The effectiveness of pulsed electrical stimulation in the management of osteoarthritis of the knee: results of a double-blind, randomized, placebo-controlled, repeated-measures trial.

OBJECTIVE: To determine the effectiveness of subsensory, pulsed electrical stimulation (PES) in the symptomatic management of osteoarthritis (OA) of the knee. METHODS: This was a double-blind, randomized, placebo-controlled, repeated-measures trial in 70 participants with clinical and radiographically diagnosed OA of the knee who were randomized to either PES or placebo. The primary outcome was change in pain score over 26 weeks measured on a 100-mm visual analog scale (VAS). Other measures included pain on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), function on the WOMAC, patient's global assessment of disease activity (on a 100-mm VAS), joint stiffness on the WOMAC, quality of life on the Medical Outcomes Study Short-Form 36 (SF-36) health survey, physical activity (using the Human Activity Profile and an accelerometer), and global perceived effect (on an 11-point scale). RESULTS: Thirty-four participants were randomized to PES and 36 to placebo. Intent-to-treat analysis showed a statistically significant improvement in VAS pain score over 26 weeks in both groups, but no difference between groups (mean change difference 0.9 mm [95% confidence interval -11.7, 13.4]). Similarly, there were no differences between groups for changes in WOMAC pain, function, and stiffness scores (-5.6 [95% confidence interval -14.9, 3.6], -1.9 [95% confidence interval -9.7, 5.9], and 3.7 [95% confidence interval -6.0, 13.5], respectively), SF-36 physical and mental component summary scores (1.7 [95% confidence interval -1.5, 4.8] and 1.2 [95% confidence interval -2.9, 5.4], respectively), patient's global assessment of disease activity (-2.8 [95% confidence interval -13.9, 8.4]), or activity measures. Fifty-six percent of the PES-treated group achieved a clinically relevant 20-mm improvement in VAS pain score at 26 weeks compared with 44% of controls (12% [95% confidence interval -11%, 33%]). CONCLUSION: In this sample of subjects with mild-to-moderate symptoms and moderate-to-severe radiographic OA of the knee, 26 weeks of PES was no more effective than placebo.

Long-term Clinical Outcomes in Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis Syndrome.

OBJECTIVE: To assess the outcome of empirical therapeutic interventions for synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. METHODS: The clinical features and treatment outcomes of a cohort of 21 patients diagnosed with SAPHO in Western Australia were reviewed retrospectively. RESULTS: All 21 patients met published diagnostic criteria; 20 (95%) were Caucasian, and the median age was 47 years. The median follow-up was 6 years (range, 2 to 32 years). Three patients (14%) received no treatment; 18 (86%) required conventional synthetic disease-modifying antirheumatic drug (DMARDs). Thirteen (62%) had an initial good response to methotrexate; 8 relapsed and progressed to biologic DMARDs (bDMARDs) during a period of 14 years. Of the 13 recipients on a tumor necrosis factor inhibitor, 11 (85%) continued treatment for a median of 4 years (range, 1 to 14 years), whereas none of 3 recipients of interleukin 17/23 continued treatment (median, 4 months). Higher Physician Global Assessment scores (better outcomes) were observed in bDMARD recipients (mean, 7.06±2.24 [SD]) compared with non-bDMARD recipients (mean, 5.63±2.50; P=.1672) after a median of 3 years of therapy. CONCLUSION: This study describes the broad range of clinical manifestations in SAPHO, variable courses over time, and inconsistent outcomes with diverse empirical therapies. Moderately good long-term treatment outcomes were observed in most recipients of tumor necrosis factor inhibitor. Poorer outcomes were observed with bisphosphonates and interleukin 17/23 axis inhibitors; however, low numbers preclude robust comparison. Suboptimal treatment may be associated with poorer clinical outcomes and greater skeletal damage. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry: ACTRN12619000445178.

Role of a LIF antagonist in LIF and OSM induced MMP-1, MMP-3, and TIMP-1 expression by primary articular chondrocytes.

