Peripheral ulcerative keratitis (PUK) is type of crescent-shaped inflammatory damage that occurs in the limbal region of the cornea. PUK is always combined with an epithelial defect and the destruction of the peripheral corneal stroma. PUK may have a connection to systemic conditions, such as long-standing rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Wegener granulomatosis (WG), relapsing polychondritis, classic polyarteritis nodosa and its variants, microscopic polyangiitis, and Churg-Strauss syndrome. However, the most common connection is with RA, which is also the focus of this review. The pathogenesis of PUK is still unclear. It is thought that circulating immune complexes and cytokines exert an important influence on the progression of this syndrome. Treatment is applied to inhibit certain aspects of PUK pathogenesis.
Autoimmune diseases (AIDs) are systemic inflammatory diseases that generally involve most of the organs in the body, such as the synovium of the diarthrodial joints. Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are the most common AIDs. The aetiology of AIDs is a topic of research, and AIDs lead to many complications. The eye, especially the ocular surface, is frequently invaded by AIDs. In some cases, it may be the first sign of the disease [
The epidemiology of PUK associated with autoimmune disease is difficult to investigate preciously, because some autoimmune diseases are common while others are not. According to an investigation, PUK was the second most common ocular complication of autoimmune diseases compared with anterior uveitis, which ranks first place. In a previous study, among the three most frequent underlying diseases, rheumatoid arthritis occupied 34–42% of samples with PUK. SLE and GPA are on its heels [
RA is a chronic inflammatory and autoimmune disease. The disorder can lead to lacrimal gland destruction and ocular surface inflammation [
Under normal conditions, the immune system has no response to autologous antigens. The general hypothesis predicts that synoviocytes transform into autoantigens due to a combination of genetic and environmental risk factors. Recently, it has been demonstrated that epigenetic changes are associated with autoimmune diseases. Autoantigens lead to the activation of antigen-specific T and B cells, which eventually contribute to damage in the joints and on the ocular surface [
Antigen presentation to CD4+ T cells is restricted by major histocompatibility complex (MHC) class II [
T cells occupy an important position in autoimmune diseases. Based on the type of T cell receptor (TCR), T cells can be sorted into gamma delta or alpha beta groups. The latter are further classified into CD4+ T cells and CD8+ T cells via the coreceptor molecules CD4 and CD8 expressed on their surface. Unlike CD4+ T cells or T helper (Th) cells, CD8+ T cells are known to destroy/kill cells that have been infected with foreign invading microorganisms. Both CD4+ and CD8+ T cells are important [
The production of Th17 cells is stimulated by a combination of many cell-derived cytokines, such as transforming growth factor-
The adaptive immune system is characterized by memory, which is not entirely understood [
The exact immunopathogenesis of RA is not completely elucidated. However, we have learned from previous experiments that B cell functions, such as the deletion of memory B cells, the interruption of immune activation, the antigen presentation, and the production of inflammatory cytokines, contribute to the progression of pathology [
In addition to producing autoantibodies, B cells can also secrete cytokines in the synovial environment [
Furthermore, B cells include a broad spectrum of APCs. Antigens can be processed into antigenic peptides. These antigenic peptides are then presented by B cells via MHC class II molecules. Eventually, T cells will be activated and secrete cytokines associated with RA. Therefore, B cells exert influence on the function of T cells in patients with RA [
The abnormal expression of HLA class II antigens on corneal epithelial cells and keratocytes in the area of the ulcer and vasculitis of the adjacent conjunctiva is responsible for the pathology of PUK [
The corneal extracellular stroma is composed of highly organized lamellae of collagen fibrils embedded in a framework of glycosaminoglycans. There are flattened fibroblasts (keratocytes), macrophages, lymphocytes, and polymorphonuclear leucocytes between adjacent lamellae [
It has been demonstrated that an imbalance between MMPs and their tissue inhibitors (TIMPs) contributes to disease progression [
Research suggests that both humoral and cellular immunity are associated with the pathogenesis of autoimmune systemic diseases [
Addition to MMPs, a number of apoptotic and proteolytic stromata do a lot in promoting corneal melt. There is a statement that the interaction of epithelial and stromal cells also contributes to destroying cornea structure. Moreover, a drug named nonsteroidal anti-inflammatory drugs (NSAIDs) was proved to cause corneal destruction when they are taken orally [
In some cases, topical steroids, antibiotics, and even surgical therapy with conjunctival resection of the inflamed area, as well as amniotic membrane grafting, may be successful local treatments for unilateral PUK and systemic-associated disease [
