Hollis E. Krug

Reactive arthritis following culture-confirmed infections with bacterial enteric pathogens in Minnesota and Oregon: a population-based study

Objective: To describe the epidemiology and clinical spectrum of reactive arthritis (ReA) following culture-confirmed infection with bacterial enteric pathogens in a population-based study in the USA. Methods: We conducted telephone interviews of persons age >1 year with culture confirmed Campylobacter, Escherichia coli O157, Salmonella, Shigella and Yersinia infections reported to FoodNet (http://www.cdc.gov/FoodNet/) in Minnesota, USA and Oregon, USA between 2002 and 2004. Subjects with new onset joint pain, joint swelling, back pain, heel pain and morning stiffness lasting ⩾3 days within 8 weeks of culture (possible ReA) were invited to complete a detailed questionnaire and physical examination. Results: A total of 6379 culture-confirmed infections were reported; 70% completed screening interviews. Of these, 575 (13%) developed possible ReA; incidence was highest following Campylobacter (2.1/100 000) and Salmonella (1.4/100 000) infections. Risk was greater for females (relative risk (RR) 1.5, 95% CI, 1.3 to 1.7), adults (RR 2.5, 95% CI, 2.0 to 3.1) and subjects with severe acute illness (eg, fever, chills, headache, persistent diarrhoea). Risk was not associated with antibiotic use or human leukocyte antigen (HLA)-B27. A total of 54 (66%) of 82 subjects examined had confirmed ReA. Enthesitis was the most frequent finding; arthritis was less common. The estimated incidence of ReA following culture-confirmed Campylobacter, E coli O157, Salmonella, Shigella and Yersinia infections in Oregon was 0.6–3.1 cases/100 000. Conclusions: This is the first population-based study of ReA following infections due to bacterial enteric pathogens in the USA. These data will help determine the burden of illness due to these pathogens and inform clinicians about potential sequelae of these infections.

Finger dexterity and hand function: Effect of three commercial wrist extensor orthoses on patients with rheumatoid arthritis

OBJECTIVE To investigate the effect of 3 commercial wrist orthoses on finger dexterity and hand function of patients with rheumatoid arthritis (RA). METHODS Forty-two patients with definite RA participated in the cross-over study comparing 3 styles of commercial wrist orthoses. Finger dexterity and hand function of the dominant hand were assessed while splinted and unsplinted, at the initial session and after 1 week of intermittent orthosis use. Finger dexterity was assessed using two subtests from the Purdue Pegboard Test (Purdue) and hand function was assessed using the Jebsen-Taylor Hand Function Test (Jebsen-Taylor). RESULTS Both finger dexterity and hand function were reduced by splinting; men and women were affected similarly. There was no difference in finger dexterity or hand function afforded by the 3 orthoses. Results on both the Purdue and Jebsen-Taylor tests showed a significant learning effect across time. CONCLUSIONS The 3 commercial wrist orthoses studied reduce dexterity similarly and significantly. When commercial wrist orthoses are to be used during tasks that require maximum dexterity, this reduction should be weighed against the known benefits of splinting.

Pain Behavior Measures to Quantitate Joint Pain and Response to Neurotoxin Treatment in Murine Models of Arthritis

OBJECTIVE To evaluate the validity of newly developed pain behavior measures in two murine models of inflammatory arthritis and to determine the ability of these measures to evaluate the analgesic effectiveness of intra-articular (IA) botulinum toxin type A (BoNT/A) for treatment of arthritis pain. DESIGN Acute inflammatory arthritis was produced in adult female mice by IA injection of carrageenan and chronic inflammatory arthritis by IA injection of CFA. The presence of arthritis was confirmed by the presence of swelling and erythema. A menu of pain behavior measures was devised for quantitating pain in these models including tenderness, and spontaneous nocturnal wheel running. Toxicity due to neurotoxin was measured as gross limb weakness and impaired functional ability during wheel running. RESULTS Tenderness measures and spontaneous nocturnal wheel-running are valid measures of arthritis pain and are sensitive to the effects of analgesia. Narcotic analgesics are effective, but in fully analgesic doses impair wheel-running. IA BoNT/A is an effective analgesic for chronic arthritis pain, but not for acute arthritis pain. High doses can produce local limb muscle weakness, which impairs wheel-running function. Doses of botulinum toxin that are not toxic retain their analgesic function. CONCLUSIONS Tenderness and spontaneous pain behavior measures are valid and sensitive for the measurement of pain and analgesia in murine models of inflammatory arthritis. Effective narcotic analgesia produces a decline in function in mice similar to that seen in humans. IA neurotoxin is a promising therapy for chronic inflammatory arthritis but may not be effective for acute arthritis pain.

