Objective Radiographic measures of the pathologic changes of knee osteoarthritis (OA) have shown modest associations with clinical pain. We sought to evaluate possible differences in quantitative sensory testing (QST) results and psychosocial distress profiles between knee OA patients with discordant versus congruent clinical pain reports relative to radiographic severity measures. Methods A total of 113 participants (66.7% women; mean ± SD age 61.05 ± 8.93 years) with knee OA participated in the study. Radiographic evidence of joint pathology was graded according to the Kellgren/ Lawrence scale. Central sensitization was indexed through quantitative sensory testing, including heat and pressure–pain thresholds, tonic suprathreshold pain (cold pressor test), and repeated phasic suprathreshold mechanical and thermal pain. Subgroups were constructed by dichotomizing clinical knee pain scores (median split) and knee OA grade scores (grades 1–2 versus 3–4), resulting in 4 groups: low pain/low knee OA grade (n = 24), high pain/high knee OA grade (n = 32), low pain/high knee OA grade (n = 27), and high pain/low knee OA grade (n = 30). Results Multivariate analyses revealed significantly heightened pain sensitivity in the high pain/low knee OA grade group, while the low pain/high knee OA grade group was less pain-sensitive. Group differences remained significant after adjusting for differences on psychosocial measures, as well as age, sex, and race. Conclusion The results suggest that central sensitization in knee OA is especially apparent among patients with reports of high levels of clinical pain in the absence of moderate-to-severe radiographic evidence of pathologic changes of knee OA.

Objectives Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) pathways have demonstrated survival improvements in multiple advanced cancers, but also cause immune-related adverse events (IRAEs). IRAEs with clinical features similar to rheumatic diseases have not been well described. We report patients with inflammatory arthritis and sicca syndrome secondary to ICIs. Methods We report patients evaluated in the Johns Hopkins Rheumatology clinics from 2012 to 2016 identified as having new rheumatological symptoms in the context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1) for solid tumours. Results We identified 13 patients who received ICIs and developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included melanoma, non-small cell lung cancer, small cell lung cancer and renal cell carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1 MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis, colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were positive in 5 out of 13 patients. All 13 patients were treated with corticosteroids with varying response. Two patients were treated with methotrexate and antitumor necrosis factor therapy for inflammatory arthritis. Conclusions As ICIs are increasingly used for a range of malignancies, new cases of rheumatic IRAEs are likely to emerge. Further research is required to understand mechanisms, determine risk factors and develop management algorithms for rheumatic IRAEs.

Autoantibodies to citrullinated protein antigens are specific markers of rheumatoid arthritis (RA). Although protein citrullination can be activated by numerous stimuli in cells, it remains unclear which of these produce the prominent citrullinated autoantigens targeted in RA. In these studies, we show that RA synovial fluid cells have an unusual pattern of citrullination with marked citrullination of proteins across the broad range of molecular weights, which we term cellular hypercitrullination. Although histone citrullination is a common event during neutrophil activation and death induced by different pathways including apoptosis, NETosis, and necroptosis/autophagy, hypercitrullination is not induced by these stimuli. However, marked hypercitrullination is induced by two immune-mediated membranolytic pathways, mediated by perforin and the membrane attack complex (MAC), which are active in the RA joint and of importance in RA pathogenesis. We further demonstrate that perforin and MAC activity on neutrophils generate the profile of citrullinated autoantigens characteristic of RA. These data suggest that activation of peptidylarginine deiminases during complement and perforin activity may be at the core of citrullinated autoantigen production in RA. These pathways may be amenable to monitoring and therapeutic modulation.

Objective Insomnia is prevalent in knee osteoarthritis (KOA). Research indicates that sleep disruption may amplify clinical pain by altering central pain modulation, suggesting that treating insomnia may improve pain. We sought to: 1) evaluate the efficacy of Cognitive-Behavioral Therapy for Insomnia (CBT-I) in KOA, 2) determine whether improvements in sleep predict reduced pain, and 3) determine whether alterations in pain modulation mediate improvements in clinical pain. Methods We conducted a double-blinded, randomized, active placebo-controlled clinical trial of CBT-I in 100 KOA patients with insomnia [Mean Age = 59.5(9.5)]. Patients were randomized to 8-sessions of CBT-I or Behavioral Desensitization-Placebo. We conducted in-home polysomnograms, diary assessment, and sensory tests of pain modulation at baseline, posttreatment, 3-and 6-months. Results Intent-to-treat analyses demonstrated that both groups yielded substantial improvements in sleep. CBT-I demonstrated significantly greater reductions in wake after sleep onset time (WASO), measured via diary and actigraphy [PSG trended, (p=.075)]. Both groups reported significant and comparable reductions in pain over 6 months with a third demonstrating ≥ 30% reduction in pain severity. Baseline-to-posttreatment reductions in Diary and PSG WASO predicted subsequent decreases in clinical pain. This effect was significantly greater for CBT-I compared to BD. We found no significant changes in laboratory measures of pain modulation. Conclusion Compared to active placebo, CBT-I was efficacious in reducing sleep maintenance insomnia. Treatment decreased clinical pain, but not pain modulation, suggesting that CBT-I has potential to augment pain management in KOA. Future work is needed to identify the mechanisms by which improved sleep reduces clinical pain.