MAUI, HAWAII – Small fiber neuropathy is a common and underappreciated expression of systemic sarcoidosis, Dr. Alvin F. Wells observed at the 2016 Rheumatology Winter Clinical Symposium.
Small fiber neuropathy (SFN) occurs in roughly 40% of patients with sarcoidosis. Affected patients present with painful neuropathic symptoms and/or dysautonomia. SFN is often mistaken for fibromyalgia syndrome. And it poses a special therapeutic challenge.
Dr. Alvin F. Wells
“It can be very, very difficult to treat. It’s generally resistant to methotrexate, even to corticosteroids, our treatment mainstay in sarcoidosis,” said Dr. Wells, director of the Rheumatology and Immunotherapy Center in Franklin, Wisc.
He credited researchers at the Cleveland Clinic with bringing intravenous immunoglobulin (IVIG) to wider attention as an effective treatment for refractory SFN associated with sarcoidosis (Respir Med. 2011 Jan;105[1]:101-5).
“Here you’re treating it more like an immune-mediated neuropathy,” Dr. Wells noted.”It’s expensive therapy, but when these patients have a positive biopsy and they’ve failed other types of treatment, these data show IVIG can achieve a good response.”
Indeed, the Cleveland Clinic physicians reported excellent success with IVIG dosed at 2 g/kg initially, then 1 g/kg in 2 weeks, followed by maintenance dosing at 1 g/kg every 4 weeks.
This sarcoidosis-associated neuropathy involves both myelinated and nonmyelinated small nerve fibers. The diagnosis is established by epidermal nerve fiber density testing. This entails taking three 3-mm skin punch biopsies, one each at the lateral proximal and distal thigh, the third 10 cm proximal to the lateral malleolus. Specimens obtained from these sites in normal individuals feature a rich density of small nerve fibers; in patients with SNF-associated sarcoidosis, there is a notable paucity of the fibers, the rheumatologist explained.
Treating organ involvement besides SNF
Studies have consistently shown that the lungs and thoracic lymph nodes are the organs most commonly involved in sarcoidosis, affecting more than 90% of patients. Indeed, respiratory symptoms are most often the complaint that brings patients in seeking medical attention. The skin is involved in about 30% of cases, the eyes in 20%-25%, and the liver or heart in roughly 20% each.
Osteoarticular involvement is uncommon. Moroccan investigators for a study presented at the 2015 European League Against Rheumatism (EULAR) meeting in Rome concluded that when osteoarticular sarcoidosis occurs, it most often takes the form of an inflammatory chronic polyarthritis (Ann Rheum Dis. 2015;74[Suppl2]:786). Bone involvement is rare but damaging and mostly affects small distal bones, Dr. Wells said.
With the exception of sarcoidosis-associated SNF, the other types of organ involvement typically respond well to corticosteroids.
“Dosing depends upon disease severity. Most of us use 1 mg/kg to get ocular disease under control,” according to the rheumatologist. “The disease is very organ-specific. So if someone has eye disease, we throw everything at them, including the kitchen sink, to make sure they don’t go blind.”
“Steroids are the mainstay,” Dr. Wells emphasized. “The question to ask is, ‘What can I find that’s steroid-sparing and yet keeps the same kind of clinical response?’ ”
It’s virtually all off-label therapy. There is a dearth of randomized, blinded, placebo-controlled treatment trials in sarcoidosis. Many, many agents have been tried as second-, third-, and fourth-line therapy, including various disease-modifying antirheumatic drugs, tumor necrosis factor inhibitors, and phosphodiesterase-4 inhibitors. Dr. Wells’ favorites are methotrexate, azathioprine, and mycophenolate mofetil. However, hydroxychloroquine works well for skin disease, chloroquine helps combat hypercalcemia, and pentoxifylline and thalidomide can be helpful in cases of treatment-resistant lupus pernio.
A study presented at the 2015 EULAR meeting in Rome showed high-dose methotrexate in the 25-30 mg/week range was significantly more effective than mycophenolate mofetil in preventing relapses of neurosarcoidosis (Ann Rheum Dis. 2015;74[Suppl2]:859). This study has caused Dr. Wells to change his own practice.
He noted that the oral phosphodiesterase-4 inhibitor apremilast (Otezla) at 20 mg/day added to background therapy achieved “really dramatic results” for refractory chronic cutaneous sarcoidosis in a 15-patient, open-label, phase II study (Arch Dermatol. 2012 Feb;148[2]:262-4). A definitive randomized, placebo-controlled trial is certainly warranted, he added.
A question often asked by patients with extrathoracic sarcoid is, “Am I at greater risk of mortality than if I just had pulmonary disease?” The answer is no, Dr. Wells said, citing a study presented by investigators from Barcelona at the 2015 EULAR meeting (Ann Rheum Dis. 2015;74[Suppl2]:404). Mortality during a mean follow-up of 107 months was 11% in patients with extrapulmonary involvement and similar at 14% in patients whose sarcoidosis was limited to the lungs.
He reported serving as a consultant to roughly a dozen pharmaceutical companies.