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Year : 2022  |  Volume : 2  |  Issue : 4  |  Page : 899-901

Commentary: Scleritis in granulomatosis with polyangiitis: Is tuberculosis a masquerader?

1 Department of Uvea, Aravind Eye Care System, Pondicherry, India
2 Department of Uvea, Aravind Eye Care System, Madurai, Tamil Nadu, India

Date of Web Publication11-Oct-2022

Correspondence Address:
Dr. M S Balamurugan
Department of Uvea, Aravind Eye Care System, Pondicherry
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijo.IJO_2002_22

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How to cite this article:
Balamurugan M S, Somanath A. Commentary: Scleritis in granulomatosis with polyangiitis: Is tuberculosis a masquerader?. Indian J Ophthalmol Case Rep 2022;2:899-901

How to cite this URL:
Balamurugan M S, Somanath A. Commentary: Scleritis in granulomatosis with polyangiitis: Is tuberculosis a masquerader?. Indian J Ophthalmol Case Rep [serial online] 2022 [cited 2022 Nov 30];2:899-901. Available from: https://www.ijoreports.in/text.asp?2022/2/4/899/358161

Scleritis is a severe painful, inflammatory process of the sclera with a varied clinical spectrum. If not treated appropriately, it can be vision-threatening and lead to loss of vision. Scleritis can be the initial sign of a systemic autoimmune disease such as rheumatoid arthritis, granulomatosis with polyangiitis (GPA), relapsing polychondritis, or microscopic polyarteritis.[1] Its association with an underlying systemic disease has been reported in 40%–50% of patients.[1] Rheumatoid arthritis is the most common connective tissue disease associated with scleritis, with its association being 17%–33%.[2] However, granulomatosis with polyangiitis is the most frequent systemic vasculitis associated with scleritis. Inflammation of the adjacent cornea is an indication of an underlying systemic autoimmune disease.[3]

The European Alliance of Associations for Rheumatology (EULAR) along with the European Renal Association (ERA) and the European Vasculitis Society (EUVAS) published an update on antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis in 2016.[4],[5] These guidelines do not explain the treatment in case of ocular complications, but the Canadian Vasculitis research network (CanVasc) defines severe ANCA-associated vasculitis as any lesion that represents a major organ-threatening condition, including eye involvement.[6] Ocular disease may be the sole presenting sign in patients with granulomatosis with polyangiitis. Studies on the treatment of ocular inflammation due ANCA-associated vasculitis using these guidelines has shown successful results. Thus, the EULAR guidelines can be adopted for treating ocular inflammation due to granulomatosis with polyangiitis.

The ANCA test has a high sensitivity and specificity for granulomatosis with polyangiitis, especially for the systemic form of the disease. But the clinician should remember that 30% of granulomatosis polyangiitis cases have negative ANCA result until late in the course of the disease.[7] Hence, a good clinical evaluation or skill is important.

Two specific ANCA patterns have been recognized with indirect immunofluorescence of ethanol-fixed neutrophils: a cytoplasmic diffuse staining pattern (cytoplasmic antineutrophil cytoplasmic antibody [cANCA]) and the perinuclear staining pattern (perinuclear antineutrophil cytoplasmic antibodies [pANCA]). cANCA is seen when an antibody detects a neutrophil serine proteinase. pANCA is seen when antibodies detect lysosomal enzymes such as myeloperoxidase. However, these biomarkers have a limited role in monitoring the disease activity.[8]

There is an overlap in the clinical manifestation of patients with positive ANCA test and negative ANCA test. The positive predictive value (PPV) for a cANCA is estimated to be 63%. Hence using this diagnostic test alone, there is a possibility of misdiagnosing granulomatosis with polyangiitis in 37% of the patients with a positive cANCA.[8]

ANCA positivity has been reported in patients with tuberculosis. Mycobacterium tuberculosis stimulates the release of oxygen from the activated neutrophils. Activation of neutrophils occurs following interaction with phenol glycolipids of the cell wall of M. tuberculosis. This may lead to release of lysosomal enzymes from the neutrophils in the initial stages of mycobacterial infection, and autoantibodies against the granular components of these cells can develop.[9]

Another cause for the production of ANCA in patients with tuberculosis is the treatment received. Drugs such as isoniazid can be transformed by myeloperoxidase into active metabolites with the development of cytotoxicity. Cytotoxicity could generate neutrophil damage with subsequent synthesis of proteinase-3 and myeloperoxidase-ANCA, which explains the presence of anti-myeloperoxidase autoantibodies in some patients taking drugs like isoniazid.[10]

