Atypical ANCA Associated Vasculitis with Rheumatoid Arthritis Overlap and Literature Review Andrew Jensen, DO, Ali Zaidi, DO, Stanley Skopit, DO, MSE, FAOCD, FAAD Larkin Community Hospital, Department of Dermatology

BACKGROUND ANTI-NEUTROPHIL CYTOPLASMIC ANTIBIOTICS (ANCA) OTHER ANCA ASSOCIATIONS

Our understanding of the vast world of vasculitis has dramatically improved over the past several Antineutrophil cytoplasmic antibodies or ANCA, describe a well-known immunologic constituent often targeted toward intracellular or ANCA levels may be elevated in many inflammatory conditions including inflammatory bowel disease, decades. However, despite the tremendous progress, anti-neutrophil cytoplasmic autoantibody other molecules that can have detrimental pathophysiological outcomes. C-ANCA or cytoplasmic antineutrophil cytoplasmic antibodies systemic lupus erythematosus, Sjogren’s syndrome, rheumatoid arthritis, reactive arthritis, (ANCA)-associated vasculitides (AAV) is one group of unique immune-mediated vascular diseases typically involves autoantibodies targeting antigens within the cytoplasm of neutrophils with proteinase 3 (PR3) being the suspected antiphospholipid syndrome, polymyositis, anti-glomerular basement membrane disease, autoimmune where diagnostic strategies can pose a challenge. As true for most autoimmune disease states, target. P-ANCA or perinuclear anti neutrophil cytoplasmic antibodies consist of autoantibodies targeting the protein myeloperoxidase hepatitis, primary sclerosing cholangitis, and various infections.15-19 Positive ANCA levels have also general serologic and clinical findings do not always adhere to predictable and reproducible (MPO) also within neutrophils. Detection of ANCA involves indirect immunofluorescence (IIF) of autoantibodies towards these specific been seen in patients that either have rheumatoid factor positive serology, or an actual rheumatoid outcomes, making it difficult for specialists to diagnose and subsequently manage. We present a antigens. Diffuse cytoplasmic staining or perinuclear staining correlate with C-ANCA and P-ANCA respectively. An alternative method for arthritis (RA) diagnosis.20 Typically, ANCA positivity displays years after the diagnosis of RA. Douglas case report of an atypical presentation of cutaneous vasculitis with abnormal ANCA and other screening ANCA is through the use of enzyme-linked immunosorbent assay (ELISA) to detect the specific antibodies targeting either the et al20 studied a subset of patients with positive C-ANCA a diagnosis of RA. They reported two out of serologies, and discuss other diagnostic strategies to consider when presented with atypical ANCA antigen MPO or PR3. Current guidelines recommend completing both the IIF and the ELISA for screening ANCA.9 six patients studied with positive C-ANCA and antibodies to PR3, also had positive rheumatoid factor associated vasculitis. serology. All six patients had rheumatoid arthritis and five of six patients had granulomatous vasculitis There is significant variation in the reported sensitivities and specificities in both detection methods seen in the literature. Classification of seen on biopsy being most consistent with GPA. In each patient, the manifestations of RA were seen the ANCA pattern on IIF is based on objective visual inspection, and depends partly on the examiner's skill, experience and previous prior to GPA with a length of time between the diagnosis of RA and GPA ranging from 8 months to 19 training. There are also no standardized reference ranges and cut off markers for positive and negative titers that vary among different years (mean of 7.9 +- 9.1 years). One retrospective study included six patients who were diagnosed laboratories. The ELISA testing suffers from similar pitfalls as there are also varying cutoff markers and different types of ELISA testing with RA and later developed AAV.2 One patient developed GPA and the other five developed MPA. Half methods which may prove inconsistent when comparing one laboratory to the next. It is, therefore, not surprising to read of significant of the patients had seropositive RA and only half had ANCA positivity, all being MPO-ANCA. The PATIENT PRESENTATION variation of the reported sensitivities and specificities of both testing methods in the literature. median time between the diagnosis of RA and AAV was 10.5 years (range 4-43 years).

