Anti–tumor necrosis factor α blockade in the treatment of juvenile spondylarthropathy

Objective

Persistent inflammation refractory to standard antirheumatic therapy in children with juvenile spondylarthropathy (SpA) leads to morbidity and reduced quality of life. Tumor necrosis factor α (TNFα) plays an important role in the pathogenesis of synovitis and enthesitis. This study was undertaken to examine the impact of anti‐TNFα agents on juvenile SpA that is refractory to nonsteroidal antiinflammatory drugs (NSAIDs), disease‐modifying antirheumatic drugs, and corticosteroids.

Methods

Ten juvenile SpA patients with a mean ± SEM age of 15.0 ± 0.7 years and disease duration of 4.4 ± 0.8 years, all of whom were HLA–B27 positive, were followed up for 1 year after initiation of either infliximab (n = 8) or etanercept (n = 2). Outcomes examined were within‐subject differences in the tender entheseal count (TEC) and active joint count (AJC), markers of inflammation, functional assessments (Childhood Health Assessment Questionnaire [C‐HAQ] score), and requirements for antirheumatic drugs.

Results

At baseline, all patients exhibited active arthritis and enthesitis that were resistant to NSAIDs (n = 10), methotrexate (n = 6), sulfasalazine (n = 8), corticosteroids (oral n = 6, intravenous pulse n = 3, and intraarticular n = 6), and bisphosphonates (n = 2). In 2 patients, sulfasalazine (n = 2), corticosteroids (n = 1), and bisphosphonates (n = 1) were stopped after initiation of the anti‐TNFα agent. In all patients, the arthritis and enthesitis significantly improved as evidenced by remission of the TEC and AJC by 6 months that was sustained during the 1‐year followup, markers of inflammation and C‐HAQ scores normalized, and there was a reduction in requirements for antirheumatic drugs (reduced dosage or discontinuation of NSAIDs n = 10, methotrexate n = 5, sulfasalazine n = 6, corticosteroids n = 4, and bisphosphonates n = 1).

Conclusion

Anti‐TNFα therapy is a potential novel treatment for refractory juvenile SpA. Further prospective studies are required to examine the effectiveness and long‐term outcomes of anti‐TNFα therapy in this cohort.

     

Validity of self‐administered quality of well‐being scale in musculoskeletal disease

Objective

To evaluate the self‐administered Quality of Well‐Being (QWB‐SA) Scale for patients with rheumatic diseases.

Methods

Family medicine patients (n = 562) and rheumatology patients (n = 334) were assessed using the following tools: QWB‐SA, Health Assessment Questionnaire (HAQ), Arthritis Impact Measurement Scales (AIMS), and Rapid Assessment of Disease Activity in Rheumatology (RADAR).

Results

Patients with arthritis had significantly lower QWB‐SA scores and significantly higher HAQ scores than family medicine patients with and without adjustment for covariates. The QWB‐SA was significantly associated with quartiles from the RADAR, AIMS, and HAQ, providing evidence for the validity of the generic measure in patients with arthritis. Discriminant function analysis was used to create an arthritis‐specific scoring system for the QWB‐SA. Analyses demonstrated systematic relationships between the Quality of Well‐Being arthritis composite and the disease‐specific RADAR, AIMS, and HAQ.

Conclusions

Evidence supports the validity of the QWB‐SA for patients with rheumatic diseases. QWB‐SA items can be used to calculate an arthritis‐specific score. The QWB‐SA can be used to gain generic information for cost‐utility analysis and disease‐specific outcomes information for patients with arthritis.

     

Tumor necrosis factor α and RANKL blockade cannot halt bony spur formation in experimental inflammatory arthritis

Objective

To investigate the kinetics of bony spur formation and the relationship of bony spur formation to synovial inflammation and bone erosion in 2 rat arthritis models, and to address whether bony spur formation depends on the expression of tumor necrosis factor α (TNFα) or RANKL.

