Persistent pain and its predictors after starting anti-tumour necrosis factor therapy in psoriatic arthritis: what is the role of inflammation control?

OBJECTIVE: While considerable focus has been placed on pain due to inflammation in psoriatic arthritis (PsA), less is reported on pain despite inflammation control. Here, we aimed to investigate the occurrence/predictors of persistent pain, including non-inflammatory components, after starting anti-tumour necrosis factor (anti-TNF) therapy. METHOD: Bionaïve PsA patients starting a first anti-TNF therapy 2004-2010 were identified (South Swedish Arthritis Treatment Group register; N = 351). Outcomes included unacceptable pain [visual analogue scale (VAS) pain > 40 mm], and unacceptable pain despite inflammation control (refractory pain; VAS pain > 40 mm + C-reactive protein < 10 mg/L + ≤ 1 swollen joint of 28), assessed at 0, 3, 6, and 12 months. Baseline predictors were estimated by logistic regression. RESULTS: Upon starting anti-TNF therapy, 85% of patients reported unacceptable pain, falling to 43% at 3 months and then remaining stable. After 12 months, refractory pain constituted 63% of all unacceptable pain. Higher baseline VAS pain/global, worse physical function and lower health-related quality-of-life were associated with a higher risk of unacceptable/refractory pain at 12 months. More swollen joints and higher evaluator's global assessment were associated with a lower risk of 12-month refractory pain. CONCLUSIONS: A substantial proportion of PsA patients reported unacceptable pain throughout the first anti-TNF treatment year. At 12 months, refractory pain constituted about two-thirds of this remaining pain load. More objective signs of inflammation at anti-TNF initiation were associated with less future refractory pain. This highlights insufficient effect of biologics in patients with inflammation-independent pain, warranting alternative treatments.

Validity of clinical psoriatic arthritis diagnoses made by rheumatologists in the Swedish National Patient Register.

OBJECTIVES: : Knowledge of the correspondence between clinical ICD diagnoses and classification criteria fulfilment is crucial to interpret studies identifying cases via ICD codes. We assessed the degree to which patients registered with ICD-10 diagnoses of psoriatic arthritis (PsA) in the Swedish National Patient Register (NPR) fulfil established PsA classification criteria. METHOD: Four hundred patients with at least one outpatient visit to one of five rheumatology or internal medicine departments (three university/two county departments across Sweden) in 2013-2015, with a main ICD-10 diagnosis of PsA (L40.5, M07.0-M07.3), were randomly selected (80 cases/site). Through a structured medical record review, positive predictive values (PPVs) for fulfilment of the following classification criteria were assessed: CASPAR, Moll and Wright, Vasey and Espinoza, and modified ESSG criteria for PsA. A subset analysis regarding CASPAR fulfilment was also performed among cases with available rheumatoid factor and peripheral X-ray status (central CASPAR items; n = 227). RESULTS: Of the 400 patients with a main ICD-10 diagnosis of PsA, 343 (86%) fulfilled at least one of the four PsA classification criteria. PPVs for the different criteria were: CASPAR 69% (82% in the subset analysis), Moll and Wright 51%, Vasey and Espinoza 76%, and modified ESSG 64%. Overall, only 6.5% of the 400 PsA diagnoses were judged as clearly incorrect by the medical record reviewers. CONCLUSION: The validity of rheumatologist-made, clinical ICD-10 diagnoses for PsA in the Swedish NPR is good, with PPVs of 69-82% for CASPAR fulfilment and 86% for meeting any established PsA classification criteria.

Association of female sex and positive rheumatoid factor with low serum infliximab and anti-drug antibodies, related to treatment failure in early rheumatoid arthritis: results from the SWEFOT trial population.