The topical usage of corticosteroids can directly target a corneal lesion at the time of application and decrease systemic side effects. After steroid treatment, the defect significantly declines, but epithelial healing is delayed [
As an immunosuppressive drug, cyclosporine (cyclosporine A) is the most commonly used agent. Cyclosporine A targets antigen-triggered signal transduction in T lymphocytes and inhibits the expression of many lymphokines (IL-2) and antiapoptotic proteins [
Collagenase inhibitors or collagenase synthetase inhibitors function to stop collagenase from destroying the structure of the corneal stroma. Topical l% medroxyprogesterone and topical 20% acetylcysteine have been used in the clinic for several years. Topical corticosteroids should be considered carefully before they are used for patients with PUK related to systemic autoimmune diseases. Although these drugs have immunosuppressive effects, they inhibit new collagen production and thereby increase the risk of perforation [
When corneal perforation occurs, procedures that employ cyanoacrylate glue, conjunctival resection of the inflamed area, conjunctival flap, lamellar patch flap, or penetrating keratoplasty may be necessary [
IL-17 stimulates PUK associated with RA. Therefore, we need to consider a treatment to suppress this cytokine. Secukinumab and ixekizumab are two humanized monoclonal antibodies that directly block IL-17. Ixekizumab (LY2439821) is a humanized hinge-modified IgG4 IL-17-specific antibody. This drug is in a phase III trial for psoriasis and PsA. Secukinumab (AIN457) is a fully human IL-17-specific IgG1k monoclonal antibody generated by Novartis. This molecule is in phase III trials for chronic plaque psoriasis, PsA, RA, and AS and in phase II trials for chronic noninfectious uveitis. However, the clinical efficacy is not as ideal as expected [
SLE is a chronic and systemic autoimmune disease that affects multiple organ systems, including the joints (arthritis), skin (facial rash, discoid lupus, alopecia, photosensitivity, and Raynaud’s phenomenon), kidney (proteinuria), lung (pleuritis), blood (anaemia, leukopenia, and thrombocytopenia), nervous system (psychosis and convulsion), cardiovascular system (pericarditis), and eyes [
Tissue injury not only occurs in the location where immune complexes are deposited but also is present at other sites that have been invaded by immune complexes. This may occur because the intravascular activation of complement causes the secretion of C3a and C5a into the circulation, the activation of inflammatory cells, and endothelial damage at regions away from the initial site of immune complex deposition [
As with RA, the management of SLE also requires drugs and surgical therapy, as mentioned above. The distinction between them may be the frequency and dose. In addition, there are some treatments that are not used for SLE.
IL-2 is responsible for a large proportion of the effect of autoimmune diseases. It acts as a growth, survival, and differentiation factor for activated T cells, as well as a propellant of the differentiation of effector cytolytic T cells and activation-induced cell death (AICD). Therefore, the inhibition of IL-2 is a significant method for SLE treatment and is also under investigation [
Biologic agents are used extensively in the treatment of SLE. However, only rituximab and belimumab have been used in clinical practice, and both of them are B cell targeted. There is not much difference between the use of rituximab in RA and SLE. The second mAb, belimumab, has been shown to be appropriate for use in lupus. Belimumab has been demonstrated to target BAFF [
In addition to B cell-targeted agents and TNF-
In addition to RA and SLE, WG is a life-threatening systemic granulomatous vasculitis associated with PUK, the aetiology of which is also not clear. Small arteries and veins, the upper and lower respiratory tracts, and the kidneys are often involved. Unlike classic WG, an autoimmune disorder, “limited” WG is a form of the disease that only involves one or two organs, such as the respiratory tract. Various ocular manifestations of WG may indicate the presen`tation of this disease [
WG, along with microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CSS), is associated with antineutrophil cytoplasm antibody- (ANCA-) associated small vessel vasculature (AAV) [
Patients who suffer from WG combined with PUK are not sensitive to local corticosteroid therapy unless a subsequent systemic immunosuppressive therapy is used [
Traditional therapy may fail to heal intractable WG. According to a study by Lu et at., the combination of conjunctivectomy with cryotherapy is effective. The main theory is that necrotic tissue, immune complexes, inflammatory cells, and protein lysozymes are affected [
Both oral and intravenous cyclophosphamide, in combination with corticosteroids, are good choices for patients with this disease. Cyclophosphamide 2 mg/kg per day and prednisone 1 mg/kg per day have been shown to be appropriate for the treatment of PUK with WG by Watkins et al. [
The therapy of PUK associated with autoimmune diseases.
