Effect of tocilizumab combined with methotrexate on circulating biomarkers of synovium,cartilage, and bone in the LITHE study

Objective

We investigated the effects of tocilizumab (TCZ) on joint tissue remodeling in patients with moderate to severely active RA by measuring tissue-specific biomarker.

Methods

The LITHE biomarker study (n = 740) was a phase III study of 4- and 8-mg/kg TCZ in combination with MTX. Early response was evaluated at week 16 as ±20% improvement in swollen/tender joint counts; and ACR50 was evaluated at week 52. Biomarkers (tissue inflammation: C3M, CRPM, and VICM; cartilage degradation: C2M; and bone turnover: CTx and osteocalcin) were tested in serum from baseline, week 4, 16, 24, and 52, and dose-dependent effect was investigated. Patients were divided into the following three groups: early non-responders (ENR), ACR50 responders, and non-responders; their biomarker profiles were compared.

Results

At week 52, CRP was inhibited to 4% and 40% of baseline by TCZ8 and TCZ4, respectively. CRPM (63%), C2M (84%), C3M (69%), and VICM (42%) were significantly (p < 0.05) reduced by TCZ8, but not by TCZ4. MMP3 and osteocalcin changed to <58% and >111%, respectively, in response to TCZ. CTx was not changed significantly. ENRs had significantly less inhibition of CRPM (p < 0.05), C2M (p < 0.01), and C3M (p < 0.01) compared to early responders. There was a significant difference in the C2M, C3M, and CRPM profiles of the ENRs, non-responders, and responders. ACR50 responders had significantly inhibited levels (p < 0.001), irrespective of dose.

Conclusions

TCZ8 strongly inhibited the biomarkers of joint tissue remodeling suggesting that TCZ actively suppresses key pathobiological processes at the site of inflammation in RA patients. The differences in biomarkers' profiles of responders and non-responders indicate that specific responder profiles exist.     

Health related utility measurement in rheumatology: an introduction

Utility measures of health-related quality of life are preference values that patients attach to their overall health status. In clinical trials, utility measures summarize both positive and negative effects of an intervention into one single value between 0 (equal to death) and 1 (equal to perfect health). These measures allow for comparison of patient outcomes of different diseases and allow for comparison between various health care interventions. There are two different approaches to utility measurement. The first is to classify patients into categories based on their responses to a number of questions about their functional status, as for instance the Quality of Well-Being questionnaire. The second approach is to ask patients to assign a single rating to their overall health by means of rating scale, standard gamble, time trade-off, or willingness to pay. The Quality Adjusted Life Year (QALY) as outcome measure includes both effects in terms of quality and quantity of life. Utilities are used as weights to adjust life years for the quality of life in order to calculate QALYs. Both QALYs and utilities are useful in decision-making regarding appropriate procedures for groups of patients.     

Articular involvement in human brucellosis: a retrospective analysis of 304 cases

Brucellosis is a zoonosis which in humans is caused by one of four species of the Brucella genus: B. melitensis, B. abortus, B. suis and B. canis. B. abortus is the species prevalent in North America and Europe and B. melitensis in most developing countries.Differences in disease manifestations may be accounted for either by differences in the species or by differences in the host. Articular involvement in brucellosis, although recognized since 1904, has been variably emphasized.Three hundred and four cases of human Brucellosis caused by B. melitensis, the prevalent species in Perú, were seen during a 12-yr period in one Lima hospital. Fever, malaise and hepatomegaly were the most frequent findings. Diagnosis was greatly improved when cultures were done in the biphasic Ruiz-Castañeda medium, rather than in trypticase soy broth. Serologie diagnosis is still important, and it should include standard tube testing, detection of IgG blocking antibodies and fractionation with 2-ME in chronic cases.The disease may take one of three courses: acute, (<8 wk), chronic (>8 wk) or undulant (periods of remissions and exacerbations). Four syndromes were recognized in a total of 33.8% of patients with Brucellosis. The most frequent pattern (in ~46.6% of patients with arthritis) was sacroiliitis, usually non-destructive and either uni-or bilateral. The second most frequent articular syndrome was peripheral arthritis (38.8%), manifested either as a single large lower extremity joint or as an asymmetric pauciarthritis. Rarely patients presented with a rheumatoidlike arthritis. Mixed arthritis (7.8%) was a combination of the first two. The above forms occurred in patients with an acute or undulant course. Spondylitis was the least common form of arthritis (6.8%), and differed significantly from the other forms of arthritis in the duration of symptoms (chronic course), age of patients (older individuals) and the paucity of fever and malaise. It also tended to be destructive.The arthritis usually resolved with the combined regimen of tetracycline (2 g p.o. for 21 days) and streptomycin (1 g i.m. for 21 days) without sequelae. Illustrative cases of these syndromes are presented.The relatively benign nature of most of the patients with brucellar arthritis lead us to postulate that they are for the most part reactive arthritides. Host factors are thought to be important in determining the response to the infection, but they are yet to be identified. Our own genetic studies have failed to identify an increased frequenty of B27 or CREG antigens in the patients with sacroiliitis. The demonstrations of circulating immune complexes in these patients however favors an immunopathogenic mechanism as responsible for some of the manifestations of this disease.     

