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 Table of Contents  
Year : 2021  |  Volume : 16  |  Issue : 2  |  Page : 217-220

Antineutrophil cytoplasmic antibody-associated vasculitis in a patient with diffuse scleroderma

1 Departmrnt of Rheumatology, Apollo BGS Hospital, Mysore, Karnataka, India
2 Departmrnt of Internal Medicine, Apollo BGS Hospital, Mysore, Karnataka, India

Date of Submission10-Apr-2020
Date of Acceptance13-Jul-2020
Date of Web Publication25-Jun-2021

Correspondence Address:
Dr. B N Shiva Prasad
Apollo BGS Hospital, Mysore, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_84_20

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Scleroderma is a multiorgan connective tissue disease characterized by autoantibody production and fibroproliferative stenosis of the microvasculature. The development of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in patients with scleroderma is a rare association. Renal and pulmonary complications occur more frequently than expected in scleroderma/ANCA-associated vasculitis overlap. The definitive diagnosis usually made based on autoantibody titers and biopsy of involved tissue. We present a case of diffuse scleroderma with ANCA-associated vasculitis presenting with neurological symptoms.

Keywords: Antineutrophil cytoplasmic antibody-associated vasculitis, antimyeloperoxidase antibodies, diffuse scleroderma, neuropathy

How to cite this article:
Shiva Prasad B N, Karthik Urala H A. Antineutrophil cytoplasmic antibody-associated vasculitis in a patient with diffuse scleroderma. Indian J Rheumatol 2021;16:217-20

How to cite this URL:
Shiva Prasad B N, Karthik Urala H A. Antineutrophil cytoplasmic antibody-associated vasculitis in a patient with diffuse scleroderma. Indian J Rheumatol [serial online] 2021 [cited 2022 May 27];16:217-20. Available from:

  Introduction Top

Systemic sclerosis (SSc) is a multiorgan connective tissue disease characterized by autoantibody production and noninflammatory fibroproliferative stenosis of the microvasculature. Scleroderma in overlap with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is rare, and clinical features are more mixed when either of these two conditions occurs separately.[1] Lumen-occlusive vasculopathy is a prominent feature of scleroderma, which needs to be distinguished from inflammatory vasculitic damage.[2] ANCAs have also been reported in autoimmune diseases with or without evidence of vasculitis, such as myeloperoxidase (MPO)-p-ANCA in rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, inflammatory myositis, and inflammatory bowel disease.[3] ANCA (by Immunoflorescence ) positivity in SSc is very rare and the incidence varies between 7-13%. Clinically significant AAV is still more rare (0.2%–0.8%).[4],[5],[6],[7],[8],[9],[10],[11] Majority have lung or renal involvement. I, hereby, present an interesting case of diffuse scleroderma (DsSSc) patient who developed vasculitic neuropathy five years after the initial diagnosis.

  Case Report Top

A 52-year-old woman, hypertensive and diagnosed as diffuse cutaneous SSc (DsSSC) for the past 5 years. She had skin thickening over the face and limbs, Raynaud's phenomenon, digital ulcers, gastroesophageal reflux disease, and interstitial lung disease (ILD) with pulmonary arterial hypertension (PAH). She was positive for anti-Scl-70 antibody. At the diagnosis of ILD, she was treated with steroids (tapered and stopped) and mycophenolate mofetil (2 g/d) for the past 5 years. She was on tadalafil (20 mg/d) along with home oxygen therapy for PAH and Raynaud's phenomenon. She was also on telmisartan 80 mg/d. She had not received D-penicillamine at any point of time.

She was stable with no worsening of ILD, Raynaud's, or PAH for the past 5 years. She presented with acute-onset numbness and burning sensation over both feet of 15-day duration. There was no worsening of the breathlessness, pedal edema, skin lesions, epistaxis, decreased urine output, or change in color of urine. There was no back pain, change in skin color, arthritis, or proximal muscle weakness. On examination, she had pallor, no new skin lesions, bilateral fine crackles over the lung fields (no change from the previous examinations), and her blood pressure was 130/80 mmHg. On neurological examination, bilateral lower limb weakness (distal > proximal), reduced ankle jerk response bilaterally, reduced perception of pain, touch, temperature sensation below knee. Other systemic examinations were normal and no change from the previous examinations.

