Effects of one-year tofacitinib therapy on bone metabolism in rheumatoid arthritis.

Janus kinase (JAK) inhibitors are used to treat rheumatoid arthritis (RA). We assessed the effects of tofacitinib on bone density and bone markers in association with clinical and laboratory parameters in RA. Tofacitinib stabilized bone density and resulted in a positive balance of bone turnover. INTRODUCTION: Janus kinase (JAK) inhibitors emerged as new therapeutic options in rheumatoid arthritis (RA). We have little information on how it affects areal and volumetric bone mineral density (BMD) and bone turnover markers. The aim of this study was to assess the effects of 1-year tofacitinib therapy on bone metabolism in RA. METHODS: Thirty RA patients with active disease were treated with either 5 mg bid or 10 mg bid tofacitinib for 12 months. We determined DAS28, CRP, IgM rheumatoid factor (RF), and anti-cyclic citrullinated peptide (CCP) levels, as well as serum levels of sclerostin, osteocalcin (OC), P1NP, DKK-1, OPG, RANKL, and 25-hydroxy-vitamin D3. Areal and volumetric BMD were assessed by DXA and peripheral quantitative CT (QCT), respectively. RESULTS: Twenty-six patients (13 on each arm) completed the study. Tofacitinib was clinically effective by suppressing DAS28, CRP, and HAQ. This was accompanied by the attenuation of further bone loss. Tofacitinib therapy significantly increased OC, OPG, and vitamin D3, while decreased CTX levels (p < 0.05). Age and multiple bone markers (OC, CTX, P1NP, RANKL) inversely correlated with L2-4 and femoral neck BMD by DXA. CRP, DAS28, and RANKL inversely determined volumetric BMD by QCT. Age, CRP, anti-CCP, and DKK-1 influenced the effects of tofacitinib therapy on BMD changes. CONCLUSIONS: One-year tofacitinib treatment stabilized BMD in RA patients and resulted in a positive balance of bone turnover as indicated by bone biomarkers. Further studies are needed to evaluate the potential beneficial effects of JAK inhibitors on inflammatory bone loss.

Comparison of peripheral quantitative computed tomography forearm bone density versus DXA in rheumatoid arthritis patients and controls.

Rheumatoid arthritis (RA) has been associated with osteoporosis. Quantitative computed tomography (QCT) is capable of assessing bone density and composition. We found lower bone density in RA compared to controls. Age and RA duration influenced bone density. QCT may be useful to assess bone metabolism in RA. INTRODUCTION: RA is associated with generalized and periarticular osteoporosis. In addition to DXA that determines areal bone mineral density (BMD), peripheral QCT also detects volumetric BMD. QCT differentiates between total, trabecular, and cortical BMD. Here, we compared DXA and QCT in RA patients and healthy controls. METHODS: BMD of 57 female RA patients and 32 age-matched healthy female controls were assessed by DXA. QCT of the forearm ultradistal region was also performed. Densitometry data were correlated with age, disease duration, disease activity, serum CRP, and anti-CCP levels. RESULTS: Total bone density (310.4 ± 79.7 versus 354.0 ± 54.1 mg/cm3; p = 0.007) and attenuation (0.37 ± 0.05 versus 0.40 ± 0.03 1/cm; p = 0.001), trabecular density (157.6 ± 57.0 versus 193.8 ± 48.7 mg/cm3; p = 0.005) and attenuation (0.28 ± 0.03 versus 0.32 ± 0.04 1/cm; p < 0.0001), and cortical density (434.3 ± 115.8 versus 492.5 ± 64.0 mg/cm3; p = 0.006) and attenuation (0.44 ± 0.07 versus 0.47 ± 0.04 1/cm; p = 0.004) were significantly lower in RA. Both lumbar and femoral neck BMD, as well as T-scores, were significantly lower in RA versus controls (p < 0.001 in all cases). In RA, total and cortical QCT attenuation and density were associated with age, the presence of RA, and their combination. In contrast, trabecular density and attenuation were only affected by the presence of the disease but not by age. Also in RA, total trabecular and cortical density as determined by QCT significantly correlated with lumbar and/or femoral neck BMD as measured by DXA. Finally, anti-CCP seropositivity was associated with lower trabecular density and attenuation. CONCLUSIONS: Both DXA and QCT may be suitable to study bone metabolism in RA. Areal BMD determined by DXA may correlate with volumetric bone density measured by QCT. Moreover, trabecular osteoporosis may be associated by the underlying autoimmune-inflammatory disease, while cortical osteoporosis may rather be age-related.