Cartilage degradation is mediated by matrix metalloproteinases (MMPs) and their inhibitors, tissue metalloproteinases (TIMPs), which are transcriptionally regulated by a variety of growth factors and cytokines. The levels of various MMPs as well as TIMPs have been shown to increase in response to certain cytokines. These include leukaemia inhibitory factor (LIF) and Oncostatin M (OSM), both of which have been detected in the synovial fluids of patients with rheumatoid arthritis (RA). However, the role of LIF and OSM in the regulation of various MMPs and TIMPs is still incompletely understood. The aims of this study were to examine the effects of LIF and OSM on MMP-1, MMP-3, and TIMP-1 production. In addition, the capacity of the LIF antagonist, MH35-BD, to block LIF and OSM induced MMP expression was examined. Primary chondrocytes, isolated from porcine metacarpophalangeal cartilage, were cultured in the presence and absence of LIF and OSM, with and without a predetermined concentration of the LIF antagonist. We analysed the levels of MMP-1, MMP-3 and TIMP-1 expression using qRT-PCR, Northern blot, and ELISA assays. The results indicate that LIF and OSM increase the expression of MMP-1, MMP-3, and TIMP-1 several fold. Furthermore their expression is reduced to basal levels in the presence of the LIF antagonist MH35-BD.

Undetectable mannose binding lectin is associated with HRCT proven bronchiectasis in rheumatoid arthritis (RA).

AIM: The aim of this study was to ascertain whether mannose binding lectin deficiency is implicated in coexistent rheumatoid arthritis and bronchiectasis and to determine whether undetectable mannose binding lectin confers poorer long-term survival in coexistent rheumatoid arthritis and bronchiectasis or in rheumatoid arthritis in general. MATERIALS AND METHODS: A retrospective audit was conducted in a rheumatoid arthritis cohort in which mannose binding lectin had been measured by enzyme linked immunosorbent assay from 2007-11. Rheumatoid arthritis patients with physician diagnosed HRCT proven bronchiectasis were recruited during this time and compared to those with uncomplicated rheumatoid arthritis. Survival from disease onset was recorded in October 2018. Kaplan-Meier survival estimates were performed to assess mortality over time in the two groups. Log rank tests were used for equality of survivor functions. RESULTS: The two groups were demographically comparable. A higher frequency of undetectable mannose binding lectin was observed in coexistent rheumatoid arthritis and bronchiectasis (37.5%) compared to uncomplicated rheumatoid arthritis, (8.9%, P = 0.005). Undetectable mannose binding lectin correlated with a strong trend toward poor survival in rheumatoid arthritis overall (P = 0.057). Cox regression analysis however, showed no difference in the hazard ratio for survival between the two groups when corrected for age, gender, prednisolone use ever, rheumatoid factor status and the full range of MBL concentrations. CONCLUSION: In summary, undetectable mannose binding lectin is associated with coexistent rheumatoid arthritis and bronchiectasis and correlates with poor survival in rheumatoid arthritis overall. These findings further implicate immunodeficiency in the genesis of bronchiectasis in rheumatoid arthritis.

Fc-based cytokines : prospects for engineering superior therapeutics.

The application of Fc (fragment crystallizable)-based cytokines (the fusion of the constant region of IgG to a cytokine of interest) as biotherapeutic agents to modulate inflammatory and immune responses has become increasingly popular in recent years. This is because in their monomeric form, cytokines are relatively small molecules with short serum half-lives, which necessitates frequent administration and thus limits their clinical utility. To rectify the problem, attempts have been made to improve the stability of these agents in vivo. This has been achieved through diverse strategies such as modification with polyethylene glycol (PEGylation) or by ligating the cytokine to protein moieties such as the constant heavy chain of IgG, known as the Fc fragment. The construction of Fc chimeric proteins has been shown to improve pharmacokinetics. However, since there is an inverse relationship between the size of molecules and the rate at which they diffuse through mucus, Fc fusion constructs potentially have a lower rate of diffusion. Consequently, a compromise is reached whereby Fc constructs are engineered to incorporate ligated cytokines in a monomeric form (one molecule of cytokine fused to a single Fc dimer) rather than in a dimeric form (two molecules of cytokine fused to a single Fc dimer). A recent and novel approach to improve stability in serum is a procedure that involves sheathing cytokines in protective protein covers called latency peptides. The enclosed cytokine is protected from degradation and allowed to act where needed when the outer peptide cover is removed. For some applications, a reduced serum half-life is desirable; for example, where there is a need to reduce IgG levels in antibody-mediated diseases. To achieve this goal, a strategy called AbDeg, which involves enhanced Ig degradation, has been devised. This article provides an overview of the design and construction of Fc-based cytokines, in both dimeric and monomeric forms. Several examples of recent applications of such constructs, which include cytokine antagonism, cytokine traps, gene therapy and drug delivery, are also discussed. Other antibody-engineered constructs such as Fab (fragment, antigen binding) and single chain Fv (fragment, variable) fusions are also briefly covered.

