Secondary Sjögren’s Syndrome and Rheumatoid Arthritis

Secondary Sjà ¶gren’s Syndrome and Rheumatoid Arthritis Secondary Sjà ¶gren’s Syndrome and Rheumatoid Arthritis Activity – a case of severe dry eyes Authors: Dina Christina Janse van Rensburg, MD1, 2 Catharina Cornelia Grant, PhD1, 2 Audrey Jansen van Rensburg, MSc1,2 Pieter Roelof Cronjà ¨, FC Ophth, MBChB3 Thelani Catharina Grant, BSc Agric (Hons)1, 2 Abstract Patients with Sjà ¶gren’s syndrome present with a wide range of clinical manifestations that carries a high rate of morbidity and mortality with increased risk of lymphoma development. Sjà ¶gren’s syndrome is either a primary disorder, or secondary to other autoimmune disorders e.g. rheumatoid arthritis (RA). Due to the multiple aspects of the disease and the similarity of the symptoms to other diseases, diagnosis and management of Sjà ¶gren’s syndrome is challenging. Among the symptoms, Sjà ¶gren syndrome typically presents with dry eyes that may result in severe ocular surface disorders such as persistent epithelial defects, and conventional dry eye therapy is often unsuccessful in controlling ocular signs and symptoms. We highlight the rare case of a 50 year old woman whom despite well controlled RA disease activity still manifested with severe secondary Sjà ¶grens syndrome. It was only after autologous serum was applied as a last resort that her ocular s ymptoms improved. Keywords: Rheumatoid arthritis, dry eyes, Sjà ¶gren’s syndrome, autologous serum, inflammation Introduction Sjà ¶gren’s syndrome (SS) is a systemic autoimmune disease affecting the exocrine glands. A lymphocytic infiltration in the salivary and lacrymal glands results in reduced secretion, leading to continual dryness of the mouth and eyes.1-3 SS may manifest as a primary disease presenting as a single entity, or secondary in combination with other autoimmune disorders.4 The prevalence of secondary SS relates predominantly to RA5 and associates with increased disease acivity.6 It may present with a systemic component, including painful joints, dry and itchy sunlight sensitive skin, irritable bowel, liver problems and extreme tiredness. Because of the many possible clinical pictures of SS it is a challenging diagnosis to make and may therefore go undiagnosed for many years after the onset of symptoms.3,7-9 Dryness symptoms are amplified in patients with RA, it increases with age and are associated with the severity of illness, relating to worse outcomes measures of the disease. Appr oximately 25% RA patients presents with keratoconjunctivitis sicca as the most prevailing and frequent ocular complication.5,10 Several therapies have been identified that inhibit inflammatory mediators and mechanisms in dry eye disease, however the treatment of persistent epithelial defects and severe ocular dryness by means of topical tear replacement often proofs inadequate.11 In this case study we report a RA patient who regardless of well controlled treatment with a tumor necrosis factor (TNF) inhibitor, still developed severe secondary SS. Autologous serum drops offered significant improvement of her extreme ocular surface inflammation and symptoms, when all other treatment modalities failed. Case Report A 50 year old Caucasian woman was diagnosed with RA. During the course of the illness she was treated with methotrexate, folic acid, meloxicam, prednisone, sulfasalazine and leflunomide. Seven years post RA diagnosis and despite well controlled disease on adalimumab, methotrexate and folic acid, her eyes became extremely dry and highly sensitive to light. This dryness caused severe, constant discomfort and visual blurring, rendering her partially incapacitated, even though her corrected vision was still normal at 6/6. She had to wear sunglasses indoors and could not drive independently. On examination of her corneas the various findings confirmed the severity of her dry eyes. These included a tear breakup time of 5 seconds bilaterally, mucus filaments, punctuate corneal straining and an almost non-existing tear meniscus indicating very little tear secretion. Evidence of previous (healed) peripheral ulcerative keratitis could be seen on the medial aspect of both corneas. These symptoms lead to the diagnosis of Sjà ¶gren’s syndrome. She was treated with all possible modalities including punctum plugs and multitudes of topical medication including Cyclosporine A, with no apparent improvement. A decision was made to attempt an eye drop prepared from autologous serum. Her condition improved remarkably in the year since she started the serum. Discussion Sjà ¶gren’s syndrome was first described by the eye specialist Hendrik Sjà ¶gren in 1933. It presents with a variety of symptoms, including fatigue, arthralgia, myalgia, keratoconjunctivitis sicca(dry eyes, in part known as Sicca syndrome), xerostomia (dry mouth), skin lesions, lymphoproliferative disorders, neurologic involvement, leukocytoclastic vasculitis, rhinitis, pharyngitis and laryngitis.3,9,12 In view of the wide range of severe systemic manifestations of the disease patients are often characterised with higher morbidity and mortality, which are mainly related to an enhanced probability to develop lymphoma.3,13 Most patients with SS are middle-aged women, and symptoms mostly occur with the accompaniment of, but not exclusively to, RA.3,12 Recently literature differentiates between two main types of the disease: The glandular (exocrine gland-localised) form that affects mainly the quality of life of the patient, and the systemic syndrome type which display extraglandular manifestations that may lead to lymphoma.3 The glandular phenomenon includes ocular symptoms (dry eyes, xerophthalmia) and oral involvement (dry mouth, xerostomia, caries and candidiasis).3 Extraglandular manifestations consist of musculoskeletal indications, Raynaud’s phenomenon, renal, liver and neurological involvement, vasculitis and haematologic manifestations.3,13 Diagnosis Sjà ¶gren’s syndrome is difficult to diagnose due to the multiple aspects of the syndrome, and similarity to the symptoms caused by other diseases.3,7,8 SS is a slow progressing disorder, and on average may take approximately 5 years from the onset of symptoms before the correct diagnosis is reached.8 Sjà ¶gren’s syndrome is strongly suggested in patients who present with both signs and symptoms of oral and ocular dryness and who test positive to the diagnostic criteria. From clinical experience it was found that if a patient does not suffer from both dry eyes and dry mouth, it is necessary to exclude further causes of the dry eyes by means of differential diagnoses.13 A series of tests in the diagnosis of Sjà ¶gren’s syndrome are outlined in Table 1. These criteria consider dryness symptoms, changes in salivary and lacrimal gland function, and systemic findings.8 Table 1. Tests and criteria used to diagnose Sjà ¶gren’s Syndrome8 Treatment The aim of treatment for dry eyes is mainly to provide relief of symptoms and to prevent corneal epitheliopathy. Management of the disease currently includes artificial tears, topical secretagogues, local immunomodulatory drops, lachrymal duct occlusion and hypotonic hyaluronic acid drops in the treatment of dry eyes.3 Different methods of treatment that may be used independently or in combination with tear supplements include systemic immunoactive drugs and calcineurin inhibitors, topical corticosteroids and topical non-steroidal anti-inflammatory drugs.3 Patients with dry eyes normally respond well to these treatments that focus on optimising the ocular surface environment. Some patients, however, present with more serious ocular surface disorders, that do not react to conventional treatment, which may lead to severe visual impairment.14,15 Fujita et al.10 drew attention to the exceptionally high incidence of dry eyes in patients with RA. Their conclusions are that although RA patients with SS present with systemic effects on dry eyes, there seems to be other local factors independently of the systemic process, that disturbs the ocular surface and control the severity of dry eyes in RA patients.5,16 Due to the many local elements active in dry eyes it calls for improved new therapeutic agents for managing dry eyes without making use of systemic agents.5 The various factors that contribute to a healthy ocular surface include an adequate blink reflex, normal tear production and healthy adnexae.14 Typically tears contain epitheliotrophic factors including growth factors, vitamins and fibronectin that are of vital importance to the ocular epithelial health.15 These factors support the viability, proliferation and migration of ocular surface epithelial cells.15 They are not found in pharmaceutical tear substitutes, but do however occur in blood serum. Clinical cohort studies have reported the successful useof epitheliotrophic factors in autologous serum drops to improve severe cases of dry eyes where other conventional treatments fall short.14,15 Autologous serum drops was first described in 1984 as a substitute constituent free of potentially harmful substances17 applied as unpreserved artificial tears.15 It is believed that the epitheliotrophic factors in the serum are the rationale behind its success in the treatment of extremely dry eyes.15 The use of autologous serum eye drops may in many cases be a last resort of treatment for SS patients who have not responded well to conventional tear replacement therapy. Even though the preparation thereof is costly and complex, it proofs a clinically effective treatment in ocular surface diseases.3,11 Being non-allergenic with biochemical properties akin to normal tears,3,18 it benefits the conjunctival epithelium supplementing essential vitamins, fibronectin, anti-proteases and growth factors. This may stimulate its proliferation and repair,11 and play an important role in the integrity of the cornea and conjunctiva.3,11 Autologous serum appears to be more effective in resistant cases. It may also play an essential role adjunct to therapy in other ophthalmological conditions as seen in chemical injuries of the ocular surface. Conclusion Sjà ¶gren’s syndrome may cause marked disability in patients suffering from the disease, especially when secondary to RA. In this case study, despite optimal control with a TNF inhibitor the patient still presented with SS and suffered from severe xerophthalmia. All treatment modalities had failed and as a last alternative autologous eye serum was instituted. This significantly improved the severe dry eyes and persistent epithelial defects and enabled her to live a normal life. Consent Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review. References 1.Shiel W. What is rheumatoid arthritis?. 4/24/2014; Available at: http://www.medicinenet.com/rheumatoid_arthritis/article.htm. Accessed June 26, 2014. 2.Antero DC, Parra AGM, Miyazaki FH, Gehlen M, Skare TL. Secondary Sjà ¶grens syndrome and disease activity of rheumatoid arthritis. Rev.Assoc.Med.Bras. 2011 05/20;57(3):319-322. 3.Vitali C, Palombi G, Cataleta P. Treating Sjà ¶grens Syndrome: Insights for the Clinician. Ther Adv Musculoskelet Dis 2010 06;2(3):155-166. 4.Patel R, Shahane A. The epidemiology of Sjà ¶grens syndrome. Clin Epidemiol 2014 07/30;6:247-255. 5.Lemp MA. 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