Treatment of ankylosing spondylitis with biologics and targeted physical therapy: positive effect on chest pain, diminished chest mobility, and respiratory function.

OBJECTIVE: Biologics are highly effective in ankylosing spondylitis (AS). In this self-controlled study, we assessed the additive value of complex physiotherapy in decreasing chest pain and tenderness and improving respiratory function in AS patients treated with tumor necrosis factor α (TNF-α) inhibitors. PATIENTS AND METHODS: The trial consisted of 2 parts. In study I, clinical data of AS patients with (n=55) or without biological therapy (n=20) were retrospectively analyzed and compared. Anthropometrical data, duration since diagnosis and patient assessment of disease activity, pain intensity, tender points, sacroiliac joint involvement determined by X-ray, functional condition, and physical activity level were recorded. Subjective, functional, and physical tests were performed. In study II, 10 voluntary patients (6 men and 4 women, age 52.4 ± 13.6 years) with definite AS and receiving anti-TNF therapy were recruited. It was a prospective, non-randomized physiotherapeutic trial. BASFI (Bath Ankylosing Spondylitis Functional Index), BASDAI (Bath Ankylosing Spondylitis Disease Activity Index), modified Schober Index, occiput-to-wall distance, and fingertip-to-floor distance were evaluated. Forced vital capacity, forced 1-s expiratory volume, peak expiratory flow, and maximum voluntary ventilation were recorded. Furthermore, typical tender points were recorded. A targeted physiotherapy program was conducted twice a week for 12 weeks and all above parameters were recorded at baseline and after 12 weeks. RESULTS: Differences in patient assessment of disease activity (p=0.019) and pain intensity (p=0.017) were found in study I. Pain and tenderness of the thoracic spine were observed in both groups. Back pain without biologic therapy was slightly higher than other group. In study II, we found that patient assessment of disease activity and pain intensity significantly improved after the physical therapy program (p=0.002 and p<0.001). BASFI and BASDAI increased after treatment (p=0.004 and p<0.001). The finger-to-floor distance, chest expansion, and modified Schober index increased (p=0.008, p<0.001, and p=0.031, respectively). The respiratory functional parameters showed a tendency towards improvement. CONCLUSION: AS patients already receiving biological therapy may benefit from additional targeted physiotherapy. Physical therapy may be of important additive value in AS patients being treated with biological. The exercise program presented here showed an improvement in functional parameters as well as spine and chest mobility, thereby enhancing the favorable effects of biological therapy.

Efficacy of etanercept on rheumatic signs and pulmonary function tests in advanced ankylosing spondylitis: results of a randomised double-blind placebo-controlled study (SPINE).