There are reports of scleritis being initially treated for tuberculosis [Table 1]. Due to the recurrent episodes of inflammation, the patient was evaluated. ANCA positive test required a referral to a rheumatologist and the patient required immunosuppressive drug and steroids.[11]
Table 1: ANCA positivity in patients with tuberculosis

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Immunosuppressive drugs such as methotrexate and mycophenolate mofetil are used in non-life-threatening granulomatosis with polyangiitis. They are used in conjunction with glucocorticoids. In life-threatening organ failure GPA, cyclophosphamide and rituximab are used along glucocorticosteroids. In a tuberculosis endemic region or individuals who are susceptible to acquiring tuberculosis, they will need detailed evaluation to rule out this infectious cause before proceeding with the treatment. Activation of granulomatous systemic disease, especially tuberculosis, is a major concern for use of biologicals in treatment of uveitis in a tuberculosis-endemic region such as India.

Assuming a positive ANCA report without further evaluation can be life-threatening. ANCA-associated scleritis requires aggressive immunosuppressive therapy. Hence extreme care has to be taken before initiating treatment and during review with biologicals, even in conditions like ANCA-positive scleritis.[13]

Granulomatosis with polyangiitis and tuberculosis have similar clinical, histopathological, and immunological features. The release of cytokines and chemokines plays a key role in both diseases and in the development of granulomas. When there are no extrapulmonary manifestations of the disease, it is less likely that an ANCA-positive result is indicative of primary systemic vasculitis, especially granulomatosis with polyangiitis. However, the diagnostic delay is a key issue in terms of prognosis, which mainly depends on kidney and lung involvement.

To conclude, an ANCA-positive result should be thoroughly investigated, with an early referral to a rheumatologist to prevent complication. In a tuberculosis-endemic country like India, this infectious cause for scleritis needs to be excluded before proceeding with aggressive immunomodulatory therapy.

  References Top

Raiji VR, Palestine AG, Parver DL. Scleritis and systemic disease association in a community-based referral practice. Am J Ophthalmol 2009;148:946-50.  Back to cited text no. 1
Okhravi N, Odufuwa B, McCluskey P, Lightman S. Scleritis. Surv Ophthalmol 2005;50:351-63.  Back to cited text no. 2
Sainz-de-la-Maza M, Foster CS, Jabbur NS, Baltatzis S. Ocular characteristics and disease associations in scleritis-associated peripheral keratopathy. Arch Ophthalmol 2002;120:15-9.  Back to cited text no. 3
Yates M, Watts RA, Bajema IM, Cid MC, Crestani B, Hauser T, et al. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis. 2016;75:1583-94  Back to cited text no. 4
Geetha D, Jefferson JA. ANCA-associated vasculitis: Core curriculum 2020. Am J Kidney Dis 2020;75:124-37.  Back to cited text no. 5
McGeoc L, Twilt M, Famorca L, Bakowsky V, Barra L, Benseler SM, et al. CanVasc recommendations for the management of antineutrophil cytoplasm antibody-associated vasculitides. J Rheumatol 2016;43:97-120.  Back to cited text no. 6
Foster CS. Ocular manifestations of the potentially lethal rheumatologic and vasculitic disorders. J Fr Ophtalmol 2013;36:526-32.  Back to cited text no. 7
Rao JK, Weinberger M, Oddone EZ, Allen NB, Landsman P, Feussner JR, et al. The role of antineutrophil cytoplasmicnantibody (c-ANCA) testing in the diagnosis of Wegener granulomatosis. A literature review and meta-analysis. Ann Intern Med 1995;123:925-32.  Back to cited text no. 8
Faldt J, Dahlgren C, Karlsson A, Ahmed AM, Minnikin DE, Ridell M. Activation of human neutrophils by mycobacterial phenolic glycolipids. Clin Exp Immunol 1999;118:253-60.  Back to cited text no. 9
Jiang X, Khursigara G, Rubin RL. Transformation of lupus-inducing drugs to cytotoxic products by activated neutrophils. Science 1994;266:810-3  Back to cited text no. 10
Anterior Nodular Scleritis –Tuberculosis or GPA? A series of 3 cases. (Manuscript number: IJO-751-22R1).  Back to cited text no. 11
Flores-Suárez LF, Cabiedes J, Villa AR, van der Woude FJ, Alcocer-Varela J. Prevalence of antineutrophil cytoplasmic autoantibodies in patients with tuberculosis. Rheumatology (Oxford) 2003;42:223-9.  Back to cited text no. 12
Dutta Majumder P, Sudharshan S, George AE, Ganesh SK, Biswas J. Antineutrophil cytoplasmic antibody-positive scleritis: Clinical profile of patients from a tuberculosis-endemic region. Indian J Ophthalmol 2018;66:1587-91.  Back to cited text no. 13


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