Effect of Pulsed Low-Intensity Ultrasonography on Symptom Relief and Tibiofemoral Articular Cartilage Thickness Among Veterans Affairs Enrollees With Knee Osteoarthritis: A Randomized Clinical Trial.

Importance: Osteoarthritis (OA) is a major cause of disability in the US, with no approved treatments to slow progression, but animal models suggest that pulsed low-intensity ultrasonography (PLIUS) may promote cartilage growth. Objective: To evaluate the efficacy of PLIUS in providing symptom reduction and decreased loss of tibiofemoral cartilage thickness in patients with knee OA. Design, Setting, and Participants: A phase 2A, sham-controlled, parallel, double-blind randomized clinical trial was conducted at 2 Veterans Affairs hospitals in Salt Lake City, Utah, and San Diego, California, from May 22, 2015, to January 31, 2019. Data were analyzed from June 27, 2020, to October 20, 2020. Participants recruited through the US Department of Veterans Affairs (N = 132) with clinical and radiographic evidence of early knee OA were randomly assigned to receive PLIUS or a sham device, self-administered for 20 minutes daily over the medial compartment of the knee. All enrollees participated in a 4-week prerandomization sham run-in period, followed by a 48-week treatment period. Randomization was stratified by study site and Kellgren-Lawrence grades 1 (n = 15), 2 (n = 51), and 3 (n = 66). Intervention: Participants either received 48 weeks of PLIUS or sham ultrasonography. Main Outcomes and Measures: The trial incorporated 2 coprimary outcomes: symptomatic improvement assessed by Outcome Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society International Responder Criteria (ie, met if either >50% improvement in pain and function with at least a 20% absolute improvement of at least 2 of the following 3 factors: improvement by at least 20% [pain, function, and patient global assessment] with at least a 10-mm absolute improvement), and cartilage preservation assessed as change in central medial femoral condyle cartilage thickness by magnetic resonance imaging. Intention-to-treat analysis was used. Results: The mean (SD) participant age was 63.6 (10.7) years and 119 were men (90.2%). The mean (SD) duration of OA symptoms was 13.4 (12.3) years. In the PLIUS group, 70.4% (95% CI, 58.2%-82.6%) of the participants experienced symptomatic improvement, compared with 67.3% (95% CI, 54.9%-79.7%) of participants in the sham group (P = .84); there was no statistically significant difference in response rates between the treatment groups, and the between-group rate difference of 3.1% (95% CI, -14.3% to 20.5%) did not meet the predefined 10% threshold for clinically significant symptomatic improvement from application of PLIUS. At 48 weeks of treatment, central medial femoral condyle cartilage thickness decreased by a mean (SD) of 73.8 (168.1) µm in the PLIUS group and by 42.2 (297.0) µm in the sham group. This 48-week mean change between the 2 groups did not reach statistical significance (P = .44), and the between-group 48-week difference of -31.7 µm (95% CI, -129.0 µm to 65.7 µm) did not meet the predefined threshold. There were 99 nonserious adverse events in the PLIUS group and 89 in the sham group during the trial. No serious adverse events were deemed related to the study device. Conclusions and Relevance: PLIUS, as implemented in this study, demonstrated neither symptomatic benefit nor a decrease in loss of tibiofemoral cartilage thickness in knee OA. Trial Registration: ClinicalTrials.gov Identifier: NCT02034409.

A hyperactivating proinflammatory RIPK2 allele associated with early-onset osteoarthritis.

Osteoarthritis (OA) is a common debilitating disease characterized by abnormal remodeling of the cartilage and bone of the articular joint. Ameliorating therapeutics are lacking due to limited understanding of the molecular pathways affecting disease initiation and progression. Notably, although a link between inflammation and overt OA is well established, the role of inflammation as a driver of disease occurrence is highly disputed. We analyzed a family with dominant inheritance of early-onset OA and found that affected individuals harbored a rare variant allele encoding a significant amino acid change (p.Asn104Asp) in the kinase domain of receptor interacting protein kinase 2 (RIPK2), which transduces signals from activated bacterial peptidoglycan sensors through the NF-κB pathway to generate a proinflammatory immune response. Functional analyses of RIPK2 activity in zebrafish embryos indicated that the variant RIPK2104Asp protein is hyperactive in its signaling capacity, with augmented ability to activate the innate immune response and the NF-κB pathway and to promote upregulation of OA-associated genes. Further we show a second allele of RIPK2 linked to an inflammatory disease associated with arthritis also has enhanced activity stimulating the NF-κB pathway. Our studies reveal for the first time the inflammatory response can function as a gatekeeper risk factor for OA.