Methods

Analysis of the kinetics of synovial inflammation, bone erosion, osteoclast formation, and growth of bony spurs was performed in rat collagen‐induced arthritis (CIA) and adjuvant‐induced arthritis (AIA). In addition, inhibition experiments were performed to assess whether inhibition of TNFα and RANKL by pegylated soluble TNF receptor type I (pegTNFRI) and osteoprotegerin (OPG), respectively, affected bony spur formation.

Results

Bony spurs emerged from the periosteal surface close to joints, and initial proliferation of mesenchymal cells was noted as early as 3 days and 5 days after onset of CIA and AIA, respectively. Initiation of bony spur formation occurred shortly after the onset of inflammation and bone erosion. Neither pegTNFRI nor OPG could significantly halt the osteophytic responses in CIA and AIA.

Conclusion

These results suggest that bony spur formation is triggered by inflammation and initial structural damage in these rat models of inflammatory arthritis. Moreover, emergence of bony spurs depends on periosteal proliferation and is not affected by inhibition of either TNFα or RANKL. Bony spur formation can thus be considered a process that occurs independent of TNFα and RANKL and is triggered by destructive arthritis.

     

Demyelination occurring during anti–tumor necrosis factor α therapy for inflammatory arthritides

Objective

To review the occurrence of neurologic events suggestive of demyelination during anti–tumor necrosis factor α (anti‐TNFα) therapy for inflammatory arthritides.

Methods

The Adverse Events Reporting System of the Food and Drug Administration (FDA) was queried following a report of a patient with refractory rheumatoid arthritis who developed confusion and difficulty with walking after receiving etanercept for 4 months.

Results

Nineteen patients with similar neurologic events were identified from the FDA database, 17 following etanercept administration and 2 following infliximab administration for inflammatory arthritis. All neurologic events were temporally related to anti‐TNFα therapy, with partial or complete resolution on discontinuation. One patient exhibited a positive rechallenge phenomenon.

Conclusion

Further surveillance and studies are required to better define risk factors for and frequency of adverse events and their relationship to anti‐TNFα therapies. Until more long‐term safety data are available, consideration should be given to avoiding anti‐TNFα therapy in patients with preexisting multiple sclerosis and to discontinuing anti‐TNFα therapy immediately when new neurologic signs and symptoms occur, pending an appropriate evaluation.

     

Increased risk of coccidioidomycosis in patients treated with tumor necrosis factor α antagonists

Objective

To describe a group of patients who were treated with tumor necrosis factor α (TNFα) antagonists and who developed coccidioidomycosis, and to test the hypothesis that patients with inflammatory arthritis receiving TNFα antagonist therapy are at higher risk for developing symptomatic coccidioidomycosis.

Methods

Cases of coccidioidomycosis were identified and reviewed from among patients receiving TNFα antagonist therapy from May 1998 through February 2003 in 5 practices within the areas endemic for coccidioidomycosis (Arizona, California, and Nevada). In addition, the relative risk of developing symptomatic coccidioidomycosis was calculated in patients with inflammatory arthritis who were receiving treatment with infliximab, in comparison with patients with inflammatory arthritis who were not receiving infliximab, from January 2000 to February 2003 in a single medical center.

Results

Thirteen cases of documented coccidioidomycosis were associated with TNFα antagonist therapy. Twelve cases were associated with the use of infliximab and 1 case with etanercept. Among the cohort of patients from a single medical center, 7 of the 247 patients receiving infliximab and 4 of the 738 patients receiving other therapies developed symptomatic coccidioidomycosis (relative risk 5.23, 95% confidence interval 1.54–17.71; P < 0.01).

Conclusion

Patients with inflammatory arthritis who are undergoing treatment with infliximab appear to be at higher risk for developing symptomatic coccidioidomycosis as compared with those not receiving infliximab.

     

Stress activation of cellular markers of inflammation in rheumatoid arthritis: Protective effects of tumor necrosis factor α antagonists

Objective

Psychological stress is thought to aggravate disease activity in rheumatoid arthritis (RA), although the physiologic mechanisms are unclear. Tumor necrosis factor α (TNFα) is an inflammatory cytokine involved in the exacerbation of RA, and TNFα antagonists have emerged as efficacious treatments. The purpose of this study was to determine whether RA patients show increased monocyte production of TNFα following acute psychological stress and whether such responses are abrogated in RA patients taking TNFα antagonists.