Analgesic effects of intra-articular botulinum toxin Type B in a murine model of chronic degenerative knee arthritis pain.

Objective: To evaluate the analgesic effectiveness of intra-articular botulinum toxin Type B (BoNT/B) in a murine model of chronic degenerative arthritis pain. Methods and materials: Chronic arthritis was produced in adult C57Bl6 mice by intra-articular injection of Type IV collagenase into the left knee. Following induction of arthritis, the treatment group received intra-articular BoNT/B. Arthritic control groups were treated with intra-articular normal saline or sham injections. Pain behavior testing was performed prior to arthritis, after induction of arthritis, and following treatments. Pain behavior measures included analysis of gait impairment (spontaneous pain behavior) and joint tenderness evaluation (evoked pain response). Strength was measured as ability to grasp and cling. Results: Visual gait analysis showed significant impairment of gait in arthritic mice that improved 43% after intra-articular BoNT/B, demonstrating a substantial articular analgesic effect. Joint tenderness, measured with evoked pain response scores, increased with arthritis induction and decreased 49.5% after intra-articular BoNT/B treatment. No improvement in visual gait scores or decrease in evoked pain response scores were found in the control groups receiving intra-articular normal saline or sham injections. Intra-articular BoNT/B was safe, and no systemic effects or limb weakness was noted. Conclusions: This study is the first report of intra-articular BoNT/B for analgesia in a murine model of arthritis pain. The results of this study validate prior work using intra-articular neurotoxins in murine models. Our findings show chronic degenerative arthritis pain can be quantitated in a murine model by measuring gait impairment using visual gait analysis scores (spontaneous pain behavior) and joint tenderness scores (evoked pain responses). Reduction of joint pain seen in this study is consistent with our hypothesis of inhibition of release of pain mediators by intra-articular BoNT/B, supporting further investigation of this novel approach to treatment of arthritis pain with intra-articular neurotoxins.

A comparison of DigiGait™ and TreadScan™ imaging systems: assessment of pain using gait analysis in murine monoarthritis

Purpose Carrageenan-induced arthritis is a painful acute arthritis model that is simple to induce, with peak pain and inflammation occurring at about 3 hours. This arthritis model can be evaluated using semiquantitative evoked or non-evoked pain scoring systems. These measures are subjective and are often time- and labor-intensive. It would be beneficial to utilize quantitative, nonsubjective evaluations of pain with rapid assessment tools. We sought to compare the DigiGait™ and TreadScan™ systems and to validate the two gait analysis platforms for detection of carrageenan-induced monoarthritis pain and analgesic response through changes in gait behavior. Methods Non-arthritic mice and carrageenan-induced arthritic mice with and without analgesia were examined. A painful arthritic knee was produced by injection of 3% carrageenan into the knee joint of adult mice. Analgesic-treated mice were injected subcutaneously with 0.015 mg/mL (0.5 mg/kg) buprenorphine. Five-second videos were captured on the DigiGait™ or TreadScan™ system and, after calculating gait parameters, were compared using student’s unpaired t-test. Results We found the DigiGait™ system consistently measured significantly longer stride measures (swing time, stance time, and stride time) than did TreadScan™. Both systems’ measures of variability were equal. Reproducibility was inconsistent on both systems. While both systems detected alterations in some gait measures after carrageenan injection, none of the alterations were seen with both systems. Only the TreadScan™ detected normalization of gait measures after analgesia, but the system could not detect normalization across all measures that altered due to arthritis pain. Time spent on analysis was dependent on operator experience. Conclusion Neither the DigiGait™ nor TreadScan™ system was useful for measuring changes in pain behaviors or analgesic responses in acute inflammatory monoarthritic mice.