The effectiveness of pulsed electrical stimulation (E-PES) in the management of osteoarthritis of the knee: a protocol for a randomised controlled trial.

BACKGROUND: Osteoarthritis (OA) of the knee is one of the main causes of musculoskeletal disability in the western world. Current available management options provide symptomatic relief (exercise and self-management, medication and surgery) but do not, in general, address the disease process itself. Moreover, adverse effects and complications with some of these interventions (medication and surgery) and the presence of co-morbidities commonly restrict their use. There is clearly a need to investigate treatments that are more widely applicable for symptom management and which may also directly address the disease process itself. In two randomised controlled trials of four and 12 weeks duration, pulsed electrical stimulation was shown to be effective in managing the symptoms of OA of the knee. Laboratory and animal studies demonstrate the capacity of externally applied electric and electromagnetic fields to positively affect chondrocyte proliferation and extracellular matrix protein production. This latter evidence provides strong theoretical support for the use of electrical stimulation to maintain and repair cartilage in the clinical setting and highlights its potential as a disease-modifying modality. METHODS/DESIGN: A double-blind, randomised, placebo-controlled, repeated measures trial to examine the effectiveness of pulsed electrical stimulation in providing symptomatic relief for people with OA of the knee over 26 weeks. Seventy people will be recruited and information regarding age, gender, body mass index and medication use will be recorded. The population will be stratified for age, gender and baseline pain levels. Outcome measures will include pain (100 mm VAS and WOMAC 3.1), function (WOMAC 3.1), stiffness (WOMAC 3.1), patient global assessment (100 mm VAS) and quality of life (SF-36). These outcomes will be measured at baseline, four, 16 and 26 weeks. Activity levels will be measured at baseline and 16 weeks using accelerometers and the Human Activity Profile questionnaire. A patient global perceived effect scale (11-point Likert) will be completed at 16 and 26 weeks. DISCUSSION: This paper describes the protocol for a randomised, double-blind, placebo-controlled trial that will contribute to the evidence regarding the use of sub-sensory pulsed electrical stimulation in the management of OA of the knee. TRIAL REGISTRATION: Australian Clinical Trials Registry ACTRN12607000492459.

In vitro evaluation of leukemia inhibitory factor receptor antagonists as candidate therapeutics for inflammatory arthritis.

Leukemia inhibitory factor (LIF) and oncostatin M (OSM) are found in appreciable concentrations in synovial fluid from patients with rheumatoid arthritis (RA) but not osteoarthritis. Accordingly, both are potential therapeutic targets in inflammatory diseases of the joints. Several LIF antagonists have been developed. They have the capacity to inhibit the biologic activities of not only LIF but also other interleukin-6 (IL-6) subfamily cytokines, including OSM. Both LIF and OSM share the same receptor, which is part of a cytokine receptor super family in which the glycoprotein 130 (gp130) subunit is a common constituent. The aim of this study was to evaluate the antagonistic potentials of two LIF mutants, LIF05 and MH35-BD. Both are mutant forms of human LIF with reduced affinity for gp130 and greater LIF receptor (LIFR) binding affinity. The results, using Ba/F3 cell proliferation assay, acute-phase protein (haptoglobin) induction analysis in HepG2 human hepatoma cells, a porcine cartilage glycosaminoglycan release assessment for proteoglycan degradation, and a collagen release assay, show that these antagonists inhibit relevant LIF, OSM, and other IL-6 subfamily cytokines in vitro albeit with differential potencies and have, therefore, therapeutic potential for treatment of RA and perhaps other diseases.

