Seroconversion in a Case of Granulomatosis with Polyangiitis – Treatment Considerations
1Department of Internal Medicine, Rutgers/Robert Wood Johnson Barnabas Health, Jersey City Medical Center
2Department of Rheumatology, Rutgers/Robert Wood Johnson Barnabas Health, Jersey City Medical Center
Alebna PL, Castillo MH, Mekhail R, Marian V. Seroconversion in a Case of Granulomatosis with Polyangiitis – Treatment Considerations. Consultant. 2023;63(2):e10. doi:10.25270/con.2022.11.000007
Received April 6, 2022. Accepted October 18, 2022. Published online November 30, 2022.
The authors report no relevant financial relationships.
This research did not receive grants from any funding agency.
The authors report that informed patient consent was obtained for publication of the images used herein.
Pamela Alebna MD, MPH, Jersey City Medical Center, Internal Medicine Department, 355 Grand Street, NJ, 07302 (email@example.com
Introduction. Granulomatosis with polyangiitis (GPA) is the most common of the antineutrophil cytoplasmic antibodies (ANCA)-associated small vessel vasculitides1, with an estimated prevalence of 30 in 100,000 cases, usually occurring between 35 to 55 years of age with a slight male preponderance (male to female ratio of 1.5:12). GPA is immune-mediated with 90% antinuclear antibody (ANA) positivity.3 There are many potential triggers of GPA4, though it is generally thought to have a complex genetic and environmental factor interaction.5 Up to 40% of cases are idiopathic. The typical presentation is a triad of upper respiratory disease, lower respiratory disease, and glomerulonephritis. Because of the nonspecific nature of its presentation, most patients usually go undiagnosed until late in the disease course. Overall, it has a poor prognosis with increased morbidity when diagnosis is delayed.6 Treatment for GPA is usually tailored towards disease severity.
This case illustrates the diagnostic challenges with GPA, the consequence of delayed diagnoses, and the peculiarities in the management of seronegative GPA.
Key words. Seronegative GPA, Rituximab, Plasmapheresis, Delayed diagnoses
Patient case. A 71-year-old Russian-speaking man with a past medical history of hypertension and benign prostatic hyperplasia presented to the emergency department (ED) for evaluation of severe hemoptysis.
Patient history. Six months before admission, the patient started experiencing flu-like symptoms with intermittent fever, sinus pain, stuffiness, and weight loss which he could not quantify but described as a significant drop in weight. After a failed first antibiotics course, he was seen by his primary care physician (PCP) who sent him for a computed tomography (CT) scan of his sinuses, which revealed mucosal inflammatory thickening of the sinuses. Laboratory studies done at the time were significant for creatinine of 0.88 mg/dl (normal range 0.74 - 1.35). His c-reactive protein (CRP) was 10.3 mg/d (normal range <10), erythrocyte sedimentation rate (ESR) was 25 mm/h (normal range <22), and negative ANA. He again failed a second course of antibiotics.
Four months before admission, he reported generalized malaise and weight loss. Another month went by, and laboratory studies were repeated. This time there was a noticeable change in renal function: creatinine increased to 1.36 mg/dL, CRP remained elevated at 8.8 mg/dL, and ESR increased to 51 mm/h. ANA was once again negative and anti-dsDNA was negative.
One month prior to admission, the patient started coughing up blood. He reported intermittent headaches (10-20 times a day). His primary care physician was concerned for a possible malignancy since the patient continued to report unintentional weight loss. He underwent upper gastrointestinal endoscopy and colonoscopy because there was high suspicion that the bleeding could be originating in the gastrointestinal tract. However, both studies were unremarkable. He later developed a maculopapular rash on bilateral ear lobes, elbows, knees, and legs (Figure 1).
Figure 1. Skin Vasculitis - purpuric, palpable, and non-blanching.
On the day of presentation, the patient experienced an episode of acute shortness of breath, prompting his visit to the ED. He also reported decreased urine output. He denied tobacco or illicit drug use but consumed alcohol socially.
Physical examination. On physical examination, the patient appeared ill, but he was alert and oriented. We noted traces of dried blood in his nostrils with an intact nasal septum. Skin pallor was present, as well as several groups of healing maculopapular lesions with fine scales on both calves, knees, and ear lobes ranging from 2 mm to 10 mm in diameter, and Churg nodules were noticed on his knees and elbows (Figures 2 and 3).