Tolerability and efficacy of Nabumetone and naproxen in the treatment of rheumatoid arthritis

OBJECTIVE The purpose of this study was to compare the tolerability and efficacy of nabumetone and naproxen in the treatment of patients with rheumatoid arthritis (RA). The occurrence of gastrointestinal (GI) adverse events was compared. BACKGROUND Nonsteroidal anti-inflammatory drugs (NSAIDs) have similar efficacy at equipotent doses, but the therapeutic response to various NSAIDs often differs in individual patients. METHODS This was a 3-month, randomized, double-blind, multicenter, parallel-group study conducted in adult patients with RA. The study had 2 phases: a 3- to 14-day washout period and a 12-week treatment period. During the treatment phase, the tolerability and efficacy of nabumetone 2000 mg/d were compared with those of naproxen 1000 mg/d. The change from baseline in efficacy variables, including global assessments, number of tender or swollen joints, and pain, was evaluated. The study was sized to provide an 80% power to detect a 15% difference in the percentage improvement on the physicians global assessment (alpha = 0.05). GI safety was assessed by monitoring the occurrence of clinically important adverse GI events. RESULTS A total of 346 RA patients at 31 US rheumatology centers were randomly assigned to treatment (173 patients per group). The study population was predominantly white (87.0%) and female (70.5%), with a mean age of 54 years. Both treatments improved the signs and symptoms of RA, with no statistically significant differences between groups for any efficacy variables. No serious GI adverse events occurred with either NSAID. The most frequent treatment-related adverse events in both groups were predominantly GI in origin, as were those that resulted in withdrawal from the study. Diarrhea with lower abdominal pain was the most common adverse event in the nabumetone group; upper abdominal pain was the most common adverse event in the naproxen group. The only significant difference between the 2 groups was a higher incidence of diarrhea (P < 0.01) in patients receiving nabumetone. CONCLUSIONS Nabumetone 2000 mg/d was as effective as naproxen 1000 mg/d in relieving the signs and symptoms of RA. In this study, no serious GI adverse events were observed with either NSAID, but nabumetone was associated with a higher incidence of diarrhea.

The importance of identifying depression in patients with rheumatoid arthritis: evaluation of the beck depression inventory.

Depression is common in patients with chronic illness including rheumatoid arthritis (RA). Identifying depression accurately and treating it appropriately are important for helping to maintain function in patients with RA. Several self-administered screening tools are available that are sensitive for the detection of depression in medical outpatients and are easy to use in a clinic setting. There has been debate regarding the validity of some of these tools for detecting depression in RA patients because of “arthritis-biased” questions. In this study, we evaluated 77 patients with RA and measured their responses to one of these screening tools, the Beck Depression Inventory (BDI). We compared disease activity and severity measures and measures of functional status between patients who were designated as depressed by BDI score and patients without depressive symptoms.We were unable to demonstrate differences in specific objective measures of disease activity, severity, or objective functional measures between nondepressed and depressed RA patients. However, depressed patients reported greater disease activity and poorer physical function, and observer global assessment of depressed patients was poorer. We conclude that the “arthritis-biased” questions in the BDI did not interfere with the detection of depression in patients with RA and should not be a deterrent for its use. We found that the BDI can be used effectively in a clinic setting as a screening tool for depression in patients with RA.

The effect of intra-articular vanilloid receptor agonists on pain behavior measures in a murine model of acute monoarthritis.

Arthritis is the most common cause of disability in the US, and the primary manifestation of arthritis is joint pain that leads to progressive physical limitation, disability, morbidity, and increased health care utilization. Capsaicin (CAP) is a vanilloid agonist that causes substance P depletion by interacting with vanilloid receptor transient receptor potential V1 on small unmyelinated C fibers. It has been used topically for analgesia in osteoarthritis with variable success. Resiniferatoxin (RTX) is an ultra potent CAP analog. The aim of this study was to measure the analgesic effects of intra-articular (IA) administration of CAP and RTX in experimental acute inflammatory arthritis in mice. Evoked pain score (EPS) and a dynamic weight bearing (DWB) device were used to measure nociceptive behaviors in a murine model of acute inflammatory monoarthritis. A total of 56 C57B16 male mice underwent EPS and DWB testing – 24 nonarthritic controls and 32 mice with carrageenan-induced arthritis. The effects of pretreatment with 0.1% CAP, 0.0003% RTX, or 0.001% RTX were measured. Nociception was reproducibly demonstrated by increased EPS and reduced DWB measures in the affected limb of arthritic mice. Pretreatment with 0.001% RTX resulted in statistically significant improvement in EPS and DWB measures when compared with those observed in carrageenan-induced arthritis animals. Pretreatment with IA 0.0003% RTX and IA 0.01% CAP resulted in improvement in some but not all of these measures. The remaining 24 mice underwent evaluation following treatment with 0.1% CAP, 0.0003% RTX, or 0.001% RTX, and the results obtained were similar to that of naïve, nonarthritic mice.