Work productivity loss and fatigue in psoriatic arthritis.

OBJECTIVE: To explore the relationship between fatigue and work productivity loss (WPL) in people with psoriatic arthritis (PsA). METHODS: Data were collected from participants in the Utah Psoriasis Initiative Arthritis registry between January 2010 and May 2013. WPL was measured with the 8-item Work Limitations Questionnaire. Fatigue was assessed with question 1 from the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI#1), "How would you describe the overall level of fatigue/tiredness you have experienced?" and with question 1 from the Psoriatic Arthritis Quality of Life Questionnaire (PsAQOL#1) "I feel tired whatever I do." Psoriatic activity was evaluated with tender joint count (TJC), swollen joint count (SJC), dactylitis count, enthesitis count, inflammatory back pain (IBP), physician global assessment, body surface area, and psoriasis pain and itch. RESULTS: Among 107 participants, work productivity was reduced by 6.7%, compared to benchmark employees without limitations. Fatigue was reported by 54 patients (50.5%) on PsAQOL#1, and 64 (60.0%) were classified as high fatigue by BASDAI#1. TJC, SJC, enthesitis count, IBP, and depressed mood were highest or most frequent in participants reporting fatigue. After adjustments for psoriatic activity and depressed mood, WPL was associated with fatigue, as measured by PsAQOL#1 (p = 0.01) and BASDAI#1 (p = 0.002). CONCLUSION: WPL was associated with fatigue, and the association was not entirely explained by the evaluated musculoskeletal, cutaneous, or psychiatric manifestations of PsA.

Autophagy is a key feature in the pathogenesis of systemic sclerosis.

Autophagosomes are formed during autophagy, which is activated by hypoxia and starvation. Autophagy is important for mast cell degranulation. We hypothesized that autophagy is a key feature in the pathogenesis of systemic sclerosis (SSc). We examined SSc clinical features and mast cell density across the presence and severity of autophagy. Skin punch biopsy was performed on 33 SSc patients and 6 healthy controls (HC). Autophagy was evaluated by immunofluorescence on paraffin sections using LC3-FITC staining on these patients. The intensity of staining and mast cell density was examined across clinical features in 19 of the SSc patients. Presence of autophagosome formation was assessed by EM in 17 of the SSc patients and 4 HC. In our SSc study population, 29 of subjects were female and 23 were limited cutaneous. Twenty-nine of 33 SSc patients had autophagy by LC3-FITC staining. Intensity of staining decreased with longer duration of SSc (p = 0.09) and RP (p = 0.10). Bloating and distention differed across level of intensity staining (Wilcoxon signed-rank test, p = 0.05), with the greatest levels among those with moderate intensity. On EM, autophagosome formation was present in 16 of 17 SSc patients and no HC. All SSc patients had perivascular mast cells. Autophagy was present in 29 of 33 SSc patients, and none of our HC suggesting importance in pathogenesis. Autophagy staining was greater among those with shorter duration of SSc. Bloating and distention were higher in patients with moderate autophagy staining. Perivascular mast cells were present in all SSc patients. The role of autophagy in vasculopathy and mast cell activation in SSc warrants further studies.

Nutraceuticals in the management of osteoarthritis : a critical review.

Osteoarthritis (OA) is a chronic, highly prevalent and disabling disease that is expected to increase in prevalence secondary to longer life expectancy and a disproportionately aging population. Treatment of OA is only marginally effective and has been focused primarily on symptom control using weight loss, physical therapy, nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, intra-articular steroids or viscosupplementation, topical NSAIDs and analgesics, diacerein (an oral interleukin-1ß inhibitor) and finally joint replacement surgery. The use of nutraceuticals in the treatment of OA is common, and scientific studies examining the effects of nutraceuticals on the pathogenesis and treatment of OA are increasing. This review examines the efficacy and safety of select nutraceuticals for the treatment of OA. The reviewed nutraceuticals include glucosamine, chondroitin, collagen hydrolysates (CHs) and avocado-soybean unsaponifiables (ASUs). There have been several clinical trials examining the efficacy of these products and the results demonstrate significant heterogeneity. Significant improvements in pain, function and structural outcomes have been shown for some of the treatment arms or subgroups of patients, but the effects are not consistent across the studies. Glucosamine, chondroitin and the two in combination have been the most extensively studied. Significant improvement in pain and functional indices and a decrease in the loss of joint space width were demonstrated in some but not all studies. CHs showed significant improvement in pain and functional indices for several subgroups of patients, but these findings were not pervasive amongst the treatment arms. ASU has demonstrated positive results with respect to decreased NSAID use in several studies and functional and pain end points in most of the reviewed studies; however, in the two studies examining structural end points, the results were mixed. The safety of these nutraceuticals has been demonstrated across all of the reviewed trials, and there were no significant issues with tolerance. Given the good safety profile of nutraceuticals, the marginal efficacy of conventional treatments, the high prevalence and rate of disability from OA and the possible benefit of nutraceuticals to patients with OA, use of nutraceuticals in select patients is appropriate. An overall recommendation to use nutraceuticals in the treatment of all patients with OA is not strongly supported by the available data. Future studies should focus on standardization of symptomatic and structural outcome measures, be of longer duration and pay careful attention to the content of the investigational product.