Methods

A standardized stress task was administered to 3 groups of subjects: RA patients taking TNFα antagonists, RA patients not taking such medications, and healthy controls. Lipopolysaccharide‐stimulated monocyte production of inflammatory cytokines was repeatedly measured using intracellular staining and flow cytometry. Subjective stress, cardiovascular responses, adrenocorticotropic hormone (ACTH) levels, and cortisol levels were also measured.

Results

The stress task induced increases in subjective stress, cardiovascular activity, and levels of ACTH and cortisol, with similar responses in the 3 groups. In addition, the stress task induced a significant increase (P < 0.001) in monocyte production of TNFα among RA patients who were not taking TNFα antagonists. However, monocyte production of TNFα did not change following psychological stress in RA patients taking TNFα antagonists or in healthy controls.

Conclusion

Brief psychological stress can trigger increased stimulated monocyte production of TNFα in RA patients. The use of TNFα antagonists protects against stress activation of cellular markers of inflammation in RA patients.

     

Anti–tumor necrosis factor agents for rheumatoid arthritis in the setting of chronic hepatitis C infection

Objective

To examine the safety of using anti–tumor necrosis factor (TNF) therapy in patients with rheumatoid arthritis (RA) in the setting of hepatitis C virus (HCV) infection.

Methods

The charts of 5 patients known to have RA requiring anti‐TNF therapy as well as established HCV infection were reviewed retrospectively for laboratory data of hepatic parenchymal inflammation and viral proliferation while taking these agents.

Results

In a mean ± SD followup period of 41 months (± 28.2 months), no patient displayed evidence of sustained elevation of serum aminotransferases during therapy with anti‐TNF. Additionally, 1 patient was observed to have a decreased HCV viral load after extended treatment with only anti‐TNF (no therapy for HCV).

Conclusion

Anti‐TNF therapy for RA in the setting of HCV appears to be safe and well tolerated without apparent influence on the underlying HCV infection. Therefore, this approach should be further evaluated prospectively for longterm safety.

     

Antiinflammatory effects of tumor necrosis factor on hematopoietic cells in a murine model of erosive arthritis

Objective

To investigate the mechanisms leading to the influx of inflammatory hematopoietic cells into the synovial membrane and the role of tumor necrosis factor receptor I (TNFRI) and TNFRII in this process in an animal model of rheumatoid arthritis (RA).

Methods

We performed bone marrow transplantations in human TNF–transgenic mice using hematopoietic cells from wild‐type, TNFRI^−/−, TNFRII^−/−, and TNFRI/II^−/− mice as donors and assessed the severity of arthritis histologically. Generation of osteoclasts from the different genotypes was analyzed in vitro and in vivo. Apoptosis was analyzed using annexin V staining as well as TUNEL assays.

Results

Despite lacking responsiveness to TNF in their hematopoietic compartment, mice not only developed full‐blown erosive arthritis but even showed increased joint destruction when compared with mice with a TNF‐responsive hematopoietic compartment. We demonstrated different roles of the 2 different TNFRs in the regulation of these processes. The absence of TNFRI on hematopoietic cells did not affect joint inflammation but markedly attenuated erosive bone destruction via reduced synovial accumulation of osteoclast precursors. In contrast, the absence of TNFRII on hematopoietic cells increased joint inflammation as well as erosive bone destruction via the regulation of osteoclast precursor apoptosis.

Conclusion

Our findings indicate that selective blockade of TNFRI, leaving the antiinflammatory effects of TNFRII unaltered instead of unselectively blocking TNF, might be advantageous in patients with RA.

     

Tumor necrosis factor α inhibitor therapy and cancer risk in chronic immune‐mediated diseases

Objective

To compare the incidence of cancer following tumor necrosis factor α (TNFα) inhibitor therapy to that with commonly used alternative therapies across multiple immune‐mediated diseases.