Generation of mutant leukaemia inhibitory factor (LIF)-IgG heavy chain fusion proteins as bivalent antagonists of LIF.

Two leukaemia inhibitory factor (LIF) mutants, designated MH35-BD and LIF05, have been shown to have a capacity to inhibit the biological activities of not only human LIF (hLIF) but also other interleukin-6 (IL-6) subfamily cytokines such as human oncostatin M (hOSM). These cytokines share the same receptor complex in which the glycoprotein 130 (gp130) subunit is a common constituent. However, at low concentrations and in their monomeric forms, such molecules have a relatively short plasma half-life due to rapid clearance from the kidneys. Here, to prolong their serum half-lives, we have used a multi-step polymerase chain reaction (PCR) to fuse each of the LIF05 and MH35-BD cDNA fragments to a sequence encoding the Fc portion, and the hinge region, of the human immunoglobulin G (hIgG) heavy chain. The linking was achieved through an oligomer encoding a thrombin-sensitive peptide linker thus generating MH35-BD:Fc and LIF05:Fc, respectively. Both Fc fusion constructs were expressed in insect cell Sf21 and the proteins were purified by two successive affinity chromatography steps using nickel-nitrilotriacetic acid (Ni-NTA) agarose and protein A beads. The Ba/F3 cell-based proliferation assay was used to confirm that the proteins were biologically active. In addition, preliminary pharmacokinetics indicates that the Fc fusion constructs have a longer serum half-life compared to their non-fusion counterparts.

Undetectable Mannose Binding Lectin and Corticosteroids Increase Serious Infection Risk in Rheumatoid Arthritis.

BACKGROUND: Infection is the leading cause of death in rheumatoid arthritis (RA). Corticosteroid (CS) use is a known and important risk factor for serious infections (SIs). Mannose binding lectin (MBL) is a genetically determined component of the innate immune system implicated in neonatal infections. OBJECTIVE: Our aim was to determine whether MBL deficiency is a risk factor for SIs in RA and to compare it with CS use and also synthetic and biologic disease-modifying antirheumatic drug (DMARD) therapy. METHODS: Data on 228 patients with RA were collected for up to 7 years (median = 5.9 years). Serum MBL concentrations were determined in all patients receiving synthetic (n = 96) or biologic (n = 132) DMARD therapy. RESULTS: High rates of SIs were observed in RA irrespective of treatment (17%). Similar rates of SIs were observed in synthetic and biologic DMARD users. The rates of single and multiple SIs were similar, irrespective of the use of a biologic agent. Undetectable MBL (<56 ng/mL) concentrations and maintenance prednisolone at 10 mg per day or higher were associated with an increased risk for an SI, with incident risk ratio of 4.67 (P = .001) and 4.70 (P < .001), respectively. CONCLUSIONS: Undetectable MBL and prednisolone confer a high risk for an SI. The use of biologic DMARDs did not confer substantial SI risk in this observational study. MBL deficiency is hitherto an unrecognized risk factor for an SI in RA.

Polyarticular osteoarthritis--two major phenotypes hypothesized.

Osteoarthritis is the commonest form of arthritis, at least amongst Caucasians and is frequently polyarticular. Genetic factors are now considered pivotal in the aetiopathogenesis of polyarticular osteoarthritis (POA). This document proposes a nexus between the gene most commonly mutated amongst Caucasian peoples, notably the HFE gene and an appreciable subset of POA patients who have a clinically recognisable OA phenotype. It is hypothesised that there are at least 2 major POA phenotypes each of which is associated with discrete genotypes. Type 1 POA characterized by Heberden's or Bouchard's nodes with prominent DIP, PIP, knee joint (medial compartment) and Great toe MTP joint involvement corresponds to the putative nodal generalized form of OA or NGOA (proposed Type 1 POA phenotype). As yet no genetic marker has been defined for this POA subset. The second is a hitherto less well recognized phenotype characterized by involvement of the index and/or middle finger metacarpophalangeal (MCP2,3) joints and the elbows, ankles and possibly the intertarsal and tarsometatarsal joints. The hip and knee joints may sometimes also be involved. This different joint distribution corresponds closely to the pattern observed in the arthropathy that often accompanies hereditary haemochromatosis. It is predicted that mutations in the HFE gene will associate strongly with the proposed Type 2 POA phenotype and serve as a genetic marker for this clinically recognisable subset.

