Significance of Anti-Neutrophil Cytoplasmic Antibodies in Systemic Sclerosis

Jayne Moxey; Molla Huq; Susanna Proudman; Joanne Sahhar; Gene-Siew Ngian; Jenny Walker; Gemma Strickland; Michelle Wilson; Laura Ross; Gabor Major; Janet Roddy; Wendy Stevens; Mandana Nikpour


Arthritis Res Ther. 2019;21(57) 

In This Article


Systemic sclerosis (SSc) is a multisystem autoimmune disease characterised by a triad of progressive skin and internal organ fibrosis, autoantibody production and small vessel vasculopathy.[1,2] Clinically, SSc patients are classified as having limited (lcSSc) or diffuse (dcSSc) SSc, defined by the extent of skin thickening.[3]

Abnormal autoantibody production is a characteristic feature of SSc, and the presence of specific autoantibodies is of prognostic and clinical significance. Anti-centromere antibodies are classically associated with lcSSc and pulmonary arterial hypertension (PAH), while anti-Scl-70 antibodies are more frequently observed in dcSSc and interstitial lung disease (ILD).[4]

Anti-neutrophil cytoplasmic antibodies (ANCA) are autoantibodies directed against enzymes found within primary granules of neutrophils and lysosomes in monocytes and are implicated directly in the pathogenesis of the small vessel vasculitis.[5,6] There are three different types of ANCA, which display distinct patterns under indirect immunofluorescence (IIF). These are the cytoplasmic pattern (c-ANCA), perinuclear pattern (p-ANCA) and "atypical" ANCA.[5] c-ANCA directed against proteinase-3 (PR3) is associated with granulomatosis with polyangiitis (GPA), while p-ANCA is typically directed against myeloperoxidase (MPO) and is commonly detected in microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA) and pauci-immune idiopathic crescentic glomerulonephritis.[7] In addition, p-ANCA can be directed against antigens other than MPO and is observed in a variety of autoimmune disorders including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), polymyositis (PM) and dermatomyositis (DM).[8] Alternative target antigens for p-ANCA include elastase, lactoferrin, bactericidal/permeability-increasing protein (BPI) and cathepsin G, and the pathophysiological significance, and specific disease associations of these minor target antigens are unclear.[8,9]

The presence of ANCA in the sera of patients with SSc is relatively uncommon, with previous studies estimating a prevalence between 0 and 12%.[7,10,11] Despite up to 12% of SSc patients having a positive ANCA titre, only a minority of these patients will develop an overlap syndrome with AAV. A 2013 review found a total of only 51 cases of AAV in SSc published in the literature.[10] A study of 2200 SSc patients found only 8 patients (0.4%) with comorbid AAV and SSc.[12] The majority of published cases of AAV and SSc overlap describe MPA or renal-limited vasculitis.[10] Anti-MPO and p-ANCA are most commonly found, and c-ANCA positivity and GPA are rarely reported.[13]

The underlying features of SSc that are associated with ANCA and AAV are contentious. AAV has been described in both lcSSc and dcSSc, with conflicting reports as to which SSc disease subtype has a higher prevalence of AAV.[13,14] Anti-Scl-70 antibodies have been frequently associated with the development of AAV, with reports of up to 77% of SSc patients with AAV having anti-Scl-70 antibodies.[10,13,15] SSc patients who have overlap syndromes with other connective tissue diseases may have an increased prevalence of AAV. Case series have suggested up to 50% of SSc patients with AAV also have clinical features of other connective tissue diseases such as SLE.[14]

Another consideration is the possibility of drug-induced ANCA or AAV in SSc. Although no longer part of the therapeutic armamentarium in SSc, D-penicillamine has been associated with the development of ANCA-associated glomerulonephritis (AAGN) and some cases of AAGN in SSc may be reflective of prior D-penicillamine therapy.[10,16–19] However, it is difficult to ascertain whether D-penicillamine therapy or SSc itself is the underlying cause of ANCA production, particularly in cases where AAGN occurs several years after cessation of therapy.[15,19]

The clinical significance of ANCA in SSc patients who do not manifest AAV is controversial. An association between ANCA in SSc and ILD has been suggested.[12,20–22] However, this has not been consistently reported in all case series.[15] It has also been suggested that ANCA in SSc patients may indicate an inflammatory component to the illness and that ANCA should be treated as a "red flag", prompting a thorough investigation and follow-up.[23] In the present study, we examined the clinical significance of ANCA in a large, well-characterised SSc cohort, including the association between ANCA and SSc clinical characteristics, autoantibodies, treatments and mortality.