Therapy | Classification | Agent | Target |
---|---|---|---|
Topical therapy | Corticosteroid | Prednisolone | Immune system [ |
Immunosuppressant | Cyclosporine A | Antigen-triggered signal transduction in T lymphocytes and expression of many lymphokines (IL-2) and antiapoptotic proteins [ | |
Collagenase inhibitors | l% medroxyprogesterone | Collagenase [ | |
20% acetylcysteine | |||
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Surgical therapy | Cyanoacrylate glue, conjunctival flap, lamellar patch flap, or penetrating keratoplasty [ | ||
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Systemic therapy | Corticosteroid | Prednisolone | Immune system [ |
Immunosuppressant | MTX | Immune system [ | |
CTX | |||
Cyclosporine | |||
Azathioprine | |||
Biologic therapy | Etanercept | TNF- | |
Infliximab | |||
Adalimumab | |||
Golimumab | |||
DMARDs | |||
Rituximab | B cell [ | ||
Etanercept | |||
Adalimumab | |||
Abatacept | T cell [ | ||
Anakinra | IL-1 [84] | ||
Tocilizumab | IL-6 [84] | ||
Ixekizumab | IL-17 [94–97] | ||
Secukinumab | |||
Brodalumab | |||
Ustekinumab | IL-12/IL-23 [80, 98–100] | ||
Guselkumab | IL-23 [80, 98–100] | ||
Belimumab (mentioned in SLE) | BAFF [ | ||
INF (interferon alpha and gamma), TLRs, pDCs, and JAK/STAT inhibitors (mentioned in SLE) | INF (interferon alpha and gamma), TLRs, pDCs, and JAK/STAT |
Most of the therapies are similar. However, there are some different places among these diseases.
Patients suffering from peripheral keratitis and ulceration must have a detailed personal and family history about autoimmune systemic diseases. Therefore, collecting medical history is an important part of differential diagnosis [
The specific pathogenesis of PUK associated with autoimmune diseases still remains a mystery. RA, SLE, and AAV are topical disorders of autoimmune diseases and have close correlations with ocular manifestations. The existing data indicate that both humoral immunity and cell-mediated immunity are involved in these ocular effects, which are commonplace among these disorders. However, RA emphasizes the function of CD4+ T cells, while SLE and AAV involve autoantibodies. Proteinases eventually lead to corneal melt. The ocular complications may threaten vision and require timely diagnosis and treatment. Recently, some research has suggested that IL-17 and other drug targets affect people’s vision. Traditional therapy, steroids, and immunosuppressive therapies are no longer the issues that scientists focus on. Biological therapy, including the inhibition of B cells (rituximab), T cells (abatacept), IL-1 (anakinra), IL-6 (tocilizumab), and TNF-
The funding sponsors had no role in the writing of this review.
The authors declare no conflicts of interest.
Yan Cao searched and reviewed the literature, drafted the manuscript, and made the revisions; Wensong Zhang discussed and revised the manuscript; Jie Wu provided critical comments; and Hongyan Zhou designed and formulated the review theme and finalized the manuscript.
This study was supported by the Science and Technology Department of the Jilin Province Research Fund (20160101011JC) and the Development and Reform Commission of Jilin Province (2016C044-1).