I would like to thank the ORA for supporting me to attend the 2019 ACR Sate of the Art Clinical Symposium in Chicago. It was a weekend of well-packed clinical content. Below are some of the highlights:
Microbiome. While the concept of microbiome as a determinant of health and disease is not new, in his keynote speech, Dr. Jose Scher (NYU) shed interesting light on pharmacomicrobiomics (ie what bugs do to drugs). We are familiar with the oral absorption issue with methotrexate, which leads to unreliable bioavailability at higher doses. It has now been shown that human microbiome also metabolizes methotrexate extensively in the gut before it is even absorbed. In his research, Dr. Scher’s team examined new onset drug naive RA patients who were started on methotrexate and followed for 4 months. He found differences in the baseline bacterial metagenome of methotrexate responders and non-responders. Then through taxonomy, microbial pathways, and machine learning, his team constructed a model to predict whether a patient will have a high or low clinical response to methotrexate based on patient’s baseline microbiome (Data not yet published). Outside of rheumatology, he also showed some emerging data illustrating the microbiota-dependent effects of checkpoint inhibitors in cancer patients as well as biologics in IBD patients. More research will no doubt be forthcoming as we move towards the era of precision medicine.
Antiphospholipid Antibody Syndrome Update. The update here is the TRAPS trial comparing rivaroxaban vs warfarin (moderate intensity INR 2-3) in high-risk patients (triple aPL positivity) with antiphospholipid antibody syndrome (Pengo et al. Blood. 2018; 132 (13):1365‐1371). The trial was stopped early due to excess events in the rivaroxaban group. Thrombosis rate was 12% vs 0% in warfarin group. Until further data, NOAC is not recommended for secondary thromboprophylalxis in APS.
Maintenance of Remission in ANCA-associated vasculitis. Dr. Alexandra Villa-Forte (Cleveland Clinic) focused her talk on the maintenance treatment of these conditions. While there are still many unanswered questions, she has distilled a number of learning points from existing data when it comes to relapses. She noted that >80% of 1st relapses occur after discontinuation of maintenance therapy (WGET, NORAM, RAVE, WEGENT). Dose also matters as relapses are more likely when methotrexate is <15mg/week or azathioprine <50mg/day. Risk factors associated with increase in relapse rate are history of previous relapse, shorter maintenance therapy duration (<48 months), persistent hematuria after remission, PR3-ANCA positivity, persistence of ANCA positivity, increase in ANCA titres, HLA-DPB1, variations in serum level of calprotectin, urinary soluable CD 163. Factors that lower relapse rate are longer maintenance therapy duration, longer duration of corticosteroid (controversial), rituximab as maintenance drug (uncertain), certain disease phenotypes (uncertain), and negative PR3.
Medication Safety. Cardiovascular safety of febuxostat was one of the highlights from Dr. Gabby Schmajuk (San Francisco VA Hospital). The CARES trial randomized 6200 patients with gout and CV disease to allopurinol vs febuxostat. The primary endpoint was composite CV events and no increased risk was seen between the two groups (HR 1.03 [95% CI, 0.87 to 1.23]). However, secondary endpoints including all-cause and cardiovascular mortality were higher in the febuxostat group than in the allopurinol group (hazard ratio for death from any cause, 1.22 [95% CI, 1.01 to 1.47]; hazard ratio for cardiovascular death, 1.34 [95% CI, 1.03 to 1.73]). (White et al. N Engl J Med. 2018 Mar 29;378(13):1200‐1210). There are some important caveats when interpreting the results. One is that patients dropped out from the trial at a high rate (56% stopped meds; 45% lost to follow up). When post-hoc ascertainment efforts added 199 deaths to the original 442 deaths, all-cause HR dropped to 1.09 [95% CI, 0.94 to 1.28]. Secondly, 85% of events occurred while patients were not receiving study drugs. Furthermore, there was no placebo group. It is unknown whether allopurinol has beneficial effects while febuxostat rates are similar to the untreated. Until further data becomes available, the speaker felt that it is sensible to avoid febuxostat as first line treatment in those with CV disease.
Checkpoint inhibitor-associated autoimmunity. There are several interesting highlights from this talk. One is that most immune related adverse events(irAE) were found to be associated with actually improved patient survival. In one cohort with 137 NSCLC, receiving nivolumab or pembrolizumab, the HR for overall survival was 0.42 [95%CI 0.24-0.71] for those having experienced irAEs versus those without irAEs [Toi Y. JAMA Oncol 2018 Epub]. Dr. Anne Bass (Weil Cornell Medicine) shared some data from their checkpoint inhibitors-arthritis registry (n=36). Median months to arthritis onset was 4 [range of 0.8 to 12] with arthritis duration of 15 months [range of 6 to 24]. ANA was positive in 74% and 30% had positive RF/anti-CCP. The most common phenotype was RA/small joints phenotype at a prevalence of 47%, followed by arthralgia (25%), large joint arthritis +/- enthesitis and tenonsynovitis (17%), and PMR (11%). In this registry, prednisone >20mg was used in 47%,50%, 11%, and 75% of patients in RA-like, large joint, arthralgia, and PMR group, respectively. Use of biologic was in 18%, 17%, 0%, and 25% of those groups, respectively. In terms of therapeutics, low dose prednisone is probably safe. High dose prednisone >20mg/day may reduce cancer survival. As for conventional DMARDs, no new data on their safety profile but they are being used in practice. As for anti-TNFs, there is little data and it does not seem to be associated with worsening survival at this point [Wang. J ImmunoTherapy 2018; 6(37)]. Safety is unknown regarding IL-6 inhibitors. There is some published retrospective data (Stroud. J Oncol Pharm Practice 2017) but they are probably best to be reserved for refractory cases. Lastly, avoid JAK inhibition as there is indirect evidence that it can cause harm as JAK1/2 mutations have been shown to cause anti-PD-1 resistance [Zaretsky JM. N Engl J Med 2016;375:819-29. Shin DA. Cancer Discov. 2017;7(2): 188–201].