In a large cross-sectional study of 856 patients, it was demonstrated that the IIF had greater sensitivity than the ELISA.11 However, the Furthermore, Draibe et al. analyzed a total of 29 case reports with association of RA and AAV. Nineteen A 76 year-old female presented to our dermatology office complaining of a rash on her lower ELISA had greater specificity and almost double the positive predictive value for AAV. The sensitivity of ANCA based on IF was 67% and of the patients had renal impairment, four of which had GPA and 15 with MPA.2 Seven of the subjects extremities for several months. She stated the rash was mildly itchy with persistent color changes of the specificity was 93% for AAV, while the sensitivity of ANCA based on ELISA was only 55%, but the specificity was 99%. The were either C-ANCA or PR3-ANCA positive, 11 were P-ANCA or MPO-ANCA positive, seven were red to brown. Her past medical history consisted of atrial fibrillation for which she was taking warfarin combination of a positive IIF and ELISA lead to a much greater likelihood ratio than either test alone which illustrates the importance of ANCA negative, 26 were RF positive, and 10 had a positive ANA. Consensus on the exact etiology of and atenolol. Review of systems was positive for small joint pain and stiffness in the hands and using the combination of the two tests together for diagnostic purposes. the association of RA and AAV has not currently been defined. PTPN22 has been suggested to play a wrists which the patient states were chronic. On physical exam she displayed generalized non- role in the development of RA and certain AAV.21-23 It also worth mentioning again that numerous blanching red to brown palpable purpura on bilateral lower extremities. The patient also showed mild medications have been linked to the development of ANCA associated vasculitis such TNF antagonists ulnar deviation of digits on both hands. FIGURE 1 and penicillamine. Five cases reported by Draibe et al. were reported to be on at least one of these medications and before developing the positive ANCA.2 Two 4mm punch biopsies were collected on the lower legs and the patient was given topical steroids Chart 2: Correlation Between Psoriasis and Comorbidities for symptomatic relief. Laboratory studies were collected (Figure 1). Biopsy results showed an unremarkable epidermis with underlying dermal mononuclear inflammatory infiltrate around the superficial vascular plexus. After pathological and serological review, the patient was diagnosed with an atypical ANCA-associated vasculitis with rheumatoid arthritis overlap. She was started on prednisone 40mg daily with vitamin D and calcium supplementation. She was also given colchicine 0.6mg twice daily and referred to rheumatology. BIBLIOGRAPHY

1. Jennette JC, Falk RJ, Bacon PA, et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis & Rheumatism. 2012;65(1):1-11. ANCA-ASSOCIATED VASCULITIS (AAV) 2. Draibe J, Salama AD. Association of ANCA associated vasculitis and rheumatoid arthritis: a lesser recognized overlap syndrome. SpringerPlus. 2015;4(1). 3. D'cruz D, Chesser A, Lightowler C, et al. Antineutrophil Cytoplasmic Antibody-Positive Crescentic Glomerulonephritis Associated With Anti-Thyroid Drug Treatment. Rheumatology. 1995;34(11):1090-1091. 4. Gaffey CM, Chun B, Harvey JC, Manz HJ. Phenytoin-induced systemic granulomatous vasculitis. Arch Pathol Lab Med. 1986;110(2):131–135 (Feb) FIGURE 2 5. Ashok D, Dubey S, Tomlinson I. C-ANCA positive systemic vasculitis in a patient with rheumatoid arthritis treated with infliximab. Clinical Rheumatology. Vasculitis is a common condition involving inflammation of vessel walls which can lead to a 2007;27(2):261-264. 6. Noh JY, Asari T, Hamada N, et al. Frequency of appearance of MPO-ANCA in Graves’ disease patients treated with propylthiouracil and the relationship between MPO- disruption of blood supply via either ischemic or hemorrhagic pathways. Any blood vessel may be ANCA and clinical manifestations. Clin Endocrinol 2001; 54:651–654. affected including arteries, arterioles, veins, venules, and capillaries (see figure 2). Vasculitis can 7. Jarrett SJ, Cunnane G, Conaghan PG, Bingham SJ, Buch MH, Quinn MA, Emery P. Anti-tumour necrosis factor-α therapy induced vasculitis. J Rheumatol. 2003;30:102287–102292 generally be classified as either primary, in which the cause of the vascular inflammation is 8. Eriksson C, Engstrand S, Sundqvist K-G, Rantapaa-Dahlqvist S. Autoantibody formation in patients with rheumatoid arthritis treated with anti-TNFα. Ann Rheum Dis. idiopathic, or secondary in which the inflammation can be incited by other inflammatory autoimmune 2005; 64:403–407 9. Savige J, Gilles D, Benson E, et al. International consensus statement on testing and reporting of antineutrophil cytoplasmic antibodies (ANCA). Am J Clin Path 1999; conditions, medications, infections or malignancies. The International Chapel Hill Consensus 111:507–513. Conference (CHCC) has established a nomenclature for noninfectious vasculitides.1 One broad 10. Schulte-Pelkum J, Radice A, Norman GL, et al. Novel Clinical and Diagnostic Aspects of Antineutrophil Cytoplasmic Antibodies. Journal of Immunology Research. 