Current Rheumatology Reviews - Volume 7, Issue 1, 2011

Welcome to 2011 from the editorial staff of Current Rheumatology Reports! As Henry David Thoreau eloquently stated, “Could a greater miracle take place than for us to look through each other's eyes for an instant?” While the eyes are a fascinating window into the systemic manifestations of rheumatic diseases, a surprising lack of awareness of the ocular manifestations of rheumatic diseases exists. In this issue of the journal, we attempt to correct this discrepancy by presenting several expertly written articles on the topic. I am sure that the readership will find great practical value in these wonderful articles and I invite you to provide any comments or vignettes that come to mind. In the second part of this issue, we present thought provoking articles about issues that come up in the treatment of rheumatoid arthritis with biologic agents. The issue of whether biologic agents increase the risks for cancer and infection has been debated since the advent of the biologic era. While no consensus has been achieved on these topics, Drs. Bongartz and Finckh provide us with an uptodate review of the literature. Dr. De Keyser tackles the question of failure of a TNF blocker and provides expert guidance in this often encountered clinical scenario. We look forward to your continued readership.

The eye can be involved in many different rheumatological and vasculitic disorders. Most rheumatological diseases have ocular complications, many of which are specific to the particular disease and the occurrence of which may help in diagnosis. Indeed, ocular involvement may be the presenting feature of systemic disease, or the involvement of the eye may help to bring together a variety of symptoms and signs and thus make the diagnosis. It is therefore of prime importance that both physicians and ophthalmologists are aware of the ocular symptoms and signs involved in this group of disorders. The first aim of this series of articles is to assist physicians in understanding the range of ocular complications that can be associated with systemic disease and to indicate when urgent referral to an ophthalmologist is necessary. To this end, various ocular complications are discussed. Dry eye disease, synonymous with keratoconjunctivitis sicca, is the commonest ocular manifestation of rheumatological disease, and varies enormously in severity. In its milder forms, topical lubricants may be sufficient, but severe disease may require corticosteroid or immunosuppressive therapy in addition to aggressive lubrication and measures such as lacrimal punctual plugging. Episcleritis and scleritis are common manifestations, particularly in association with rheumatoid arthritis, but require different treatment and have different prognoses, so their differentiation is useful. Necrotising scleritis is a complication that occurs most commonly in association with Wegener's granulomatosis and constitutes an ophthalmological emergency; prompt diagnosis and treatment are of the essence. Uveitis and retinal vasculitis also occur in association with rheumatological disease, and can form a major cause of morbidity, as occurs in Behcet's disease. Anterior uveitis generally responds to topical corticosteroids, but treatment can cause complications in the form of raised intraocular pressure and cataract, and requires regular review by an ophthalmologist. Juvenile idiopathic arthritis is a special case, as ‘silent’ anterior uveitis can occur, necessitating regular screening if complications are to be avoided. Posterior uveitis is more serious and generally requires systemic corticosteroids and immunosuppression, although the biological agents are increasingly being used in refractory cases. A similar approach is required for the management of orbital disease causing proptosis or optic nerve compression, as also occurs in Wegener's granulomatosis. One often neglected area in which rheumatological disease can lead to ophthalmic complications is related to the sideeffects of drug therapy. Hydroxychloroquine is well-known to cause a potentially irreversible maculopathy, but other drugs can also have ocular complications, including opportunistic infection in patients immunocompromised for the management of systemic rheumatological disease. The last article in this series addresses the complications of drug therapy in rheumatological and vasculitic disease, and suggests when screening may be appropriate.

Dry eyes are a frequent feature of routine ophthalmic clinical practice, but also form one of the commonest ocular manifestations of rheumatological disease. The spectrum of dry eye disease ranges from mild tear film instability through to severe dry eye which can threaten the integrity of the ocular surface and even lead to ocular perforation. This article discusses the disease pathophysiology and clinical manifestations of dry eye disease and also explores methods of diagnosis and assessment of dry eye. Current and emerging treatment modalities are also discussed, including the different types of ocular lubricants, the role of topical cyclosporine in the management of associated ocular inflammation, and mechanical measures such as plugging of the lacrimal punctum.

Episcleritis and scleritis describe chronic inflammation of the outermost coats of the eye, and frequently occur as ocular complications of rheumatological disease. It is important to distinguish them, as episcleritis is usually a mild, self-limiting condition, but scleritis is frequently painful and has vision-threatening complications. Necrotising scleritis is a variant which is associated with the vasculitides, especially Wegener's granulomatosis, and is an ocular emergency that can damage the integrity of the globe if not treated urgently with high-dose immunosuppression. This article reviews the pathophysiology and clinical features of the different variants of episcleritis and scleritis, and also discusses current and emerging treatment modalities, including the biological agents and the putative role of periocular corticosteroid injections.

Uveitis is a common extra-articular manifestation of many rheumatic diseases and can be associated with considerable morbidity, both in terms of vision loss and the need for systemic immunosuppression. Anterior uveitis is symptomatic in adults, presenting as a red, painful eye with photophobia, and is most commonly associated with HLAB27 disease. In contrast, chronic anterior uveitis can be silent in children with juvenile idiopathic arthritis, necessitating regular screening to detect its presence. Posterior segment inflammation carries a worse prognosis for vision, and usually manifests as floaters and visual impairment. This article reviews the pathophysiology and clinical features of uveitis occurring in association with systemic inflammatory disease, as well as discussing the current and emerging therapies available for treating its various manifestations.