Methods

The Safety Assessment of Biological Therapeutics study used data from 4 sources: national Medicaid and Medicare databases, Tennessee Medicaid, pharmacy benefits plans for Medicare beneficiaries in New Jersey and Pennsylvania, and Kaiser Permanente Northern California. Propensity score–adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) were computed to estimate the relative rates of cancer, comparing those treated with TNFα inhibitors to those treated with alternative disease‐modifying therapies. The cancer‐finding algorithm had a positive predictive value ranging from 31% for any leukemia to 89% for female breast cancer.

Results

We included 29,555 patients with rheumatoid arthritis (RA) (13,102 person‐years), 6,357 patients with inflammatory bowel disease (1,508 person‐years), 1,298 patients with psoriasis (371 person‐years), and 2,498 patients with psoriatic arthritis (618 person‐years). The incidence of any solid cancer was not elevated in RA (HR 0.80 [95% CI 0.59–1.08]), inflammatory bowel disease (HR 1.42 [95% CI 0.47–4.26]), psoriasis (HR 0.58 [95% CI 0.10–3.31]), or psoriatic arthritis (HR 0.74 [95% CI 0.20–2.76]) during TNFα inhibitor therapy compared to disease‐specific alternative therapy. Among RA patients, the incidence of any of the 10 most common cancers in the US and of nonmelanoma skin cancer was not increased with TNFα inhibitor therapy compared to treatment with comparator drugs.

Conclusion

Short‐term cancer risk was not elevated among patients treated with TNFα inhibitor therapy relative to commonly used therapies for immune‐ mediated chronic inflammatory diseases in this study.

     

A disease‐specific self‐help program compared with a generalized chronic disease self‐help program for arthritis patients

Objective

Both the Arthritis Self‐Management Program (ASMP) and the generic Chronic Disease Self‐Management Program (CDSMP) have been shown to be successful in improving conditions in patients with arthritis. This study compared the relative effectiveness of the 2 programs for individuals with arthritis.

Methods

Patients whose primary disease was arthritis were randomized to the ASMP (n = 239) or to the CDSMP (n = 116). Analyses of covariance were used to compare the outcome measures for the 2 programs at 4 months and 1 year. Measures included quality of life outcomes (self reported, health distress, disability, activity limitation, global health, pain, and fatigue), health behaviors (practice of mental stress management, stretching and strength exercise, aerobic exercise), self efficacy, and health care utilization (physician visits and hospitalizations).

Results

Both programs showed positive results. The disease‐specific ASMP appeared to have advantages over the more generic CDSMP for patients with arthritis at 4 months. These advantages had lessened slightly by 1 year.

Conclusion

The disease‐specific ASMP should be considered first where there are sufficient resources and participants. However, both programs had positive effects, and the CDSMP should be considered a viable alternative.

     

Zoledronic acid protects against local and systemic bone loss in tumor necrosis factor–mediated arthritis

Objective

Increased osteoclast activity is a key factor in bone loss in rheumatoid arthritis (RA). This suggests that osteoclast‐targeted therapies could effectively prevent skeletal damage in patients with RA. Zoledronic acid (ZA) is one of the most potent agents for blocking osteoclast function. We therefore investigated whether ZA can inhibit the bone loss associated with chronic inflammatory conditions.

Methods

Human tumor necrosis factor (TNF)–transgenic (hTNFtg) mice, which develop severe destructive arthritis as well as osteoporosis, were treated with phosphate buffered saline, single or repeated doses of ZA, calcitonin, or anti‐TNF, at the onset of arthritis.

Results

Synovial inflammation was not affected by ZA. In contrast, bone erosion was retarded by a single dose of ZA (−60%) and was almost completely blocked by repeated administration of ZA (−95%). Cartilage damage was partly inhibited, and synovial osteoclast counts were significantly reduced with ZA treatment. Systemic bone mass dramatically increased in hTNFtg mice after administration of ZA, which was attributable to an increase in trabecular number and connectivity. In addition, bone resorption parameters were significantly lowered after administration of ZA. Calcitonin had no effect on synovial inflammation, bone erosion, cartilage damage, or systemic bone mass. Anti‐TNF entirely blocked synovial inflammation, bone erosion, synovial osteoclast formation, and cartilage damage but had only minor effects on systemic bone mass.