Objective: Infliximab-treated patients with rheumatoid arthritis (RA) may respond insufficiently due to low serum infliximab (sIFX) levels, caused by anti-drug antibodies (ADAs). However, monitoring of sIFX and ADAs is not routinely implemented, and levels for optimal outcome have not been validated. We searched for predictors for sIFX < 0.2 µg/mL and ADA development in a randomized setting. Methods: In the SWEFOT trial, of 128 patients randomized to methotrexate + IFX therapy, 101 had serum samples at 3, 9, and 21 months that were analysed for sIFX [enzyme-linked immunosorbent assay (ELISA)] and ADAs [ELISA, and precipitation and acid dissociation (PandA) when sIFX > 0.2 µg/mL]. The primary and secondary outcome measures were low disease activity [LDA = 28-joint Disease Activity Score (DAS28) ≤ 3.2] and remission (DAS28 < 2.6). Baseline characteristics were assessed as potential predictors of sIFX < 0.2 µg/mL or ADA positivity, using logistic regression. Results: Categorization of sIFX levels into < 0.2, 0.2-2.9, 3.0-7.0, and > 7.0 µg/mL showed a dose-response association with LDA (30%, 64%, 67%, and 79%, respectively, p = 0.008) and remission (10%, 45%, 39%, and 66%, p = 0.004) at trial cessation (21 months). Female patients had sIFX < 0.2 µg/mL more often than males (35% vs 7%, p = 0.006), with a similar trend for rheumatoid factor (RF)-positive vs RF-negative patients (34% vs 16%, p = 0.059). ADA positivity showed similar patterns, also after adjustment for potential confounders (female sex: p = 0.050; RF positivity: p = 0.067). PandA captured four highly ADA-reactive patients with sIFX > 0.2 µg/mL, of whom three were ADA positive at other time-points, all with high DAS28 at follow-up. Conclusion: In early RA patients receiving IFX as a second-line agent, sIFX < 0.2 µg/mL and ADA development were associated with treatment failure and were more common in females, with a similar trend for RF positivity. Our findings support the use of therapeutic drug monitoring, and PandA in ADA-negative non-responders. Trial registration: SWEFOT NCT00764725 ( https://clinicaltrials.gov/ct2/show/NCT00764725 ).

What PASSes for good? Experience-based Swedish and hypothetical British EuroQol 5-Dimensions preference sets yield markedly different point estimates and patient acceptable symptom state cut-off values in chronic arthritis patients on TNF blockade.

OBJECTIVES: Health utilities derived from answers to generic health-related quality of life (HRQoL) questionnaires such as the EuroQol 5-Dimensions (EQ-5D) are often used in cost-utility analyses (CUAs) of new and expensive treatments. Different preference sets (tariffs) used in the computation of utility values and quality-adjusted life-years (QALYs) from questionnaire responses (health states) yield varying results, potentially affecting decisions of resource allocation. The objective of the present study was to compare British (UK), hypothetical, and Swedish (SE), experience-based, EQ-5D utilities using data from clinical practice. METHOD: UK and SE EQ-5D utilities were computed in an observational cohort of patients with rheumatoid arthritis (RA), spondyloarthritis (SpA), and psoriatic arthritis (PsA) treated with tumour necrosis factor (TNF) blockers, comparing point estimates and patient acceptable symptom state (PASS) cut-off levels. RESULTS: SE utilities were found to be consistently higher than UK utilities, and PASS cut-offs were essentially stable over time. CONCLUSIONS: With higher baseline utilities, there may be less room for improvement after an intervention and thus less accumulation of QALYs in CUAs applying the SE, as opposed to the UK, EQ-5D tariff.

Cranial CT of autosomal recessive osteopetrosis.

Eight infants with radiographic and bone biopsy evidence of autosomal recessive osteopetrosis were evaluated by cranial CT. The clinical presentations and CT characteristics support the theory that this disorder exhibits severe and mild variants. At an early stage the severe variant demonstrates small optic canals, small orbits with proptosis, and a small nasoethmoid complex without significant bone thickening. The paranasal sinuses show bud formation but no pneumatization. The temporal bone retains a fetal appearance with trumpet-shaped internal auditory canals, prominent subarcuate fossae, and no mastoid pneumatization. The ventricles and subarachnoid spaces are enlarged. Bone thickness increases with age, leading to further orbital encroachment. Similar but less severe features are present in the mild variant. Underdevelopment of the orbits, nasoethmoid complex, and temporal bone suggests that delayed maturation is the primary morphologic abnormality of the skull base in osteopetrosis, and that bone thickening is a secondary manifestation caused by reduced bone turnover.