Precocious bilateral hip joint osteoarthritis is a "form-fruste" of the arthropathy of hereditary haemochromatosis.

Osteoarthritis (OA) of the hip joint is a common disorder, especially in aging peoples of Caucasian descent. Hip OA like OA in other joints is heterogeneous and may manifest in early or late adult life. The aetiology of early onset (precocious) bilateral hip OA is poorly understood, but the clinical and radiological characteristics of this form of OA suggest that chondral resorption due to biochemical or metabolic factors is likely to be of pre-eminent importance. The hip arthropathy which occurs in Hereditary Haemochromatosis (HH) and the ostensibly idiopathic precocious bilateral concentric form of hip OA are virtually indistinguishable. Accordingly, the possibility exists that the causal factors for these conditions may be very similar. On the basis of this premise and in the light of the finding in a small observational study that HFE gene mutations are very common in precocious bilateral hip OA (100% amongst 8 sequentially collected patients), it is hypothesised that precocious bilateral hip OA is a "form-fruste" of the arthropathy of HH in which HFE gene mutation mediated articular iron deposition in hip joint tissues may be of pivotal pathogenetic importance. Confirmation of this hypothesis could have implications for the prevention and strategic medical management of this form of OA.

Interleukin-6 subfamily cytokines and rheumatoid arthritis: role of antagonists.

Many cytokines have been implicated in the inflammatory pathways that characterize rheumatoid arthritis (RA) and related inflammatory diseases of the joints. These include members of the interleukin-6 (IL-6) family of cytokines, several of which have been detected in excess in the synovial fluid from RA patients. What makes the IL-6 group of cytokines a family is their common use of the glycoprotein 130 (gp130) receptor subunit, to which they bind with different affinities. Several strategies have been developed to block the pro-inflammatory activities of IL-6 subfamily cytokines. These include the application of monoclonal antibodies, the creation of mutant form(s) of the cytokine with enhanced binding affinity to gp130 receptor and the generation of antagonists by selective mutagenesis of the specific cytokine/gp130 receptor-binding site(s). The rationale for the use of anti-cytokine therapy in inflammatory joint diseases is based on evidence from studies in vitro and in vivo, which implicate major cytokines such as interleukin-1 (IL-1), tumour necrosis factor (TNF)-alpha and IL-6 in RA pathogenesis. In particular, IL-6 subfamily antagonists have a wide range of potential therapeutic and research applications. This review focuses on the role of some of the IL-6 subfamily cytokines in the pathogenesis of the inflammatory diseases of the joints (IJDs), such as RA. In addition, an overview of the recently developed antagonists will be discussed.

Targeting the glycoprotein 130 receptor subunit to control pain and inflammation.

The glycoprotein 130 (gp130) is a shared signal-transducing-membrane-associated receptor for several hematopoietic cytokines. Its activation is implicated in pain and in a variety of diseases via signaling of proinflammatory cytokines. These include interleukin-6 (IL-6) subfamily cytokines, many of which play important roles in the pathogenesis of diseases such as rheumatoid arthritis, Castleman's disease, and Kaposi's sarcoma. Several strategies have been developed to block gp130-receptor-mediated signaling. These include the application of monoclonal antibodies, the creation of mutant form(s) of the gp130 with increased binding affinity for such ligands as IL-6/sIL-6R complex, and the generation of antagonists by selective mutagenesis of the specific cytokine/gp130 receptor binding site(s). Other strategies include targeting gp130-mediated signaling pathways such as that involving signal transducer and activator of transcription-3. This review provides a summary of the latest research pertaining to the role of gp130 in the pathogenesis of inflammatory and other diseases in which the gp130 receptor is implicated. An overview of antagonists targeting the gp130 receptor is included with particular emphasis on their mechanism of action and their limitations and potential for therapeutic application.