Vascular leak is a central feature in the pathogenesis of systemic sclerosis.

OBJECTIVE: The main histopathological focus of systemic sclerosis (SSc) has concentrated on fibrotic changes. We investigated the microvasculature alterations in the skin of patients with SSc at various stages of disease duration with whole-field digital microscopy. METHODS: Twenty consecutive patients with SSc, 1 with Raynaud's phenomenon (RP) without SSc, and 4 healthy controls underwent punch biopsy on the medial forearm. Eighteen patients were included in the primary analysis. Two with recent-onset diffuse cutaneous disease, 1 repeat SSc biopsy, and 1 patient with RP without SSc were also evaluated. All specimens were processed with histochemical stains and immunohistochemistry. We analyzed microvasculature abnormalities in an objective and systematic manner taking advantage of recent advances in whole-field digital microscopy. This analysis was coupled with ultrastructural evaluation performed with transmission electron microscopy (TEM). RESULTS: Whole-field digital microscopy and TEM of SSc skin biopsies revealed that endothelial abnormalities are a universal feature regardless of clinical features and/or duration of disease. These features were not seen in any healthy control specimens or in the single RP patient samples. Whole-field digital microscopy identified increased interstitial edema (31.0% ± 9.6% vs 17.6% ± 3.3% in controls; p = 0.009) and fibrosis (75.6% ± 5.7% vs 66.1% ± 9.8% in controls; p = 0.02) in all patients with SSc. Lower CD34 staining was seen in SSc compared to healthy controls (0.32% ± 0.22% vs 1.31% ± 0.34%; p < 0.0001) and within the SSc population with interstitial lung disease (0.55% ± 0.22% vs 0.15% ± 0.16%; p = 0.01). Perivascular and interstitial infiltrate of mast cells was present in all SSc specimens. CONCLUSION: Whole-field digital microscopy offers a means of rapidly carrying out objective, fully quantitative, and reproducible measurements of microscopic features of SSc microvascular change. The universal morphologically abnormal endothelial cells and interstitial edema in all patients with SSc biopsied suggests that SSc may be intrinsically a disease of the endothelium characterized by vascular leak.

The prevalence and clinical correlates of an auscultatory gap in systemic sclerosis patients.

Introduction. Accurate blood pressure (BP) measurement is essential to the diagnosis and management of hypertension in patients with systemic sclerosis (SSc) to help prevent renal and cardiovascular complications. The presence of an auscultatory gap during manual BP measurement-the temporary disappearance of the Korotkoff sounds during cuff deflation-leads to a potentially important underestimate of systolic BP if undetected. Objectives. Since the presence of an auscultatory gap is frequently associated with increased vascular stiffness, we investigated its presence and correlates in 50 consecutive SSc patients. Methods. For each patient, BP was measured sequentially using three different approaches performed in the same order. Results. Sixteen of 50 patients (32%) had an auscultatory gap which if undetected would have resulted in clinically important underestimates of systolic BP in 4 patients. The presence of an auscultatory gap was statistically associated with the presence of antibodies to RNA polymerase III (P<0.0068) and SSc diagnosis type (P<0.01). Conclusions. Our study demonstrates that auscultatory gaps are relatively common in SSc and correlate with markers for SSc vasculopathy. If undetected auscultatory gaps may result in clinically important underestimation of BP. Thus, electronic oscillometric BP may be preferred in SSc patients.

Low-dose naltrexone for pruritus in systemic sclerosis.