Conclusion

ZA appears to be an effective tool for protecting bone from arthritic damage. In addition to their role in antiinflammatory drug therapy, modern bisphosphonates are promising candidates for maintaining joint integrity and reversing systemic bone loss in patients with arthritis.

     

Interferon‐γ protects against the development of structural damage in experimental arthritis by regulating polymorphonuclear neutrophil influx into diseased joints

Objective

Local interaction between soluble mediators within the inflamed synovium is a key factor that governs the pathologic outcome of inflammatory arthritides. Our aim was to investigate the interplay between the Th1 lymphokine interferon‐γ (IFNγ) and pivotal cytokines that drive rheumatoid arthritis (RA) pathology (interleukin‐1β [IL‐1β] and tumor necrosis factor α [TNFα]) in modulating inflammation and arthritis in vitro and in vivo.

Methods

Monarticular antigen‐induced arthritis (AIA) was initiated in IFNγ‐deficient (IFNγ^−/−) mice and age‐matched wild‐type (IFNγ^+/+) mice. Joint swelling was measured and histologic analysis was performed in order to assess changes in both inflammatory and degenerative parameters in vivo. In vitro, the influence of IFNγ in regulating IL‐1β– and TNFα‐driven CXCL8 and CCL2 production was quantified by enzyme‐linked immunosorbent assay.

Results

In murine AIA, both inflammatory and degenerative arthritis parameters were significantly exacerbated in the absence of IFNγ. IFNγ appeared to be a crucial factor in regulating CXCR2+ neutrophil influx in the joint. In in vitro studies using RA fibroblast‐like synoviocytes, IFNγ modulated both IL‐1β– and TNFα‐driven chemokine synthesis, resulting in the down‐regulation of CXCL8 production.

Conclusion

IFNγ exerts antiinflammatory, chondroprotective, and antiosteoclastogenic effects in murine AIA through a mechanism that involves the regulation of chemokine synthesis and local neutrophil recruitment. These studies suggest a potential therapeutic role of modulating IFNγ signaling in the treatment of inflammatory arthritides.

     

Tumor necrosis factor–inhibiting therapy preferentially targets bone destruction but not synovial inflammation in a tumor necrosis factor–driven model of rheumatoid arthritis

Objective

To investigate how tumor necrosis factor (TNF)–inhibiting therapy affects bone destruction and inflammation in a TNF‐driven mouse model of rheumatoid arthritis.

Methods

In order to evaluate the influence of TNF on osteoclastogenesis in vitro, different concentrations of TNF were added to spleen cell–derived monocytes in the absence or presence of different concentrations of RANKL. In addition, the effects of TNF inhibition on osteoclast precursors as well as local bone destruction in vivo were assessed by treating TNF‐transgenic mice with different doses of adalimumab.

Results

TNF stimulated osteoclastogenesis mainly by increasing the number of osteoclast precursor cells in vitro. This TNF effect was independent of the presence of RANKL. In the hTNF‐transgenic mouse model of destructive arthritis, low‐dose TNF‐inhibiting therapy with adalimumab had no effect on synovial inflammation but significantly inhibited local bone destruction and the generation of osteoclasts. This inhibition was accompanied by a reduction in the number of c‐Fms–positive osteoclast precursor cells in the bone marrow and a reduction of the osteoclast precursor pools in the blood and inflamed synovial membrane of hTNF‐transgenic mice.

Conclusion

Low‐dose TNF‐inhibiting therapy significantly reduces bone erosions by reducing the number of circulating and joint‐invading osteoclast precursors. This effect is uncoupled from its antiinflammatory action.

     

sE‐selectin for stratifying outcome in rheumatoid arthritis

Objectives

To determine the usefulness of sE‐selectin as a marker for early diagnosis and stratification of rheumatoid arthritis.

Methods

We investigated several markers of disease activity, including circulating adhesion molecules and other standard laboratory tests, in a 2–3 year followup analysis of patients with rheumatoid arthritis.

