapy (RAVE trial).⁸ Rituximab is typically thought to be more effective in the vasculitic phase rather than the granulomatous phase, as recent reports have suggested that rituximab may be less effective for the treatment of necrotizing granulomatous lesions. However, small studies have shown good results with limited GPA.⁹

In conclusion, a limited form of GPA can co-exist with UC, which may confuse the clinical picture, especially if the patient is receiving mesalazine. Awareness of such association may help to minimize this confusion.