The ACR’s annual State-of-the-Art Clinical Symposium took place April 13–15 in Chicago. Here are some highlights from the symposium.
Exciting Year for Gout
In “Selected Topics in the Advanced Management of Crystal Disease,” Lloyd B. Klickstein, MD, PhD, a rheumatologist in the translational medicine depatment of Novartis Institutes for Biomedical Research in Cambridge, Mass., provided an update on recent findings in gout and covered management of calcium crystal disease in dialysis patients—something “rheumatologists don’t do all that well,” he says. “They assume the nephrologists handle it, and the nephrologists assume the rheumatologists do it.”
Research is helping us understand the mechanism of crystal-induced arthritis for the first time. A paper published in Nature showed that gout-associated uric acid crystals activate the NALP3 inflammasome, leading to the production of interleukin-1 (IL-1). A second study from University of Massachusetts demonstrated an absolute requirement for IL-1 receptor signaling for gouty inflammation.
“MSU [monosodium urate] crystals trigger IL-1beta release from resident inflammatory cells, and IL-1beta then activates pro-inflammatory pathways in many cell types,” he says. “If all this is correct, then anti–IL-1 therapy should be really effective in crystal-induced disease.”
Dr. Klickstein provided an overview of the status of drugs in late stage clinical trials for gout, including febuxostat and puricase. He also discussed alternative therapeutic options for gout patients, which included a combination treatment using anti-hyperuricaemic agents together with fenofibrate and/or losartan to provide a modest additional benefit in lowering uric acid. Another randomized trial showed that the organic polymer sevelamer (Renagel) lowered uric acid levels by an average of 0.72 mg/dl, compared to 0.15 mg/dl in the control group.
Research is helping us understand the mechanism of crystal-induced arthritis for the first time.
Rasburicase may become a new tool for the treatment of hyperuricemia in refractory gout, according to a series of recent case reports. It is currently approved in the U.S. for tumor lysis syndrome. “It does have significant drawbacks,” says Dr. Klickstein. “It’s a cancer drug, so it’s very expensive. Allergic reactions are very common and can be rather ferocious. And … patients with G6PD deficiency are at risk for acute drug-induced methemoglobinemia.”
For the management of calcium crystal disease in dialysis patients, Dr. Klickstein stresses that a top priority is getting the phosphate (PO4) level under control, with a goal of lowering it below 5.5 mg.
“MSU is to gout what PO4 is to calcium crystal disease in dialysis patients,” he says, offering these management recommendations:
- Before dialysis, measure serum calcium, PO4, and immunoreactive parathyroid hormone;
- Stress the importance of dietary counseling;
- Prescribe PO4 binders, preferably sevelamer;
- Use vitamin D analogs such as paricalcitol instead of calcitriol;
- If the previous steps have no effect, consider a new class of drugs called calcimimetics; and
- If all else fails, use longer dialysis runs.
Eye on Ocular Inflammatory Diseases
James T. Rosenbaum, MD, chair of the arthritis and rheumatologic diseases division at Oregon Health & Science University in Portland, presented cutting-edge information on “Inflammatory Eye Disease.”
He began with an overview of ocular inflammatory diseases, including uveitis and Blau syndrome, the rarest form of uveitis.
“There are different diseases for the front and the back of the eye,” explained Dr. Rosenbaum, “and uveitis affects the middle of the eye.” Blau syndrome, which affects children, is caused by a mutation in a gene called NOD2. Blau is closely related to Crohn’s disease, but no patient has ever presented with both.
Dr. Rosenbaum outlined the clinical considerations of tubulo-interstitial nephritis with uveitis (TINU). “You ought to recognize this, but you’ve probably never heard of it,” he says. It presents with a bilateral, sudden onset anterior uveitis; a variable degree of vitreous involvement; fever, myalgias, and fatigue; and a high sed rate, anemia, mildly abnormal liver function, and abnormal urinalysis. TINU is “far more common than we thought,” he said, but it responds well to corticosteroids.