Figures 2 and 3. Churg nodules on knees and elbows.
Vital signs were significant for a blood pressure of 184/100 mm Hg, a heart rate of 113 beats/min, and a respiratory rate of 26 cycles/min. He was afebrile and maintaining an oxygen saturation level of 98% on room air.
Laboratory and diagnostic testing. The results of laboratory tests were consistent with a hemoglobin of 6.9 g/dL (normal range 14-18), acute kidney injury with creatinine level of 12.9 mg/dL (normal range 0.7 - 1.3), and blood urea nitrogen of 147 mg/dL (normal range 9-23). Additional laboratory values are included in Table 1.
Table 1. Laboratory Results
Test (Reference range)
6 months before admission
3 months before admission
1 month later
Hemoglobin (13.5-17.5 g/dl)
Fibrinogen (200-400 mg/dl)
Cryoglobulin (100-300 mg/L of normal serum proteins)
BUN/CR (BUN 6-24 mg/dl; Creatinine 0.74-1.35 mg/dl)
P-ANCA (<20 AU/ml)
Anti-Myeloperoxidase (MPO) (< 0.4 antibody index)
C-ANCA (<20 AU/ml)
Anti-Proteinase 3 (PR-3) (<3.5 EU/ml)
C3/C4 (C3: 80-178 mg/dl; C4: 12-42 mg/dl)
Anti GBM (Negative results)
ANA (titers <1:40)
Rheumatoid Factor (0-20 IU/ml)
Cyclic Citrullinated Peptide (<20 u/ml)
On imaging, a CT scan of the sinuses showed mucosal thickening without evidence of bony destruction (Figure 4).
Figure 4. CT of the sinuses showing extensive inflammation.
Chest CT scan findings included diffuse bilateral areas of pulmonary parenchymal, areas of ground-glass disease, and airspace consolidation, suggestive of pulmonary hemorrhage (Figures 5-6).
Figures 5 and 6. CT scan of the chest demonstrating extensive pulmonary hemorrhages.
Treatment and management. The patient was admitted to the intensive care unit and started on dialysis. Clinical and laboratory findings favored the diagnosis of pulmonary-renal syndrome. GPA was suspected given the findings on his sinus CT scan. However, microscopic polyangiitis and Goodpasture disease were also part of the differential diagnosis. Of note, ANCA antibodies were negative at this point and renal biopsy was pending. He was started on a pulse dose of steroids: 1g methylprednisolone after each dialysis session for the first 3 dialysis sessions. Blood products were administered and supportive therapy with intravenous fluids was initiated.
On day 2, plasmapheresis was initiated and continued every other day for 7 days. Daily fibrinogen and PT/PTT were also assessed. The patient still had intermittent shortness of breath and persistent hemoptysis, but to a lesser degree.
On day 3, after two high doses of steroids, he developed delirium possibly secondary to steroid-induced psychosis. He had to be restrained and given antipsychotics. The dose of glucocorticoid was lowered to 40 mg/day of methylprednisolone. Renal biopsy was obtained, and histopathologic evaluation revealed a pauci-immune necrotizing crescentic glomerulonephritis with 59% global glomerulosclerosis, mild-to-moderate interstitial fibrosis, tubular atrophy, and mild arteriosclerosis. From days 7 to 14, he received several sessions of dialysis and blood products and completed a total of five sessions of plasmapheresis.
Due to the unclear benefit of rituximab in seronegative patients, our patient received a one-time dose of cyclophosphamide (750 mg) and all the scheduled sessions of plasma exchange were completed. He was later discharged on a 3 times per week dialysis schedule. Additionally, he was switched from intravenous methylprednisolone to oral prednisone 30 mg/day, as well as a SMZ-TMP prophylaxis dose 3 times per week.
Patient follow-up. At follow-up, the patient tolerated a second 900 mg dose of cyclophosphamide, which was given 4 weeks after the initial dose of 750 mg. Interestingly, the result of the laboratory tests showed an indeterminate result for anti-proteinase 3 antibody. Given the seroconversion from negative to indeterminate anti-proteinase 3 antibody, and no renal response to treatment as patient was still on hemodialysis, we started the patient on rituximab at 375 mg/m2 weekly for 4 weeks.