Pruritus is a common symptom in systemic sclerosis (SSc), an autoimmune disease which causes fibrosis and vasculopathy in skin, lung, and gastrointestinal tract (GIT). Unfortunately, pruritus has limited treatment options in this disease. Pilot trials of low-dose naltrexone hydrochloride (LDN) for pruritus, pain, and quality of life (QOL) in other GIT diseases have been successful. In this case series we report three patients that had significant improvement in pruritus and total GIT symptoms as measured by the 10-point faces scale and the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0) questionnaire. This small case series suggests LDN may be an effective, highly tolerable, and inexpensive treatment for pruritus and GIT symptoms in SSc.

Probiotics for the treatment of systemic sclerosis-associated gastrointestinal bloating/ distention.

OBJECTIVES: Treatment for gastrointestinal tract (GIT) disease in systemic sclerosis (SSc) is challenging as no immunosuppressive or anti-fibrotic therapy is available with clearly proven efficacy. Probiotics are viable, non-pathogenic microorganisms that are hypothesized to improve the composition of the intestinal microbiota from a potentially harmful composition to a composition that is beneficial to the host. Our hypothesis is that GIT symptoms in SSc patients with moderate bloating would improve with probiotic implementation. METHODS: Ten patients with a moderate-to-severe distention/bloating score (1.25-3.00) on the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0), but otherwise stable organ disease not requiring any medication adjustment were recruited from the University of Utah Scleroderma Center. We compared the GIT 2.0 scores at baseline and after 2 months of use of Align (bifidobacterium infantis; 109 CFU per capsule) or Culturelle (lactobacillus GG; 109 CFU per capsule) using paired t-test and calculated effect size (ES). RESULTS: Significant improvement in total GIT 2.0 score (ES = 0.82), reflux (ES = 0.33), bloating/distention (ES = 1.76), and emotional scales (ES = 0.18) were reported after two months of daily probiotic use. CONCLUSIONS: This pilot study suggests probiotics significantly improve the reflux, distention/ bloating, and total GIT scales in SSc patients. As hypothesized, the largest effect was seen in distention/bloating scale. Probiotics may be useful for treatment of SSc-associated distention/ bloating.

Enzyme-linked immunosorbent assay screening then indirect immunofluorescence confirmation of antinuclear antibodies: a statistical analysis.

The purpose of this study was to analyze antinuclear antibody (ANA) screening by enzyme-linked immunosorbent assay (ELISA) followed by indirect fluorescent antibody (IFA) testing to confirm and characterize the pattern and titer of the antibody. We evaluated 4 ANA ELISAs and 1 HEp-2 IFA substrate in 224 clinically defined serum samples consisting of 30 from systemic lupus erythematosus (SLE) cases, 94 from rheumatoid arthritis cases, and 100 from healthy donors plus 495 serum samples submitted for routine ANA testing and 12 reference serum samples distributed by the Centers for Disease Control and Prevention. IFA tests were read independently by 2 certified medical technologists. ELISA sensitivities ranged from 90% to 97% compared with 80% by IFA in the SLE serum samples. The ELISAs had specificities of 36% to 94%, whereas the IFA had 99% specificity. Overall, ELISAs for ANA assays demonstrated better sensitivity and good specificity, suggesting ELISA is a more cost-effective alternative to IFA testing for initial ANA screening. Samples positive by ANA ELISA should be tested on HEp-2 to determine the titer and pattern.

Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT.

BACKGROUND: Knee osteoarthritis (OA) is a major cause of pain and functional limitation in older adults, yet longer-term studies of medical treatment of OA are limited. OBJECTIVE: To evaluate the efficacy and safety of glucosamine and chondroitin sulphate (CS), alone or in combination, as well as celecoxib and placebo on painful knee OA over 2 years. METHODS: A 24-month, double-blind, placebo-controlled study, conducted at nine sites in the US ancillary to the Glucosamine/chondroitin Arthritis Intervention Trial, enrolled 662 patients with knee OA who satisfied radiographic criteria (Kellgren/Lawrence grade 2 or 3 changes and baseline joint space width of at least 2 mm). This subset continued to receive their randomised treatment: glucosamine 500 mg three times daily, CS 400 mg three times daily, the combination of glucosamine and CS, celecoxib 200 mg daily, or placebo over 24 months. The primary outcome was a 20% reduction in Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain over 24 months. Secondary outcomes included an Outcome Measures in Rheumatology/Osteoarthritis Research Society International response and change from baseline in WOMAC pain and function. RESULTS: Compared with placebo, the odds of achieving a 20% reduction in WOMAC pain were celecoxib: 1.21, glucosamine: 1.16, combination glucosamine/CS: 0.83 and CS alone: 0.69, and were not statistically significant. CONCLUSIONS: Over 2 years, no treatment achieved a clinically important difference in WOMAC pain or function as compared with placebo. However, glucosamine and celecoxib showed beneficial but not significant trends. Adverse reactions were similar among treatment groups and serious adverse events were rare for all treatments.