Results

The mean ± SD levels of sE‐selectin (91.68 ± 31.8 ng/ml versus 49.83 ± 14.76 ng/ml) and rheumatoid factor (375.7 ± 394.4 U versus 44.66 ± 37.63 U) were strongly elevated in severe (n = 15) versus mild (n = 7) courses of disease. Statistical calculation of mean and standard deviation revealed that sE‐selectin represents a highly significant marker for the presence of persistent and aggressive disease over time, regardless of therapeutic intervention and observation time points (P = 0.0004). Notably, regression analysis identified constant values for all parameters analyzed and, therefore, a stable course of the disease could be predicted from the beginning.

Conclusion

sE‐selectin appears to be a powerful marker to predict the severity of rheumatoid arthritis.

     

Inflammatory lesions of the spine on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis: Evidence of a relationship between inflammation and new bone formation

Objective

To determine whether a vertebral corner that demonstrates an active corner inflammatory lesion (CIL) on magnetic resonance imaging (MRI) in patients with ankylosing spondylitis (AS) is more likely to evolve into a de novo syndesmophyte visible on plain radiography than is a vertebral corner that demonstrates no active inflammation on MRI.

Methods

MRI scans and plain radiographs were obtained for 29 patients recruited into randomized placebo‐controlled trials of anti–tumor necrosis factor α (anti‐TNFα) therapy. MRI was conducted at baseline, 12 or 24 weeks (n = 29), and 2 years (n = 22), while radiography was conducted at baseline and 2 years. A persistent CIL was defined as a CIL that was found on all available scans. A resolved CIL was defined as having completely disappeared on either the second or third scan. A validation cohort consisted of 41 AS patients followed up prospectively. Anonymized MRIs were assessed independently by 3 readers who were blinded with regard to radiographic findings.

Results

New syndesmophytes developed significantly more frequently in vertebral corners with inflammation (20%) than in those without inflammation (5.1%) seen on baseline MRI (P ≤ 0.008 for all reader pairs). They also developed more frequently in vertebral corners where inflammation had resolved than in those where inflammation persisted after anti‐TNF treatment. This was confirmed in the analysis of the prospective cohort, in which significantly more vertebral corners with inflammation (14.3%) compared with those without inflammation (2.9%) seen on baseline MRI developed new syndesmophytes (P ≤ 0.003 for all reader pairs).

Conclusion

Our findings indicate that a syndesmophyte is more likely to develop from a prior inflammatory lesion, supporting a relationship between inflammation and ankylosis.

     

Tie2 receptor tyrosine kinase,a major mediator of tumor necrosis factor α–induced angiogenesis in rheumatoid arthritis

Objective

Rheumatoid arthritis (RA) is an inflammatory disease and an angiogenic disease. However, the molecular mechanisms promoting angiogenesis in RA are not clearly identified. Our objective was to study the role of an endothelium‐specific receptor tyrosine kinase, Tie2, in angiogenesis of inflammatory arthritis.

Methods

Expression of Tie2 and its ligand, angiopoietin 1 (Ang1), in human synovium was examined by immunohistochemistry and Western blot. A novel synovium vascular window model was established to study the role of Tie2 in angiogenesis in vivo. Primary cultured endothelial cells and synoviocytes were used to study tumor necrosis factor α (TNFα)–induced Tie2 and Ang1 expression.

Results

Tie2 was implicated in pathologic angiogenesis. We observed that Tie2 and Ang1 were elevated in human RA synovium. Using a novel collagen‐induced arthritis synovial window model, we demonstrated that Tie2 signaling regulated arthritis angiogenesis in vivo. We also showed that Tie2 mediated TNFα‐induced angiogenesis in a mouse cornea assay. In addition, we observed that TNFα can regulate Tie2 activation in multiple ways that may involve interactions between endothelial cells and synoviocytes. TNFα up‐regulates Tie2 in endothelial cells through nuclear factor κB, and it up‐regulates Ang1 in synoviocytes. These findings suggest paracrine regulation of angiogenesis between endothelial cells and synoviocytes.

