CHAPTER Section 5: Pharmacotherapy and Surgery

KEY FEATURES (PHARMACOLOGY)

Rheopheresis is a form of therapeutic plasma apheresis that utilizes a novel nanopore, hollow-fiber, membrane technology configured in a differential filtration array with two single-use, in-line, membrane filters (Figure 46.1). It is designed to deplete excess concentrations of soluble high-molecular-weight plasma components by mechanically sieving circulating species larger than 25 nm (as measured across their shortest linear axis) or approximately 500 kDa by weight from the blood. As such, the therapy provides physiologic depletion of a targeted bandwidth of plasma species, including immune complexes, immunoglobulin M (IgM), α2-macroglobulin, fibrinogen, von Willenbrand factor, low-density lipoprotein (LDL) cholesterol, and others.1,2

INTRODUCTION AND HISTORY

The Center of Ophthalmology of the University of Cologne has been employing various strategies to decrease fibrinogen and high-molecu- lar plasma proteins in ocular diseases in interdisciplinary cooperation since 1988. Besides other effects, blood circulation capacity is improved and this in turn leads to a measurable upgrading of the ocular hemodynamics.4,5

The simultaneous elimination of a defined spectrum of high- molecular-weight rheologically relevant plasma proteins (>25 nm or 500 kDa, i.e., alpha-2-macroglobulin, fibrinogen, fibronectin, LDL cholesterol, IgM, von Willebrand factor, putatively multimeric vitronectin) immediately results in the pulsed reduction of plasma and whole-blood viscosity.1,6–9

Thus, rheopheresis is successfully used to improve microcirculatory impairment. Rheopheresis treatment appears to restore and activate or stabilize the functional reserve of the retina at microcirculatory levels. Results from clinical trials, evaluations of patients suffering from agerelated macular degeneration (AMD) and other microcirculatory disorders (e.g., diabetic retinopathy, central retinal vein occlusion (CRVO), and uveal effusion syndrome) and basic research in the field of AMD pathogenesis describing structural and functional features of impaired microcirculation in AMD can all be referenced as proof of principle. Serial pulses of plasma protein elimination reduce plasma viscosity and thus lead to a sustained improvement in microcirculation.1,2,4,6,9–11

RHEOPHERESIS IN RETINAL DISEASES

AGE-RELATED MACULAR DEGENERATION

AMD is one of the leading causes of blindness in the elderly in the industrial world and is therefore of increasing socioeconomic interest. The pathogenesis of AMD is, however, not yet fully understood.2,10–13 Pigment epithelium detachment or clumping, atrophy of the chorio­ capillaris, and a decrease in choroidal perfusion are common and consistent findings in AMD.10 The diminished perfusion of the choroid

seems to play a decisive role in the pathogenesis of pigment epithelium damage, leading to worsening of the visual function and the pro­ gression of morphological changes. It is thus receiving greater attention.10,14

Even in its early stages, AMD showing drusen and changes in the pigment epithelium can cause considerable impairment of central vision, including distortions and difficulties in reading. Risk factors for AMD besides old age are, for example, obesity, hypertension, elevated serum cholesterol, diabetes, and smoking, which further indicate a correlation between AMD and perfusion or microcirculation.15–17

The treatment of age-related maculopathy and the early stages of dry AMD, based on current diagnostic findings, aims at the stabilization and improvement of central vision in order to enhance patients’ quality of life and level of independence. Due to a lack of generally accepted therapies, in many cases only good cardiovascular adjustment controls and ophthalmologic follow-up are recommended.

Rheopheresis has been clinically investigated over the past years and shown to have a positive influence on the natural course of AMD. Long-term evaluations have further proven that the improvements brought about by rheopheresis are stable over a period of years.2,10,11

MAC-1 trial

Findings of a nonblind randomized trial evaluating 40 patients treated with 10 rheopheresis treatments have been documented in the eye journal Retina.10 AMD patients with soft drusen benefited most greatly from the rheopheresis treatments and demonstrated an average 2.3 lines of improvement compared to the control group (no treatment). One year posttreatment, 30% of the control group lost ≥ 3 lines of acuity, compared with only 10% of the rheopheresis group.2

In addition, 15% of the rheopheresis group’s vision improved by ≥ 2 lines compared with only 5% of the control group. With respect to patients with vision worse than 20/40 prior to treatment, 37% of patients in the rheopheresis group gained at least 20/40 vision after treatment, compared with only 10% of the control group. (The 20/40 vision threshold is important because it defines the legal driving limit imposed by most countries.2)

Multicenter investigation of rheopheresis for AMD (MIRA-1)

The most extensive study on rheopheresis application was performed in the USA as part of an ongoing Food and Drug Administration (FDA) trial. Over 1200 procedures were administered to 150–180 patients.2,11 MIRA-1 was designed to provide type 1 evidence-based information on the safety and efficacy of the rheopheresis procedure for select patients with dry AMD. The primary aim of the study was to compare the results between the rheopheresis group (which received rheopheresis) and the placebo group (which did not receive active treatment).2,11 In the autumn of 2001, the company in question received authorization from the FDA to conduct an interim analysis of the first 43 patients in the form of a 12-month follow-up. A total of 29 rheopheresis patients and 14 placebo patients were included in the analysis. The primary objective of the procedure is to slow down or completely stop the disease. At the 12-month postbaseline interval, rheophoresis-treated