OBJECTIVES: Patients with advanced ankylosing spondylitis (AS) experience disability because of reduced spinal mobility and pulmonary function impairment. This placebo-controlled study evaluated the effect of etanercept (ETN) in patients with advanced AS. METHODS: A multicentre randomised double-blind placebo-controlled trial of 12 weeks' duration was performed. Patients had definite (modified New York criteria), active (Bath AS Disease Activity Index (BASDAI) ≥40), severe (radiological intervertebral bridges) AS refractory to non-steroidal anti-inflammatory drugs and were antitumour necrosis factor naive. They were treated with ETN 50 mg once weekly or identical placebo (PBO). RESULTS: Of the 95 patients screened, 82 were randomised to receive ETN (n=39) or PBO (n=43). At baseline the disease was active (mean BASDAI 61.0±13.4, C reactive protein (CRP) 20.7±25.5 mg/l) and severe (mean Bath AS Metrology Index (BASMI) 5.7±1.3, mSASSS 36.5±20.5); forced pulmonary vital capacity (FVC) was 3.3±0.7 l. Improvement in BASDAI (normalised net incremental area under the curve between baseline and week 12, primary end point) was significantly greater in the ETN group than in the PBO group (-19.8±16.5 vs -11.0±16.4, p=0.019). Moreover, at week 12, ETN gave better results than PBO for the BASDAI (-26.4±19.7 vs -14.4±19.7; p=0.008), total back pain (-29.2±24.0 vs -14.9±24.0; p=0.010), BASFI (-21.7±17.6 vs -10.1±17.6; p=0.004), BASMI (-0.6±0.6 vs -0.2±0.6; p=0.011), CRP level (-15.7±14.2 vs -1.3±14.2; p<0.001) and FVC (+160±280 ml vs -20±280 ml; p=0.006). CONCLUSIONS: ETN has short-term efficacy for patients with advanced AS, as was previously reported for less advanced disease. The efficacy is observed for the main symptoms (pain) and on markers of inflammation (CRP), as well as disease severity in terms of spinal mobility and pulmonary function.

Comparison of the Psoriatic Arthritis Quality of Life (PsAQoL) questionnaire, the functional status (HAQ) and utility (EQ-5D) measures in psoriatic arthritis: results from a cross-sectional survey.

OBJECTIVES: To compare the Psoriatic Arthritis Quality of Life (PsAQoL) instrument, the Health Assessment Questionnaire (HAQ) as a measure of functional status, and the generic health status (utility) measure the EuroQoL (EQ-5D) in terms of ability to assess disease severity in psoriatic arthritis (PsA). METHODS: The differences between known groups and correlations of the PsAQoL, the HAQ and the EQ-5D with clinical measures were analysed in a sample of 183 PsA patients. RESULTS: Different severities of PsA determined by known groups were distinguished well by all three questionnaires; more severe disease was associated with significantly worse values of the instruments. The correlations revealed a strong relationship between each of the measures, and with the patients' pain on the visual analogue scale (VAS), the patient global VAS, and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and a weak relationship with the disease duration and the Psoriasis Area Severity Index (PASI). The PsAQoL also correlated strongly with the 28-joint Disease Activity Score (DAS28). CONCLUSIONS: The PsAQoL, the HAQ, and the EQ-5D are able to distinguish well across levels of PsA severity.

Systemic sclerosis-rheumatoid arthritis overlap syndrome: a unique combination of features suggests a distinct genetic, serological and clinical entity.

OBJECTIVE: To determine the genetic, clinical and serological characteristics of systemic sclerosis (SSc)-rheumatoid arthritis (RA) overlap syndrome. METHODS: Clinical manifestations and immunolaboratory features of 22 SSc-RA patients were assessed. The HLA-DR genotype of the 22 SSc-RA patients determined by SSP-PCR was compared with that of 38 SSc patients, 100 RA patients and 50 healthy controls. RESULTS: All overlap patients fulfilled the American College of Rheumatology (ACR) criteria for SSc and RA. Five of the 22 patients (23%) had diffuse cutaneous SSc (dcSSc) and 17 patients (77%) had limited cutaneous SSc (lcSSc). Antinuclear antibody, anti-Scl70, IgM rheumatoid factor and anti-CCP antibody positivity were detected in 22 (100%), 5 (23%), 16 (73%) and 18 patients (82%), respectively. Seventeen patients (77%) had pulmonary fibrosis, 12 (55%) had oesophageal dismotility, 11 (50%) had cardiac and five (23%) had renal involvement. Hand joint destruction was observed in 18 patients (82%). Significantly increased frequencies of HLA-DR3 (36% vs 5%), HLA-DR7 (9% vs 4%), HLA-DR11 (36% vs 7%) and HLA-DRw53 (23% vs 5%) were observed in SSc-RA compared with RA patients (P < 0.05). Allele frequencies of the 'shared epitope' (HLA-DR1 and -DR4) were significantly increased in SSc-RA (32% and 27%, respectively) and RA patients (46% and 31%, respectively) in comparison with SSc patients (10.5% and 16%, respectively) or healthy controls (16% and 14%, respectively) (P < 0.05). CONCLUSIONS: To date this is the largest SSc-RA overlap cohort. Genetics, clinical and immunolaboratory features suggest a mixed phenotype. Our data suggest that SSc-RA overlap syndrome may be a distinct genetic, immunological and clinical entity.