Conclusion

This study demonstrates that Tie2 regulates angiogenesis in inflammatory synovium. Tie2 signaling is an important angiogenic mediator that links the proinflammatory cytokine TNFα to pathologic angiogenesis.

     

Reduction of CpG‐induced arthritis by suppressive oligodeoxynucleotides

Objective

Bacterial DNA contains immunostimulatory CpG motifs that cause inflammation when injected into the knee joints of normal mice. We examined whether synthetic oligodeoxynucleotides (ODN) that suppress CpG‐induced immune responses prevent CpG‐induced arthritis.

Methods

CpG, suppressive, and/or control ODN were injected into the knees of BALB/c mice. Joint swelling and inflammation were evaluated by physical measurement, by histologic analysis of joint tissue, and by magnetic resonance imaging.

Results

Immunostimulatory CpG DNA induced local arthritis, characterized by swelling of the knee joints, the presence of inflammatory cell infiltrates, the perivascular accumulation of mononuclear cells, and hyperplasia of the synovial lining. Administering suppressive (but not control) ODN reduced the manifestations and severity of arthritis up to 80%.

Conclusion

Suppressive ODN may be useful for the prevention or treatment of arthritis induced by bacterial DNA.

     

Mammalian target of rapamycin signaling is crucial for joint destruction in experimental arthritis and is activated in osteoclasts from patients with rheumatoid arthritis

Objective

Activation of the mammalian target of rapamycin (mTOR) pathway is important for immune cell activation and bone metabolism. To date, the contribution of mTOR signaling to joint inflammation and structural bone and cartilage damage is unknown. The aim of this study was to investigate the potential of inhibiting mTOR as a treatment of inflammatory arthritis.

Methods

Human tumor necrosis factor–transgenic mice in which inflammatory arthritis was developing were treated with 2 different mTOR inhibitors, sirolimus or everolimus. The effects of treatment on clinical disease activity, inflammation, and localized joint and cartilage destruction were studied. In addition, the effects of mTOR inhibition on osteoclast survival and expression of key molecules of osteoclast function were analyzed in vitro. Moreover, synovial tissue from patients with rheumatoid arthritis (RA) was assessed for activation of the mTOR pathway.

Results

Inhibition of mTOR by sirolimus or everolimus reduced synovial osteoclast formation and protected against local bone erosions and cartilage loss. Clinical signs of arthritis improved after mTOR inhibition, and histologic evaluation showed a decrease in synovitis. In vitro, mTOR inhibition down‐regulated the expression of digestive enzymes and led to osteoclast apoptosis. Moreover, mTOR signaling was shown to be active in the synovial membrane of patients with RA, particularly in synovial osteoclasts.

Conclusion

Signaling through mTOR is an important link between synovitis and structural damage in inflammatory arthritis. Current pharmacologic inhibitors of mTOR could be effective in protecting joints against structural damage.

     

Bone mineral density in patients with Crohn's disease during long-term treatment with azathioprine

Florén C-H, Ahrén B, Bengtsson M, Bartosik J, Obrant K (Lund University, Malmö, Sweden). Bone mineral density in patients with Crohn's disease during long-term treatment with azathioprine. J Intern Med 1998; 243 : 123–26.

Objectives

To ascertain whether patients with Crohn's disease treated with azathioprine maintained bone mineral mass better than patients treated with steroids alone.

Design

Retrospective study.

Setting

University Hospital of Malmö, Sweden.

Subjects

A total of 59 patients with ileocolonic, ileocaecal or colonic Crohn's disease.

Methods

Bone mass was assessed by dual photon X-ray absorptiometry at the level of L2 – L4.

Results

Patients treated with a high lifetime dose of steroids (> 5 g prednisolone) had significantly (P= 0.011) lower Z-score of L₂–L₄ (?0.87 ± 1.11; 11 SD) than steroid-treated patients, who had received a low dose of prednisolone (< 5 g) (0.08 ± 1.16 SD). Azathioprine did not negatively influence the steroid effect on bone mineral density.

Conclusions

Azathioprine does not seem to affect bone mineral density by itself. However, by being steroid-saving, it seems to conserve bone mineral mass in patients with Crohn's disease.