Pathological anatomy in the teaching of rheumatology

Summary Whereas rheumatology regroups nosological entities, its teaching must be partly based on a presentation of the corresponding anatomopathological aspects which in fact are various patchworks made up of elementary, generally nonspecific lesions of osteoarticular pathology. Such an approach will provide an objective guideline between the needs of the practitioner (who often thinks in terms of morphology through radiological images) and the plethora of modern basic data. Thus the methods can be adapted to the needs of various audiences (medical students, specialists in training, paramedical personnel) and to every material and financial possibilities. In all cases it must be integrated with clinical and radiological lectures, based on macroscopic and radiological correlations and complemented, as far as possible, with appropriate histological images.     

Intrathecal IgG synthesis and blood-brain barrier impairment in patients with systemic lupus erythematosus and central nervous system dysfunction

Paired serum and cerebrospinal fluid specimens from 19 patients with SLE and central nervous system dysfunction were studied with respect to cerebrospinal fluid IgG index (a measure of intrathecal IgG synthesis), isoetectric focusing using immunoperoxidase staining techniques to detect ollgoclonal IgG, and determination of the cerebrospinal fluid/serum albumin quotient (Q albumin) as a measure of blood-brain barrier integrity. Twenty-five patients without neurologic disease and 70 patients with a variety of non-SLE neurologic disorders were also studied for comparison. Of most interest was the observation that 42 percent of the patients with SLE had cerebrospinal fluid ollgoclonal IgG, usually in association with elevation of the cerebrospinal fluid IgG index. In addition, two of the cerebrospinal fluid specimens that exhibited oligoclonal IgG also had increased titers of alpha-lnterferon. Q albumin was normal (under 9.0) in 12 of 13 patients with SLE, who had seizure, psychosis, or cranial neuropathy as principal central nervous system manifestations (mean ± SD = 5.3 ± 2.4), but was significantly elevated (mean ± SD = 27.4 ± 18.8, p < 0.001) in five of six patients with diffuse, major central nervous system injury, for example, encephalopathy with coma, transverse myetopathy, paraparesis. Blood-brain barrier impairment was not correlated either with presence of circulating immune complexes or with other clinical or serologic evidence for extra-central nervous system disease activity. Taken together, the data suggest that, within the limitations of the techniques used, impairment of the blood-brain barrier in SLE may be secondary to the central nervous system lesion, rather than a result of systemic immune complex injury. In addition, substantial evidence is provided for an ongoing humoral immune response within the central nervous system in this disorder, which, in certain patients, may be associated with the production of intrathecal alpha-interferon.     

Cryosectioning of undecalcified tissues for immunofluorescence.

The present report describes a procedure for preparing 4--6 micrometers cryostat sections of undecalcified fresh frozen tissue which contain hard tissue, for immunofluorescence. The apparatus used is a cryomicrotome originally designed for cutting sections for whole body autoradiography. To obtain cryostat sections suitable for tissue immunofluorescence the standard procedure was modified with respect to the hardness and edges of the microtome knife, the temperature of the cryostat and the carboxymethyl cellulose concentration of the embedding material.