Adenosine inhibits the release of arachidonic acid and its metabolites (AAM) in activated human peripheral mononuclear cells.

OBJECTIVE: The effects of adenosine (Ado) and subtype-specific activators of adenosine receptors (A(1), A(2A), A(2B) and A(3)) were studied on the release of arachidonic acid (AA) and its metabolites (AAM) from human peripheral mononuclear cells (monocytes). MATERIALS AND METHOD: Adenosine and the selective agonists and antagonists of adenosine receptors were used. (3)H-AA and its metabolites released into the medium were determined by measurement of the total (3)H radioactivity released without separating the AAM. RESULTS: In the cells activated by protein kinase C specific phorbol ester (phorbol 12-myristate 13-acetate) and Ca(2+) ionophore (A23187), adenosine and two subtype-specific receptor agonists, CPA(A(1)) and CGS 21680 (A(2A)) induced concentration-dependent inhibition of the release of AAM, whereas stimulation of A(2B) or A(3) receptors was ineffective. The rank order of potency for the inhibition of AAM release was as follows: CGS 21680 = CPA > adenosine > NECA (in the presence of ZM 24185 and DPCPX as A(2A) and A(1) adenosine receptor antagonists, respectively) = IB-MECA. Adenosine inhibited the release of AAM only at and above the concentration of 100 muM, whereas the inhibitory effect of A(1) and A(2A) receptor specific agonists appeared at a concentration of 10(-7) M. CONCLUSIONS: It can be concluded that adenosine physiologically may not have a significant effect on the AAM release of circulating monocytes, but in pathological conditions, where the local Ado concentrations increases, this nucleoside, through activation of A(2A) and A(1) receptors can exert, at least in part, an antiinflammatory action by decreasing proinflammatory AAM production.

Disease-associated qualitative and quantitative trait loci in proteoglycan-induced arthritis and collagen-induced arthritis.

Two autoimmune murine models--proteoglycan (aggrecan)-induced arthritis (PGIA) and collagen-induced arthritis (CIA)--were developed in parent strains, F1 and F2 hybrids of major histocompatibility complex (MHC)-matched (H-2) BALB/c x DBA/2 and MHC-unmatched (H-2/H-2) BALB/c x DBA/1 intercrosses. The major goal of this comparative study was to identify disease (model)-specific (PGIA or CIA) and shared clinical and immunologic loci in 2 types of genetic intercrosses. Qualitative (binary/susceptibility) and quantitative (severity and onset) clinical trait loci were separated and analyzed independently or together with various pathophysiologic/immunologic traits, such as antigen-specific T- and B-cell responses and cytokine production. The major quantitative trait locus (QTL) was the MHC on chromosome 17, which was especially dominant in CIA. In addition, chromosomes 3, 5, 10, and X contained shared clinical loci in both models, and a total of 8 QTLs (clinical traits together with immunologic traits) were colocalized in PGIA and CIA.

Decreased arachidonic acid release in peripheral blood monocytes of patients with systemic lupus erythematosus.