Hemogram showed normocytic, normochromic anemia with hemoglobin of 9.6 g/dL, total count was 8000 with differential of 76% (neutrophils), 22% (lymphocytes), 2% (eosinophils), and platelet was 3.4 lakh/cmm. ESR was 44 mm/1st h (<10 mm 1st h). CRP was 24 mg/L (<6 mg/L). Renal function and liver function tests were normal. Urine was negative for protein/glucose/sediments. Nerve conduction study showed bilateral sensory motor axonopathy in peroneal, sural, and tibial nerves. Rheumatoid factor was negative. pANCA was positive and anti-MPO antibody titer was elevated, 37.87 U/mL (normal <20 U/mL). Serum protein electrophoresis was negative for M band. Computed tomography of the thorax did not show any new lesions apart from old ILD changes (nonspecific interstitial pneumonia). Left sural nerve biopsy revealed leukocytoclastic vasculitis with axonolysis [Figure 1] and [Figure 2].
Figure 1: Microphotograph showing longitudinal section of nerve funicles with perivascular and transmural inflammation in the epineurium. Fibrinoid necrosis is also seen (H and E, ×100)

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Figure 2: Microphotograph showing longitudinal section of nerve funicles with perivascular and transmural inflammation in the epineurium. Fibrinoid necrosis is also seen (H and E, ×200)

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The diagnosis of AAV in a patient of diffuse scleroderma was made. Since she was already on mycophenolate, cyclophosphamide/rituximab was considered. The patient chose rituximab for the treatment. She was given rituximab (total of 2 g, 1 g each at an interval of 2 weeks) and steroid pulse (1 g methylprednisolone for 3 doses). Oral steroids were started at 1 mg/kg and tapered over a period of time. Her neuropathic symptoms improved completely. She is on follow-up for 2 years and no relapse of neuropathic or other vasculitic symptoms, with stable pulmonary symptoms.

  Discussion Top

The underlying features of SSc that are associated with ANCA and AAV are controversial. In majority of SSc cases, ANCA is not associated with systemic vasculitis and clinical significance is unclear. The incidence of serologically positive ANCA in patients with SSc varies between 7% and 13%. A positive ANCA test associated with clinical evidence of vasculitis is still more rare in the context of SSc.[2],[4] Patients with MPO-ANCA are more susceptible to present clinical features, whereas those with PR3-ANCA rarely have clinical consequences.[2],[4] Majority of the studies have reported more commonly among females with LcSSc (79%–88%), those with anti-Scl-70 antibody (59%–77%).[5],[6],[7],[8] The most commonly reported organ involvement is glomerulonephritis and the majority of published cases describe microscopic polyangiitis (MPA) or renal-limited vasculitis.[8] Vasculitic peripheral neuropathy in conjunction with other vasculitic manifestations in SSc-AAV is rarely reported.[5],[7],[9] Vasculitic neuropathy as a sole manifestation of SSc-AAV overlap is exceedingly uncommon.[10]

When we look at the literature from the earliest to the latest, there are different associations between SSc and AAV. It may be SSc or AAV related; pure SSc or overlap syndromes; LcSSc or DcSSc, anti-SCL 70 or anticentromere antibody; pANCA or cANCA; anti-MPO or anti-PR3 antibody related; and also the predominant organ involvement. Few literatures have looked in biopsy proved vasculitis in SSc initially and then looking at the serology of these patients for causes of vasculitis and found to be having ANCA positivity. In other published data, they have the serology of SSc patient cohort and look for the manifestations of vasculitis. Hence, it becomes obvious that the literature has different perspective of looking at the SSc-AAV association. We reviewed the literature of studies looking in to the association of SSc-AAV and found interesting findings [Table 1]. We look into the individual studies by the chronology of publication.
Table 1: Literature describing cases of systemic sclerosis-associated vasculitis overlap syndrome with or without features of vasculitic neuropathy

