Granulomatosis with polyangiitis (GPA) is one of three described anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). Early diagnosis and treatment of GPA is paramount, as it may help prevent irreversible end-organ damage, especially renal and pulmonary failure. A 72-year-old male with a past medical history of lung adenocarcinoma in remission, chronic sinusitis status-post multiple sinus surgeries, and coronary artery disease presented with shortness of breath, dark urine, and asymmetric polyarthralgias. He had an acute kidney injury, leukocytosis, with urinalysis demonstrating pyuria and hematuria, without casts. Chest imaging showed cavitary nodular opacities in addition to interval increase of existing nodules compared to the most recent scan one month prior. His acute kidney injury progressed to renal failure requiring hemodialysis, and he developed an inflammatory polyarthritis. GPA was suspected clinically so he was started on high-dose intravenous corticosteroids, and subsequently plasmapheresis and rituximab. Serology returned with highly positive proteinase-3 antibodies, and cytoplasmic ANCA positivity on immunofluorescence. Renal biopsy demonstrated severely active pauci-immune glomerulonephritis. Several months after discharge, the patient passed away from gram positive bacteremia. This patient's recurrent sinusitis, pulmonary nodules, and subsequent renal failure were highly suggestive of GPA. A biopsy is recommended to confirm the diagnosis of GPA, but treatment should not be delayed if there is a high index of suspicion for the disease. Induction therapy with corticosteroids combined with rituximab or cyclophosphamide has significantly decreased the mortality of patients with GPA. Patients with GPA often have preceding history of nasopharyngeal and upper airway disease, and can present with fluctuating pulmonary infiltrates. Early recognition and treatment of patients with GPA can prevent life-threatening complications and reduce mortality.

Background

Musculoskeletal ultrasound (MSUS) and the multi-biomarker disease activity (MBDA) score are outcome measures that may aid in the management of rheumatoid arthritis (RA) patients. This study evaluated tofacitinib response by MSUS/MBDA scores and assessed whether baseline MSUS/MBDA scores or their early changes predict later clinical response.

Methods

Twenty-five RA patients treated with tofacitinib were assessed at baseline, 2, 6 and 12-weeks. Power doppler (PDUS) and gray scale (GSUS) ultrasound scores, MBDA score, clinical disease activity index (CDAI), and disease activity score (DAS28) were obtained. Pearson correlations and multiple linear regression models were used to evaluate associations and identify predictors of response to therapy.

Results

MSUS, MBDA scores, CDAI, and DAS28 improved significantly over 12 weeks (p < 0.0001). Baseline MSUS and MBDA score correlated with each other, and with 12-week changes in CDAI/DAS28 (r = 0.45-0.62, p < 0.05), except for GSUS with DAS28. Two-week change in MSUS correlated significantly with 12-week changes in CDAI/DAS28 (r = 0.42-0.57, p < 0.05), except for early change in PDUS with 12-week change in CDAI. Regression analysis demonstrated significant independent associations between baseline PDUS/MBDA score and 6-week change in CDAI/DAS28, with adjustment for baseline CDAI/DAS28 (all p < 0.05); and between baseline MBDA scores and 12-week change in DAS28 (p = 0.03).

Conclusions

RA patients treated with tofacitinib for 12 weeks demonstrated improvement by clinical, imaging, and biomarker end-points. Baseline PDUS and MBDA score were predictive of CDAI and DAS28 responses. This is the first study to evaluate early measurements of MSUS and MBDA score as predictors of clinical response in RA patients treated with tofacitinib.

Trial registration

ClinicalTrials.gov NCT02321930 (registered 12/22/2014).

OBJECTIVE: Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme, that has been implicated as a biomarker of cardiovascular risk in patients with rheumatoid arthritis (RA). We aimed to investigate how different biologic therapies affect levels of PON1 and oxylipins. METHODS: 1213 adult patients with RA in the Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory CoNditions cohort study with moderate-to-high disease activity (Clinical Disease Activity Index (CDAI) >10) who initiated a new biologic (tocilizumab (TCZ), n=296; abatacept, n=374; tumour necrosis factor inhibitors, n=427; rituximab, n=116) were followed prospectively with serum specimens analysed for PON1 activity by arylesterase (ARYL), lactonase (LAC) and PON assays at baseline and after 6 months of biologic therapy. A targeted panel of oxylipins was evaluated by liquid chromatography-mass spectrometry/mass spectrometry in a subset of patients with the lowest and highest 6-month Disease Activity Score 28 (DAS28)-C reactive protein (CRP) responses in each treatment group. RESULTS: PON1 activity generally increased in the entire cohort after 6 months of new biologic therapy, showing the greatest, most consistent increases in the TCZ group. Increases in all three PON1 domains associated with significant decreases in disease activity in DAS28-CRP/CDAI (p<0.05), and increases in LAC/ARYL were significantly associated with the American College of Rheumatology 20/50/70 responses (OR (95% CI) of 1.12 (1.04, 1.22) and 1.13 (1.04, 1.23), p<0.01, respectively), after controlling for other RA disease characteristics. Some oxylipins, including 12-hydroxyeicosatetraenoic acid correlated with RA disease activity measures. CONCLUSION: Improvement in disease activity across four classes of biologics is associated with enhanced PON1 activity, which has significant implications for cardiovascular safety.