At follow-up, the patient had proteinuria of 4.6 g, but this could not be used as a marker of response to cyclophosphamide in the first few months as proteinuria resolves slowly. Based on the RAVE trial13, which showed rituximab is non-inferior to cyclophosphamide (CYC) in patients who failed treatment with the first cycle of CYC, treatment at this time was switched to rituximab. He still had intermittent shortness of breath and persistent hemoptysis, but to a lesser degree and still required hemodialysis. He received a renal transplant 13 months after index presentation.
Discussion. GPA is a rapidly progressive disease with significant morbidity. Timely treatment is paramount to improving management outcomes.7 Treatment options are usually tailored to disease activity.8 In this case, the disease appears relatively acute and aggressive since the patient had a normal renal function a few months prior to admission. Our patient initially tested ANCA negative and then later tested indeterminate for MP3 after treatment initiation. Antibodies could have emerged after the patient was started on a lower dose of steroids and was now off plasmapheresis.
The decision to start plasmapheresis was controversial, particularly in light of the newly released PEXIVAS trial9, which showed that plasma exchange did not reduce the incidence of death or end-stage renal disease (ESRD). In that trial, plasma exchange did not appear to improve mortality in patients with initial creatinine greater than 3.4 mg/dL, however this trial was done in patients with ANCA seropositivity, and our patient was ANCA negative. In addition, based on the possible reduction in organ dosage in patients with rapidly progressive glomerulonephritis, even though the benefit in pulmonary hemorrhage, death, and progress to ESRD could be null, we decided to proceed with plasma exchange. Some studies also show no real benefit with plasma exchange irrespective of creatinine levels.10 ANCA levels tend to correlate with disease activity, however in this case the patient had fulminant symptoms and ANCA was negative12. Due to the unclear benefit of rituximab in seronegative patients as the RAVE trial13 had primarily seropositive patients, our patient was started on cyclophosphamide. Nausea, vomiting, body aches, flushing, and skin changes are common side effects of these agents. Our patient was monitored closely for these to ensure compliance on therapy. Other agents for consideration include methotrexate and mycophenolate mofetil, usually used in refractory cases and for maintenance therapy.
Our case is unique because it highlights some of the diagnostic challenges in GPA, especially in circumstances where a patient is seronegative. If the index of suspicion is high, it could still be GPA even with negative ANCA. Early recognition and prompt intervention can significantly reduce morbidity. Rituximab induction therapy can be considered in cases of seroconversion.
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- Limited versus severe Wegener’s granulomatosis: baseline data on patients in the Wegener’s granulomatosis etanercept trial. Accessed April 29, 2021. https://reference.medscape.com/medline/abstract/12905485
- Csernok E, Gross WL. Current understanding of the pathogenesis of granulomatosis with polyangiitis (Wegener’s). Expert Rev Clin Immunol. 2013;9(7):641-648. doi:10.1586/1744666X.2013.811052
- Environmental triggers and susceptibility factors in idiopathic granulomatous diseases. Accessed April 29, 2021. https://reference.medscape.com/medline/abstract/19221959
- Granulomatosis with polyangiitis (gpa, formerly wegener granulomatosis): practice essentials, background, etiology. Published online April 3, 2021. Accessed April 18, 2021. https://emedicine.medscape.com/article/332622-overview#a6
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- Calich AL, Puéchal X, Pugnet G, et al. Rituximab for induction and maintenance therapy in granulomatosis with polyangiitis (Wegener’s). Results of a single-center cohort study on 66 patients. J Autoimmun. 2014;50:135-141. doi:10.1016/j.jaut.2014.03.002
- Walsh M, Merkel PA, Peh CA, et al. Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis. N Engl J Med. 2020;382(7):622-631. doi:10.1056/NEJMoa1803537
- Yamada Y, Harada M, Hara Y, et al. Efficacy of plasma exchange for antineutrophil cytoplasmic antibody-associated systemic vasculitis: a systematic review and meta-analysis. Arthritis Res Ther. 2021;23(1):28. doi:10.1186/s13075-021-02415-z
- Jayne DRW, Gaskin G, Rasmussen N, et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol JASN. 2007;18(7):2180-2188. doi:10.1681/ASN.2007010090
- Ara J, Mirapeix E, Rodriguez R, Saurina A, Darnell A. Relationship between ANCA and disease activity in small vessel vasculitis patients with anti-MPO ANCA. Nephrol Dial Transplant. 1999;14(7):1667-1672. doi:10.1093/ndt/14.7.1667
- Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221-232. doi:10.1056/NEJMoa0909905