OBJECTIVE: To investigate the release of arachidonic acid (AA) in unfractionated peripheral blood mononuclear cells (PBMC), separated monocytes and T lymphocytes of patients with systemic lupus erythematosus (SLE). METHODS: AA release was measured in cells from 56 patients with SLE and from 48 controls. Of the 56 patients with SLE, 38 were receiving glucocorticosteroids and 18 were not. [3H]AA was incorporated into the membranes of PBMC and purified subsets of monocytes and T lymphocytes. The release of [3H]AA was measured both in nonstimulated cells cultured for 24 h and in cell cultures stimulated by phorbol ester (PMA) and Ca2+ ionophore for 4 h. RESULTS: In the PBMC of SLE patients not taking glucocorticosteroids, the release of AA was decreased in both stimulated and nonstimulated cells. There was a decrease of AA production in monocytes but not in T lymphocytes. This phenomenon could be observed in the active and inactive phases of the disease. CONCLUSION: A defect in AA production may exist in the peripheral monocytes of patients with SLE, resulting in decreased release of AA in patients not receiving glucocorticosteroid therapy.

Glucocorticosteroid dependent decrease in the activity of calcineurin in the peripheral blood mononuclear cells of patients with systemic lupus erythematosus.

OBJECTIVE: To compare the activity of calcineurin in the peripheral blood mononuclear cells (PBMC) of 32 patients with systemic lupus erythematosus (SLE) and 35 healthy controls. METHODS: The activity of calcineurin was assayed in the supernatants of sonicated mononuclear cells. RESULTS: There was no significant difference in the calcineurin activity of patients with SLE not taking glucocorticosteroids (GCS) compared with the healthy controls. On the other hand, the activity of calcineurin was reduced in patients with SLE taking GCS, correlating negatively with the dose of GCS. The stimulation of PBMC by phorbol ester and calcium ionophore decreased the calcineurin activity both in patients with SLE and in healthy controls. GCS could also reduce calcineurin activity in the mononuclear cells of healthy subjects in vitro. CONCLUSIONS: In patients with SLE the decrease in the calcineurin activity of PBMC depended on the dose of GCS used for treatment, and it was not a disease specific alteration. The higher the dose of GCS, the greater the inhibition of calcineurin activity. The reduction of calcineurin activity is a new element in the immunosuppressive effects of GCS during the treatment of patients with SLE.

Differences in the changes of allergen-specific IgE serum levels and the chemiluminescence of peripheral blood phagocytes in patients with allergic rhinoconjunctivitis during the ragweed season.

The objective of this study was to compare the changes in the values of allergen-specific serum IgE levels and zymosan-induced whole blood chemiluminescence (CL) in 41 patients who had exclusively only ragweed allergy in the season of acute symptoms of disease in July, August and September. All patients had allergic rhinitis or rhinoconjunctivitis. Each patient was investigated as a self-control. The ragweed-specific IgE levels were measured by enzyme immunoassay (EIA). The luminol amplified zymosan-induced CL of whole human blood was detected. The allergen-specific serum IgE levels showed slight, but not significant, gradually increasing elevations during the whole season. On the other hand, significant increases were found in the values of the basal but especially in the zymosan-stimulated CL of peripheral blood phagocytes during the acute phase of allergy. Both the basal and the zymosan-induced CL reflected significantly the activated state of the immune system. These observations clearly show that there are well detectable signs of the systemic activation of the immune system in allergic rhinoconjunctivitis beside the local alterations. In addition, the measurements of the basal and zymosan-induced CL of peripheral phagocytes could clearly reflect the clinical state of disease in vitro.

Inhibition of calcineurin activity and protection against cyclosporine A induced cytotoxicity by prednisolone sodium succinate in human peripheral mononuclear cells.