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Ruffatti et al. in 2002 performed a prevalence study of ANCA in SSc using both immunofluorescence and ELISA (both anti-PR3 and anti-MPO) screening tests.[11] They demonstrated the presence of p-ANCA in only 5 of 115 SSc patients, with anti-PR3 antibodies in 2 patients, anti-MPO antibodies in 1 patient, and both anti-PR3 and anti-MPO antibodies in 2 patients. However, none of the patients with ANCA positivity had clinically evident vasculitis. Rho et al. in 2006 described 50 cases of AAV in SSc across 31 published reports.[6] They observed female predominance (84%) with equal representation of LcSSc and DcSSc. They found autoantibody positivity to anti-Scl-70 (70%) and anti-MPO (72%). The kidney (80%) and lung (70%) were most commonly involved organs. Outcome analysis suggested 67.9% of 7-year survival rate. Anti-Scl-70 antibody was found to be a significant predictor of developing AAV in SSc with odds ratio of 3.1. Arad et al. in 2011 described three cases with SSc-AAV overlap and reviewed 37 cases of such cases described to date the English literature (PubMed database, National Library of Medicine, Bethesda, MD, USA).[4] SSc-AAV overlap was most common in the fifth and sixth decades of life (mean age 57, range 19–82), and the male-to-female ratio is 1:4. The average duration of SSc until the appearance of overt AAV was about 9 years. The majority described had DsSSc (57%), whereas about 38% had LcSSc. Majority of SSc-AAV patients were positive Scl-70 (77%), MPO-ANCA (97%), and PR3 (3%) was rarely detected. Patients had renal manifestations of AAV (83%), followed by alveolar hemorrhage (28%), limb ischemia (13%), and skin vasculitis (10%) in sequential hierarchy of manifestations. Liang et al. described 14 patients with SSc and vasculitis overlap.[7] They reported a case and retrospective case collection using centralized electronic diagnostic index at the institution between 1976 and 2006 with both SSc and AAV. The majority (71%) were female, with the mean age at vasculitis diagnosis 53 years. Seven patients (50%) had overlap CTD features, and the majority (79%) had limited variant of scleroderma. Of the 14, 10 patients tested for ANCA (by immunofluorescence and ELISA) and were MPO/pANCA positive. One patient had anti-PR3 positivity, but cANCA was negative. Seven patients (50%) had glomerulonephritis, 11 (79%) pulmonary involvement including three with pulmonary-renal syndrome, six skin purpura, and five mononeuritis multiplex and/or peripheral neuropathy. In this study, the case selection was not uniform. There were cases of overlap features of CTD. Three cases had vasculitis first and later were diagnosed as scleroderma, while the other literature has SSc diagnosed first and then AAV. The duration between the diagnosis of SSc and AAV also varies, from almost simultaneously to 16 years after diagnosis of SSc. All patients with AAV neuropathy were associated with other organ involvement. Another study from UK in 2013 looked in to the clinical, serological, histological, and immunogenetic features of patients with SSc and AAV from a clinical database of 2200 patients between 1999 and 2010 with either limited or DcSSc.[5] Patients with a biopsy confirmed diagnosis of vasculitis who were ANCA positive with either MPO or PR3 reactivity were included. Thirty-five patients (1.6%) had evidence of vasculitis, of these 35 patients, 8 (0.4% of whole SSc cohort) had either anti-MPO or anti-PR3 antibodies and two further patients were ANCA positive without defined specificities. Of the eight ANCA-positive patients, seven had limited cutaneous SSc and anti-MPO antibodies and only one had anti-PR3 antibodies, associated with DcSSc. Two ANCA-positive patients had anti-U3RNP antibodies. The majority had glomerulonephritis, renal arteritis, and pulmonary fibrosis. This study also looked for the genetic association between the SSc and AAV. There were several shared HLA haplotypes from the DP and DQ loci in the overlap patients and also shared HLA haplotypes in patients who develop both scleroderma and AAV. All patients with neuropathy had other organ manifestations also. The French Vasculitis Study Group and members of the French Research Group on SSc published data in 2013 that included only cases with a diagnosis of systemic vasculitis proven by biopsy.[8] They described 12 cases of vasculitis out of 1120 cases. Of the 12, three had mixed cryoglobulinemic vasculitis (MCV) and nine had AAV. All had limited SSc. AAV always occurred after SSc diagnosis, with a mean delay of 7.1 years, but individually varied from simultaneous to 24 years. pANCA was present in six of seven patients, and anti-MPO antibodies in eight of nine patients. No cANCA or anti-PR3 antibodies were found. The prevalence of vasculitis in SSc patients referred to tertiary centers was less than 1%. They differentiated between two types of systemic vasculitis: MCV and AAV. SSc was mainly of the limited cutaneous type despite a high prevalence of anti-Scl-70 antibodies. Moxey et al. in 2019 reported a serologically positive ANCA (done by immunofluorescence) in 116 of 1303 patients with SSc (8.9%) in the Australian Scleroderma Cohort, of which 18 (13.8%) had PR3-ANCA and 13 (11.2%) had MPO-ANCA.[9] Only three ANCA-positive patients developed AAV (0.2% of the entire SSc cohort and 0.23% of the entire study cohort). Cases of ANCA-negative vasculitis were not included in the study. ANCA-positive patients were more likely to have had a pulmonary embolism (8.6% vs. 3.0%, P = 0.002) and malignancy (26.7% vs. 18.6%, P = 0.035). None of anti-PR3 positive patients developed vasculitis.