2014;2014:1-12. category of small vessel vasculitis includes ANCA-associated vasculitides. These include: 11. Stone JH, Talor M, Stebbing J, et al. Test characteristics of immunofluorescence and ELISA tests in 856 consecutive patients with possible ANCA-associated granulomatosis with polyangiitis (GPA) formerly known as Wegener’s vasculitis, eosinophilic conditions. Arthritis & Rheumatism. 2000;13(6):424-434. 12. Talor MV, Stone JH, Stebbing J, Barin J, Rose NR, Burek CL. Antibodies to selected minor target antigens in patients with anti-neutrophil cytoplasmic antibodies granulomatosis with polyangiitis (EGPA) formerly known as Churg-Strauss syndrome, and (ANCA). Clinical & Experimental Immunology. 2007;150(1):42-48. microscopic polyangiitis (MPA). Currently there is no classification of other non-specific ANCA 13. Locht H, Skogh T, Wiik A. Characterisation of autoantibodies to neutrophil granule constituents among patients with reactive arthritis, rheumatoid arthritis, and ulcerative colitis. Annals of the Rheumatic Diseases. 2000;59(11):898-903. associated vasculitis which is sometimes referred to as atypical ANCA-associated vasculitis. 14. Pendergraft WF 3rd, Niles JL. Trojan horses: drug culprits associated with antineutrophil cytoplasmic autoantibody (ANCA) vasculitis. Curr Opin Rheumatol. 2014; 26:42–49. Muge Kalayci, Yeditepe University, 2016 15. Afeltra A, Sebastiani GD, Galeazzi M et al., D. Caccavo, G. M. Ferri, R. Marcolongo, and L. Bonomo. Antineutrophil cytoplasmic antibodies in synovial fluid and in Certain medications have also been known to elevate ANCA levels and have been suggested to serum of patients with rheumatoid arthritis and other types of synovitis. J. Rheumatol. 1996; 23:10–15. 2. play a role in the development of AAV. Common agents include allopurinol, methimazole, 16. Bansi DS, Chapman RW, Fleming KA. Prevalence and diagnostic role of antineutrophil cytoplasmic antibodies in inflammatory bowel disease. Eur. J. Gastroenterol. Hepatol. 1996;8:881–885 propylthiouracil, TNF inhibitors, carbimazole, phenytoin, hydralazine, minocycline, and 17. Galeazzi M, Morozzi G, Sebastiani GD et al. Anti-neutrophil cytoplasmic antibodies in 566 European patients with systemic lupus erythematosus: prevalence, clinical penicillamine.2-5 Specifically, ANCA-MPO has been seen after the use of propylthiouracil in patients MINOR ANTIGENS ASSOCIATED WITH ANCA POSITIVITY associations and correlation with other autoantibodies. European Concerted Action on the Immunogenetics of SLE. Clin. Exp. Rheumatol. 1998;16:541–546. 18. Hauschild S, Schmitt WH, Csernok E, Flesch BK, Rautmann A, Gross WL. ANCA in Systemic Vasculitides, Collagen Vascular Diseases, Rheumatic Disorders and 6 5 with developing vasculitis. A case report by Ashok et al. involved a 31 year old male with Inflammatory Bowel Diseases. Advances in Experimental Medicine and Biology ANCA-Associated Vasculitides. 1993:245-251. rheumatoid arthritis who later developed a crescentic glomerulonephritis and a hemorrhagic-purpuric 19. Mulder AHL, Horst G, Haagsma EB, Limburg PC, Kleibeuker JH, Kallenberg CGM. Prevalence and characterization of neutrophil cytoplasmic antibodies in autoimmune liver diseases. Hepatology. 1993;17(3):411-417. papulovesicular rash despite being on a treatment regimen consisting of infliximab, cyclosporine, What about diagnostic results indicating ANCA positivity but fails to detect antibodies against MPO and PR3? In cases of a positive 20. Douglas G, Bird K, PF, RS, MB. Wegener’s Granulomatosis in Patients with Rheumatoid Arthritis. The Journal of Rheumatology. 30(9):2064-2069. and methotrexate. This patient was found to be C-ANCA positive with PR3 antibodies. Four years ANCA on IIF, but negative PR3 or MPO ANCA serology, one must consider the possibility of autoantibodies to a minor antigen. Atypical 21. Farago B, Talian GC, Komlosi K, et al. Protein tyrosine phosphatase gene C1858T allele confers risk for rheumatoid arthritis in Hungarian subjects. Rheumatology International 2008;29(7):793-796. later he was diagnosed with RA. It has been reported in the literature that infliximab has been ANCA on IIF is described as being a different pattern from either c-ANCA or p-ANCA and is seen when the autoantibodies are targeting 22. Jagiello P, Aries P, Arning L, et al. ThePTPN22 620W allele is a risk factor for Wegener's granulomatosis. Arthritis & Rheumatism. 2005;52(12):4039-4043. thought to induce antinuclear antibodies, anticardiolipin antibodies, P-ANCA, and anti-double minor antigens, or antigens other than PR3 or MPO. These minor antigens are thought to play a larger role in atypical AAVs. Published 23. Johansson M, Arlestig L, Hallmans G, Rantapaa-Dahlqvist S. PTPN22 polymorphism and anti-cyclic citrullinated peptide antibodies in combination strongly predicts future onset of Rheumatoid arthritis and has a specificity of 100% for the disease. Arthritis Res Ther. 2006;8(1):R19. stranded DNA antibodies.5,7,8 data on consistent minor antigens include bactericidal permeability increasing protein (BPI), human neutrophil elastase (HNE), cathepsin G, lactoferrin, and lysozyme.12,13 HNE-ANCA is frequently seen in persons who consumed levamisole contaminated cocaine.14