HFE gene mutations are associated with osteoarthritis in the index or middle finger metacarpophalangeal joints.

OBJECTIVE: . To test the hypothesis that possession of either C282Y or H63D mutations in the HFE gene is associated with primary osteoarthritis (OA) in joints commonly affected in hemochromatotic arthropathy. METHODS: HFE genotyping was performed in 87 patients with radiologically proven OA in 3 joint regions: index or middle finger metacarpophalangeal joints (MCP2,3; n = 52), elbow joints (n = 8), ankle, intertarsal or tarsometatarsal joints (ankle/IT/TMT; n = 27); and in 56 patients with radiologically proven OA in finger interphalangeal (IP) joints, but not MCP2,3 joints (IP OA control group). HFE mutation frequencies in these groups were also compared to those in a similar population (Busselton population control group). RESULTS: A statistically significant association between HFE mutations and OA was observed for the MCP2,3 joints (p = 0.0001) and the ankle/IT/TMT joint group (p = 0.002) as well as for the 3 joint regions collectively (p = 0.0001), but not for the elbow joints (p = 0.062). Comparison with the Busselton population controls showed similar statistically significant associations, except for the elbow and ankle/IT/TMT groups, where similar trends were observed. CONCLUSION: HFE gene mutations are associated with OA in the MCP2,3 joints. These mutations may be markers for a polyarticular OA phenotype.

Primary osteoarthritis in the ankle joint is associated with finger metacarpophalangeal osteoarthritis and the H63D mutation in the HFE gene: evidence for a hemochromatosis-like polyarticular osteoarthritis phenotype.

BACKGROUND AND AIM: Osteoarthritis (OA) can occur in the ankle joint. It also occurs in an appreciable proportion of subjects with hereditary hemochromatosis (HH). Might these conditions have common genetic characteristics? The aim of this study was to test the hypothesis that HFE gene mutations are associated with primary osteoarthritis in the ankle joint. METHODS: Consecutive referred patients who had primary or secondary (posttraumatic) OA of the ankle joint were assessed by a single rheumatologist and had a full physical and joint examination. Plain x-rays of the ankle joint, other clinically involved osteoarthritic joints, iron studies, HFE genotyping, and Hb electrophoresis were performed. The significance of differences was evaluated by 2-tailed Fisher exact test. RESULTS: Fourteen patients met the inclusion criteria for primary ankle OA and 6 met the criteria for secondary ankle OA. One of the 14 had had a previous subtalar joint fusion and was excluded. Among the remaining 13, 7 had OA in the index and/or middle finger metacarpophalangeal joints (MCP2,3 OA) with radiologic features similar to those found in hemochromatotic arthropathy (HA). Furthermore, 11 of the 13 had at least one HFE mutation, one subject in this group was homozygous for H63D, one was compound heterozygous for C282Y and S65C, and one was compound heterozygous for H63D and S65C. Eight were heterozygous for H63D. The 13 subjects were compared with the 6 secondary ankle OA subjects and with a previously studied population cohort (n = 3011) from the town of Busselton in whom HFE genotyping had been performed. A statistically significant increase in the frequency of HFE gene mutations was observed in the group with primary OA of the ankle joint compared with that with secondary ankle joint OA (P = 0.0095) and compared with the Busselton cohort (P = 0.0008). Furthermore, a statistically significant association between finger MCP joint OA and primary ankle joint OA was observed (P = 0.0436). Iron studies were normal in the 13 primary and 6 secondary ankle OA subjects. None of the subjects with ankle OA had clinical signs of hemochromatosis or abnormal liver function tests. CONCLUSIONS: A strong and statistically significant association was observed between HFE gene mutations and primary OA in the ankle joint. The frequent presence of MCP2,3 OA in these patients suggests the existence of a type 2 polyarticular OA phenotype that closely resembles the arthropathy of HH and which appears to be clinically differentiable from type 1 OA or nodal generalized OA (NGOA). HFE gene mutations may be a marker for the type 2 polyarticular OA phenotype and a clue to OA pathogenesis.