Giant cell arteritis or polymyalgia rheumatica after influenza vaccination: A study of 12 patients and a literature review

IntroductionGiant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are inflammatory rheumatic diseases common in people over the age of 50 years. Seasonal influenza vaccination (IV) is strongly recommended in this population, among whom it is considered to be effective and well tolerated. IV-induced GCA or PMR are thought to be exceptional.Patients and methodsWe retrieved all post-IV cases from an inception cohort of patients with newly diagnosed GCA. We also included two patients with post-IV PMR and reviewed all published reports of post-IV GCA or PMR, with selection of cases demonstrating disease onset within 1 month following IV. We compared the results of HLA-DRB1 typing, performed in seven patients with post-IV GCA or PMR, with those of 11 GCA patients with familial aggregation and 16 randomly selected GCA patients without a reported trigger.ResultsOf 358 GCA recruited since 2002, 10 (2.8%) qualified for post-IV GCA, of whom two also showed familial aggregation. Thirty-two patients (19 with GCA and 13 with PMR) including our patients were reviewed; their mean age was 71.8 ± 7.4 years and the M/F ratio was 0.8. Six patients (19%) had a history of PMR. Patients with post-IV GCA/PMR had the DRB1*13:01 haplotype more frequently compared to those with familial GCA (5/7 vs. 2/11, p = 0.048) or with GCA without a known trigger (3/16, p = 0.026). Post-IV PMR generally appeared self-limited, whereas post-IV GCA often displayed a more protracted course (chronic relapsing disease in one-third of the patients).ConclusionPost-IV onset of GCA/PMR is not an exceptional occurrence and may be part of the spectrum of the autoimmune syndrome induced by adjuvants (ASIA). IV can trigger GCA or PMR, especially in persons at higher spontaneous risk, such as those with a personal or familial history of GCA/PMR. Whether the presence of the DRB1*13:01 allele further increases the risk of post-IV GCA/PMR through a stronger vaccine-induced immune reaction deserves further investigation. Unlike PMR, GCA can be a serious complication of IV.     

Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities

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First-in-Class Selective HDAC6 Inhibitor (ACY-1215) Has a Highly Favorable Safety Profile in Patients with Relapsed and Refractory Lymphoma

Lessons Learned

• Oral selective HDAC6 inhibitors could allow for decreased toxicity compared to pan‐class inhibitors, and increased ease of use.
• ACY‐1215 is well tolerated and led to disease stabilization in 50% of patients treated on a twice‐daily dosing schedule.
• Rational drug combinations with ACY‐1215 improve efficacy in patients with lymphoma.
• Biomarkers such as XBP‐1 level or HDAC6‐score may improve patient selection.

BackgroundACY‐1215, ricolinostat, is an oral, first‐in‐class isoform‐selective HDAC6 inhibitor. HDAC6 is a class IIb deacetylase and plays a critical role in protein homeostasis via the unfolded protein response (UPR). Lymphocytes generate a large repertoire of antibodies and depend on an activated UPR to maintain proteostasis. Lymphomas utilize this biology to evade programmed cell death. In preclinical models of lymphoma, ACY‐1215 disrupted proteostasis, triggering apoptosis.MethodsWe translated these findings into a multi‐institution, open‐label, dose‐escalation phase Ib/II study aimed to determine the safety and efficacy in patients with relapsed and refractory lymphoma.ResultsTwenty‐one patients with heavily pretreated lymphoma were accrued. Patients in the phase Ib portion were enrolled on one of two dose cohorts [Arm A: 160 mg daily (n = 3) or Arm B: 160 mg twice daily (n = 10)]. ACY‐1215 was well tolerated. There were no dose limiting toxicities. Most adverse events were grade 1–2, including diarrhea (57%), nausea (57%), and fatigue (43%). Grade 3–4 toxicities were rare and included anemia (9.5%) and hypercalcemia (9.5%). An additional 8 patients were enrolled on the phase II portion, at 160 mg twice daily. Sixteen patients were evaluable for response. ACY‐1215 did not result in any complete or partial responses in patients treated. Eight patients had stable disease (50%) lasting a median duration of 4.5 months, all of whom were treated twice daily. Disease progressed in eight patients (50%) at cycle 2. Five patients were not evaluable due to disease progression prior to cycle 2. The median PFS was 56 days.ConclusionACY‐1215 is an oral selective HDAC6 inhibitor that was safe in patients with relapsed and refractory lymphoid malignancies and led to disease stabilization in half of the evaluable patients.