We have investigated the effects of prednisolone sodium succinate (Pss) and cyclosporin A (CSA), applied alone or concurrently, on the release of arachidonic acid (AA) (cytosolic phospholipase A(2) (cPLA(2)) activity) and on the calcineurin (CN) activity of human peripheral blood mononuclear cells (PBMC). The cytotoxic damage to the cells treated by the drugs was estimated by the release of lactate dehydrogenase (LDH). We found that Pss (10(-5) M) could inhibit the CN activity and higher concentrations (10(-4) M) could decrease the cytotoxic damage caused by CSA (10(-4) M) during their combined application. CSA had no specific effect on the release of AA from the cells. In the combined clinical use of glucocorticosteroids (GCS) and CSA, their additive inhibitory effect on CN activity and the protective membrane influence of GCS against the cytotoxicity of CSA may be beneficial.

ADP-ribosylation factor 6 regulates actin cytoskeleton remodeling in coordination with Rac1 and RhoA.

In this study, we have documented an essential role for ADP-ribosylation factor 6 (ARF6) in cell surface remodeling in response to physiological stimulus and in the down regulation of stress fiber formation. We demonstrate that the G-protein-coupled receptor agonist bombesin triggers the redistribution of ARF6- and Rac1-containing endosomal vesicles to the cell surface. This membrane redistribution was accompanied by cortical actin rearrangements and was inhibited by dominant negative ARF6, implying that bombesin is a physiological trigger of ARF6 activation. Furthermore, these studies provide a new model for bombesin-induced Rac1 activation that involves ARF6-regulated endosomal recycling. The bombesin-elicited translocation of vesicular ARF6 was mimicked by activated Galphaq and was partially inhibited by expression of RGS2, which down regulates Gq function. This suggests that Gq functions as an upstream regulator of ARF6 activation. The ARF6-induced peripheral cytoskeletal rearrangements were accompanied by a depletion of stress fibers. Moreover, cells expressing activated ARF6 resisted the formation of stress fibers induced by lysophosphatidic acid. We show that the ARF6-dependent inhibition of stress fiber formation was due to an inhibition of RhoA activation and was overcome by expression of a constitutively active RhoA mutant. The latter observations demonstrate that activation of ARF6 down regulates Rho signaling. Our findings underscore the potential roles of ARF6, Rac1, and RhoA in the coordinated regulation of cytoskeletal remodeling.

[Late results of Eggers' operation in spastic contracture of the knee]. / Az Eggers-mütét késöi eredményei spasztikus térdzsugorodásban.

Authors assess the late results of flexor tendon transplantation in spastic flexion contracture of the knee on the basis of the follow-up of 29 cases. It is stated that the method is suitable to eliminate the flexion contracture, however it is unable to cease the gait disturbance of the basic disease, as after the Eggers' operation patients walk characteristically with extended knees and a compensating increased lumbar lordosis. These unfavourable effects may be diminished by an individually planned, selective muscle transplantation performed after a careful preoperative clinical examination, motion analysis, perhaps also after an electromyographic examination.

[Late results of resection therapy of carcinoma of lung in patients of a department of respiratory diseases of a district (author's transl)]. / Spätresultate der Resektionsbehandlung des Lungenkarzinoms im Krankengut einer Bezirkslungenabteilung.

A report is given of the anti-cancer activity of the chest department of the XIV. District of Budapest. From 1962 to 1977 932 cancer cases were admitted; 315 of whom could be operated, the rate of resection being 33.8%. Among persons under the age of 70 this figure has been 43.7%. No selection being practised on admission this material deserves special interest. It also seemed suitable to give an answer to the question whether mass X-ray surveys had any effect on the 5 years survival rate of the patient.

Metabolic studies in physically outstanding elderly men.

Forty-seven elderly men engaged in regular and vigorous exercise had significantly lower plasma insulin levels during oral glucose tolerance tests than their controls. Pasma-glucose and growth-hormone levels showed no difference. However, when the glucose tolerance test was extended to four hours follow up, for which 19 subjects of each group volunteered, the control subjects showed a blunted post-suppression recovery of growth-hormone secretion in comparison to the athletic group. This difference could be explained by differences in hypothalamic control of the pituitary.