The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial.

OBJECTIVE: Osteoarthritis (OA) of the knee causes significant morbidity and current medical treatment is limited to symptom relief, while therapies able to slow structural damage remain elusive. This study was undertaken to evaluate the effect of glucosamine and chondroitin sulfate (CS), alone or in combination, as well as celecoxib and placebo on progressive loss of joint space width (JSW) in patients with knee OA. METHODS: A 24-month, double-blind, placebo-controlled study, conducted at 9 sites in the United States as part of the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), enrolled 572 patients with knee OA who satisfied radiographic criteria (Kellgren/Lawrence [K/L] grade 2 or grade 3 changes and JSW of at least 2 mm at baseline). Patients with primarily lateral compartment narrowing at any time point were excluded. Patients who had been randomized to 1 of the 5 groups in the GAIT continued to receive glucosamine 500 mg 3 times daily, CS 400 mg 3 times daily, the combination of glucosamine and CS, celecoxib 200 mg daily, or placebo over 24 months. The minimum medial tibiofemoral JSW was measured at baseline, 12 months, and 24 months. The primary outcome measure was the mean change in JSW from baseline. RESULTS: The mean JSW loss at 2 years in knees with OA in the placebo group, adjusted for design and clinical factors, was 0.166 mm. No statistically significant difference in mean JSW loss was observed in any treatment group compared with the placebo group. Treatment effects on K/L grade 2 knees, but not on K/L grade 3 knees, showed a trend toward improvement relative to the placebo group. The power of the study was diminished by the limited sample size, variance of JSW measurement, and a smaller than expected loss in JSW. CONCLUSION: At 2 years, no treatment achieved a predefined threshold of clinically important difference in JSW loss as compared with placebo. However, knees with K/L grade 2 radiographic OA appeared to have the greatest potential for modification by these treatments.

Abatacept and serious respiratory infections in patients with previous lung disease.

Abatacept is a biologic agent used in the treatment of rheumatoid arthritis, for which underlying chronic obstructive lung disease is listed as a precaution to its use due to concern for increased risk of respiratory adverse events. We describe two cases of severe respiratory complications affecting rheumatoid arthritis patients undergoing treatment with abatacept who had been previously diagnosed with underlying lung disease.

Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis.

BACKGROUND: Glucosamine and chondroitin sulfate are used to treat osteoarthritis. The multicenter, double-blind, placebo- and celecoxib-controlled Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) evaluated their efficacy and safety as a treatment for knee pain from osteoarthritis. METHODS: We randomly assigned 1583 patients with symptomatic knee osteoarthritis to receive 1500 mg of glucosamine daily, 1200 mg of chondroitin sulfate daily, both glucosamine and chondroitin sulfate, 200 mg of celecoxib daily, or placebo for 24 weeks. Up to 4000 mg of acetaminophen daily was allowed as rescue analgesia. Assignment was stratified according to the severity of knee pain (mild [N=1229] vs. moderate to severe [N=354]). The primary outcome measure was a 20 percent decrease in knee pain from baseline to week 24. RESULTS: The mean age of the patients was 59 years, and 64 percent were women. Overall, glucosamine and chondroitin sulfate were not significantly better than placebo in reducing knee pain by 20 percent. As compared with the rate of response to placebo (60.1 percent), the rate of response to glucosamine was 3.9 percentage points higher (P=0.30), the rate of response to chondroitin sulfate was 5.3 percentage points higher (P=0.17), and the rate of response to combined treatment was 6.5 percentage points higher (P=0.09). The rate of response in the celecoxib control group was 10.0 percentage points higher than that in the placebo control group (P=0.008). For patients with moderate-to-severe pain at baseline, the rate of response was significantly higher with combined therapy than with placebo (79.2 percent vs. 54.3 percent, P=0.002). Adverse events were mild, infrequent, and evenly distributed among the groups. CONCLUSIONS: Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee. Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain. (ClinicalTrials.gov number, NCT00032890.).