Recent studies have revealed a link between uveitis and juvenile idiopathic arthritis (JIA). For example, a Johns Hopkins study found that 36% of JIA patients had affected eyesight and 24% were legally blind. Other unpublished research points to a link between anti-neutrophil cytoplasmic antibody (ANCA) testing and scleritis. Fourteen out of 101 patients with scleritis had a positive ANCA test.
“About 40% of patients with scleritis have a systemic immunologic disease such as rheumatoid arthritis,” said Dr. Rosenbaum. “And scleritis is rarely the initial manifestation of that systemic disease. Consequently, lab tests such as [antinuclear antibody] or [rheumatoid factor] have little role in the evaluation of these patients.”
In covering treatment for uveitis, Dr. Rosenbaum focused on the most extensively tested biologics, including TNF inhibitors, alpha interferon, and the anti–IL-2 receptor daclizumab. TNF inhibitors have been tested most thoroughly and shown to be remarkably effective when used off-label. Specifically, infliximab was studied by three different groups and found to be quite potent. However, “reduction of TNF may be more toxic in uveitis,” warned Dr. Rosenbaum, “so use it very cautiously.” He also pointed out that infliximab is not FDA approved for childhood uveitis, perhaps because the dose used in tests was not high enough.
“Monoclonal antibodies to TNF hold great promise in treating uveitis,” said Dr. Rosenbaum, “but they should be used with great caution.”
Holistic Management of Central Pain
In her presentation, “Fibromyalgia,” Leslie J. Crofford, MD, chief of rheumatology and director of the Center for the Advancement of Women’s Health at the University of Kentucky in Lexington, focused on treating pain syndromes. Patients with these syndromes are primarily interested relieving chronic pain and the chronic fatigue that accompanies it.
Rheumatologists must step in at the beginning of diagnosis when necessary. “Many primary care physicians are uncomfortable dealing with the musculoskeletal exam,” she says. “We should …assist our primary care colleagues with differential diagnoses.”
She reviewed clinical criteria for fibromyalgia syndrome (FMS). “We’re talking about pain processing abnormality,” she says. “We need a unified understanding and treatment of these syndromes.” She outlined the etiology of FMS and trace genetic vulnerability to the syndrome before discussing treatment implications for the concept of central pain.
“Treatments used for nocioceptive musculoskeletal pain do not work well in most FMS patients,” notes Dr. Crofford. Treatments must address the problems of altered pain processing in the spinal cord and altered descending inhibition of pain signals. When it comes to regarding FMS symptoms as either a psychiatric or medical issue, she believes this debate is harmful and unproductive. Regardless of what you believe the underlying cause of the symptoms is, treatment should be dually focused, with pharmacologic and non-pharmacologic therapies.
“You need a holistic approach,” she says. “Prescribing a pill isn’t going to cut it.” FMS patients’ symptoms are real to them and very disabling.
Rheumatologists should make patients active participants in their own treatment, educating them on the meaning of a chronic illness and explaining clearly what they can do to alleviate symptoms—for example, following specific exercise regimens.
As for medication, Dr. Crofford urges rheumatologists to individualize treatment according to pain symptoms. This includes treating visceral pain (e.g., irritable bowel syndrome and migraine); treating peripheral pain generators (e.g., normal musculoskeletal pain) with non-narcotic analgesics and non-steroidal anti-inflammatory drugs; and treating FMS or central pain with norepinephrine/serotonin reuptake inhibitors or alpha-2-delta ligands, for example.
“Start with agents that treat the central pain syndrome,” she says. “Reduction of clinical pain is optimized when all pain sources are addressed.”
Dr. Crofford ended her presentation with a review of recent treatment research that may lead to better symptom management, including studies of gabapentin and pregabalin.
Jane Jerrard is a journalist based in Chicago.