Retinal vascular disease often occurs in conjunction with systemic inflammatory disease, particularly Behcet's disease and Systemic Lupus Erythematosus. In contrast to other manifestations of vasculitides, those affecting the posterior segment of the eye are accessible to direct visualisation by ophthalmoscopy, enabling a number of the features to be distinguished on clinical examination. Retinal vascular disease frequently carries a poor visual prognosis, and macular ischaemia leads to irreversible visual loss. Early disease identification and institution of appropriate management is therefore valuable in reducing the morbidity of these conditions. The vascular manifestations of different rheumatological diseases will be discussed, together with current and emerging therapies, including corticosteroids, second-line immunosuppression and biological agents, as well as the potential role for interferon alpha in the management of Behcet's disease.

Ophthalmic involvement in the rheumatic diseases may take the form of a broad range of orbital manifestations. Indeed, orbital involvement can be the sole or major feature of some diseases such as Wegener's granulomatosis, in which orbital masses and proptosis are common. These complications can have cosmetic implications, but can also lead to sight-threatening disease, if severe corneal exposure occurs, of if compressive optic neuropathy develops. This article discusses the clinical features of orbital involvement in the presence of systemic rheumatic disease, as well as current and emerging therapies for its management.

Systemically administered medications have long been known to produce detectable ophthalmic signs. Some of these are benign, asymptomatic phenomena that do not require screening or regular follow-up, such as the vortex keratopathy characteristic of amiodarone use, but other medications are potentially toxic to the eye and can damage vision. Ocular toxicity is an established side-effect of several of the immunosuppressive medications in routine use in rheumatological disease, including hydroxychloroqine, but corticosteroids can also cause ocular side-effects in the form of cataract and raised intraocular pressure. Ocular side-effects often occur in a dose-related and reversible manner, but some toxicity reactions are idiosyncratic, irreversible or may progress despite cessation of treatment.

The treatment options for patients with rheumatoid arthritis have undergone revolutionary changes over the last decade, in particular with the introduction of so-called biologicals. Moreover, the pipeline for new targets is still growing. This evolution has brought new perspectives for patients, with clearly improved functional and structural prognosis. The portfolio of options is growing so fast that rheumatologists face a particular challenge: how should these new compounds be used in an optimal way and when to prefer one biological over another. This mini-review looks at three issues with relevance for the rheumatologist who wants to make an evidence-based therapy choice for patients who failed conventional disease modifying antirheumatic drugs: the infection perspective, the oncology perspective and the issue of changing or not the target if a patient fails a first anti- TNF biological. There is strong evidence for each of the currently available reimbursed biologicals that it has an added value over conventional arthritis drugs, in case the latter fail. However, studies addressing the question whether one biological has an advantage over another in particular clinical situations are largely lacking. Yet, in daily practice the clinician has to take decisions and is looking for any information which is helpful in this decision process. Many other issues may potentially contribute to the choice of a particular biological compound in a particular clinical situation: mode of administration and patient preferences, safety aspects like the lipid profile, pregnancy-related considerations. Expectations have also arisen from the field of pharmacogenomics: will this new discipline soon help us in choosing between targeted therapies for individual patients? The further scientific development of arthritis therapy should certainly take into consideration some of the questions formulated in this mini-review. The field is currently asking for better insights into the optimal use of treatment strategies with already available compounds for rheumatoid arthritis patients, rather than just expanding the portfolio of existing biologicals.

Over the last decade, protein-based pharmaceuticals, so called “biologics”, have greatly expanded the therapeutic armamentarium for the treatment of rheumatoid arthritis (RA). Because antiinflammatory therapies with biologics do have multifaceted interactions with pathways involved in carcinogenesis, concerns have been raised that these agents may induce or accelerate malignant growth. Safety analyses based on clinical trial data and observational studies are facing major methodological challenges inherent to the attempt of addressing a possible impact of biologic therapies on a sparse and multifactorial event such as cancer. The expanding palette of approved biologics for the treatment of RA does add additional complexity and raises the issue of how different biologic therapies may compare to each other in terms of their oncogenic effects. This question is of particular importance in patients who have a history of previous malignancy or who develop a cancer while receiving a biologic agent. This review summarizes the published data relevant to a possible link between different biologic agents and malignancies. It explores the question of whether there is enough evidence to support preference of a particular biologic agent over another in different clinical scenarios.

Biologicals revolutionized the treatment of Rheumatoid Arthritis (RA). The targeted suppression of key inflammatory pathways involved in joint inflammation and destruction allows better disease control, which, however, comes at the price of an elevated infection risk due to relative immunosuppression. The disease-related infection risk and the infection risk associated with the use of TNF-α inhibitors (infliximab, adalimumab, etanercept, golimumab and certolizumab pegol), rituximab, abatacept and tocilizumab are discussed. Risk factors clinicians need to take into account when selecting the most appropriate biologic therapy for RA patients, as well as precautions and screening concerning a number of specific infections, such as tuberculosis, intracellular bacterial infections, reactivation of chronic viral infections and HIV are reviewed.

Tumour necrosis factor inhibitors (anti-TNF) improve considerably the signs and symptoms of severe rheumatoid arthritis (RA) in the majority of patients. Nonetheless, about a third of patients do not respond satisfactorily to this class of biological agents and many more loose response over time or can not tolerate them. In this clinical setting, randomized trials have demonstrated that a second anti-TNF or a biological agent of a different class (abatacept, rituximab, tocilizumab) may be effective. This review summarizes current evidence for existing therapeutic options in patients with an inadequate response to a first anti-TNF. The choice of an optimal treatment strategy needs to be tailored to the individual patient and take into account the reasons for prior anti-TNF interruption.