Proton magnetic resonance studies of triethyltin-induced edema during perinatal brain development in rabbits.

To better understand the role of myelin-associated water in the differentiation of white and gray matter in magnetic resonance (MR) imaging, changes in MR relaxation processes were studied in rabbits during myelination and after induction of cytotoxic edema with triethyltin (TET). Normal rabbits were killed at various age intervals ranging from premature (28 days' gestation) to adult, and changes in MR relaxation times (T1 and T2) and in water and electrolyte content were determined for various areas of brain and muscle. Similar measurements were made in rabbits of comparable age exposed to TET. Light and electron microscopy and MR imaging were used to follow myelin development and morphological changes induced by TET. During the first 30 postnatal days, both T1 and T2 declined by 50% in normal rabbits, a fall that paralleled the loss in brain water and sodium that occurred during the same period. Exposure to TET prolonged T1 and T2 in white but not gray matter, reflecting the accumulation of sodium and water (edema fluid) in white matter areas. Multiexponential analysis revealed a second, longer component in T2 magnetization decay of TET-exposed white matter, presumably attributable to accumulation of non-ordered water within intramyelinic vacuoles, a supposition consistent with electron microscopic and MR imaging findings. In contrast to reports by others, changes in T1 (but not T2) closely correlated with alterations in brain water (r = 0.93, df = 39). The absence of tissue disruption in the animals in the present study may account for these differences, but further studies will be required both to resolve this question and to fully understand MR images of white matter edema in mature and immature brain.

Bilateral lucency of the globus pallidus complicating methylmalonic acidemia.

A child was seen because of encephalopathy and metabolic ketoacidosis at 19 months. She was found to have a cobalamin-responsive form of methylmalonic acidemia of the cbl A complementation group. However, after treatment with cyanocobalamin and a protein-restricted diet, with recovery from the encephalopathy, she was found to have a tremor and bilateral dystonic posturing in association with lucencies in the globus pallidi shown by computed tomographic scan.

Mapping of normal and abnormal cerebrospinal fluid flow/motion patterns using steady state free precession imaging.

In a comparative study more than 35 brain magnetic resonance imaging examinations were analyzed by mapping the CSF flow/motion pattern using the steady state free precession technique with two different flow sensitivity directions. Significant deviations from the normal pattern were seen in ventricular enlargements due to obstruction with no evidence of CSF flow/motion and in normal pressure hydrocephalus with complex flow pattern in lateral ventricles, suggesting a diagnostic potential for this fast imaging technique with sensitivity to very slow flow.

Subclinical brain swelling in children during treatment of diabetic ketoacidosis.

Clinically apparent cerebral edema is a rare and often fatal complication of diabetic ketoacidosis. To determine whether subclinical brain swelling occurs more commonly, we obtained cranial CT scans in six children with diabetic ketoacidosis treated with fluid resuscitation and continuous low-dose insulin therapy. Control scans were obtained before hospital discharge. Compared with the scans during convalescence, the early scans of all six children showed a narrowing of the brain's ventricular system, compatible with brain swelling. Average changes in diameter were 1.3 +/- 0.1 mm for the third ventricle and 3.7 +/- 0.8 mm for the lateral ventricles (P less than 0.01). In addition, a narrowing of the subarachnoid spaces was subjectively noted during a blind reading of the early scans. Although no single scan was overtly indicative of cerebral edema, the data suggest that subclinical brain swelling may be a common occurrence during treatment of diabetic ketoacidosis in children. Sequential CT scans of the brain may provide a means of evaluating modifications of standard therapy aimed at preventing cerebral edema.