  Conclusion Top

The association between SSc and AAV has various facets. All ANCA positivity in SSc does not have clinically evident vasculitis. However, SSc-AAV overlap is more common in LcSSc, females, and associated with anti-Scl antibody. pANCA and anti-MPO are more frequently detected in this overlap. Clinical manifestation is more likely as MPA like or a renal limited vasculitis. The role of anti-PR3 is not clear. Neurologically involvement in SSc has to be evaluated for possible vasculitis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

  Acknowledgments Top

I would like to thank Dr. Nandeesh B N, Associate Professor, Department of Neuropathology, NIMHANS, for providing the microphotographs of the nerve biopsy.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Kao L, Weyand C. Vasculitis in systemic sclerosis. Int J Rheumatol 2010;2010:385938.  Back to cited text no. 1
Arad U, Balbir-Gurman A, Doenyas-Barak K, Amit-Vazina M, Caspi D, Elkayam O. Anti-neutrophil antibody associated vasculitis en systemic sclerosis. Seminars in Arthritis and Rheumatism. 2011;41:223–9.  Back to cited text no. 2
Tur BS, Süldür N, Ataman S, Tutkak H, Atay MB, Düzgün N. Anti-neutrophil cytoplasmic antibodies in patients with rheumatoid arthritis: Clinical, biological, and radiological correlations. Joint Bone Spine 2004;71:198-202.  Back to cited text no. 3
Arad U, Balbir-Gurman A, Doenyas-Barak K, Amit-Vazina M, Caspi D, Elkayam O. Anti-neutrophil antibody associated vasculitis in systemic sclerosis. Semin Arthritis Rheum 2011;41:223-9.  Back to cited text no. 4
Derrett-Smith EC, Nihtyanova SI, Harvey J, Salama AD, Denton CP. Revisiting ANCA-associated vasculitis in systemic sclerosis: clinical, serological and immunogenetic factors. Rheumatology (Oxford). 2013;52:1824-31. doi: 10.1093/rheumatology/ket213. Epub 2013 Jul 5. PMID: 23832959.  Back to cited text no. 5
Rho YH, Choi SJ, Lee YH, Ji JD, Song GG. Scleroderma associated with ANCA-associated vasculitis. Rheumatol Int 2006;26:369-75.  Back to cited text no. 6
Liang KP, Michet CJ. ANCA-associated vasculitis in scleroderma: A case series of fourteen patients. Rheumatol Rep 2011;3:2-e2.  Back to cited text no. 7
Quéméneur T, Mouthon L, Cacoub P, Meyer O, Michon-Pasturel U, Vanhille P, et al. Systemic vasculitis during the course of systemic sclerosis: Report of 12 cases and review of the literature. Medicine (Baltimore) 2013;92:1-9.  Back to cited text no. 8
Moxey J, Huq M, Proudman S, Sahhar J, Ngian GS, Walker J, et al. Significance of anti-neutrophil cytoplasmic antibodies in systemic sclerosis. Arthritis Res Ther 2019;21:57.  Back to cited text no. 9
Radwan Y, Berini S, Ernste F, Makol A. Proteinase 3 (PR3)-antineutrophil cytoplasmic antibody (ANCA)-associated vasculitic neuropathy in diffuse cutaneous systemic sclerosis: A rare duo. BMJ Case Rep 2019;12:e232987.  Back to cited text no. 10
Ruffatti A, Sinico RA, Radice A, Ossi E, Cozzi F, Tonello M, et al. Autoantibodies to proteinase 3 and myeloperoxidase in systemic sclerosis. J Rheumatol 2002;29:918-23.  Back to cited text no. 11


  [Figure 1], [Figure 2]

  [Table 1]


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