Michael Weinblatt, MD, associate director of the Center for Arthritis and Joint Diseases and John R. Riedman Professor of Medicine at Brigham and Women’s Hospital, Boston, provided an overview with regard to rheumatoid arthritis (RA). Dr. Weinblatt discussed how increased body mass index and diabetes can be associated with nonalcoholic steatohepatitis and that this condition can predispose patients on methotrexate to liver function test abnormalities. In patients on this medication who experience such side effects as gastrointestinal symptoms or oral ulcers, Dr. Weinblatt advocated for the use of leucovorin 5 mg weekly (8–24 hours after the weekly dose of methotrexate) to aid in reducing these side effects.
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Explore This IssueApril 2020
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For patients on oral methotrexate who have not found benefit at a dose of up to 20 mg weekly, split dosing—in which half the weekly methotrexate dose is given and then, from 8–24 hours later, the second half of the weekly dose is administered—can be considered.
In addition to these tips from clinical practice, Dr. Weinblatt also discussed how Janus kinase (JAK) inhibitors represent an interesting and important relatively new category of medication to be explored in the treatment of rheumatoid arthritis. In 2017, the Oral Rheumatoid Arthritis Trial (ORAL) demonstrated that tofacitinib and methotrexate combination therapy was non-inferior to adalimumab and methotrexate combination therapy in the treatment of rheumatoid arthritis in patients with an inadequate response to methotrexate. It should be noted, however, that tofacitinib monotherapy was not shown to be non-inferior to either combination.5
Dr. Weinblatt cited evidence that lack of response early in the course of treatment with tofacitinib (i.e., within one to three months of starting therapy) does predict a low probability of achieving low disease activity, thus patients who do not show clinical improvement after being on tofacitinib for 4–12 weeks may be less likely to benefit from longer periods on this treatment.6 Dr. Weinblatt noted that recent safety concerns over possible increased risk of pulmonary embolism and death in patients being treated with tofacitinib will need to be closely examined and, with the recent FDA approval of the JAK inhibitor upadacitinib, exploring this issue is of even greater importance.
Edward Behrens, MD, Joseph Lee Hollander Chair in Pediatric Rheumatology, and chief, Division of Rheumatology, The Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, provided a discussion of macrophage activating syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH).
Dr. Behrens explained that HLH is an aggressive and life-threatening syndrome of excessive immune activation. Primary HLH, also known as familial hemophagocytic lymphohistiocytosis (FHL), is caused by a genetic mutation at either one of the FHL foci or in genes responsible for one of several immunodeficiency syndromes. Secondary HLH is the term used to describe patients without a known familial mutation who develop HLH due to an acute trigger, such as an autoimmune disease, viral illness or lymphoma. MAS indicates the form of HLH that occurs primarily in patients with juvenile idiopathic arthritis or other rheumatic conditions, such as systemic lupus erythematosus; the term reactive hemophagocytic syndrome has also been used in these cases.
Dr. Behrens explained that one challenging issue in this field is how best to diagnose these conditions, especially when comparing primary and secondary forms of HLH. In 2007, the HLH-2004 diagnostic guidelines were introduced and described several criteria that can be used to help establish a diagnosis of HLH.7 However, although these criteria include low/absent NK (natural killer) cell activity, Dr. Behrens stated the function of NK cells is much more relevant in genetic rather than secondary cases of HLH.
In addition, although HLH is one of a few conditions that will result in a serum ferritin level of >10,000 ng/mL, some research indicates that serum heme oxygenase-1 (HO-1) may be of more use in differentiating secondary hemophagocytic syndrome from other similar hematological conditions.8 With respect to activity level in secondary HLH and MAS, work indicates that free interleukin (IL) 18 may be pathogenetic and may serve both as a biomarker for activity and a potential therapeutic target.