Francesca d’Onofrio

Osteoclastogenesis and arthritis

There is emerging interest for osteoclasts as key players in the erosive and inflammatory events leading to joint destruction in chronic arthritis. In fact, chronic inflammatory joint diseases such as psoriatic arthritis and rheumatoid arthritis are often characterized by destruction of juxta-articular bone and erosions due to the elevated activity of osteoclasts, which are involved in bone resorption. The main step in inflammatory bone erosion is an imbalance between bone resorption and bone formation: osteoclast formation is enhanced by proinflammatory cytokines such as TNF-α, IL-1β, and IL-17 and is not balanced by increased activity of bone-forming osteoblasts. T-cells, stromal cells, and synoviocytes enhance osteoclast formation via expression of RANKL and, under pathologic conditions, of proinflammatory cytokines. In rheumatoid arthritis, accumulation of osteoclasts in synovial tissues and their activation associated with osteoclastogenic cytokines and chemokines at cartilage erosion sites suggest that they could be usefully selected as therapeutic target. In particular, in consideration of the primary role of RANKL and TNF-α in osteoclastogenesis, the control of the production of RANKL and the inhibition of TNF-α represent important strategies for reducing bone damage in this disease.

Metabolic syndrome and chronic arthritis: effects of anti-TNF-α therapy

TNF-α plays a key role in the inflammatory cytokine cascade involved in the pathogenesis of chronic arthritis, including rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Systemic inflammation and the increased production of pro-inflammatory cytokines in these patients may favor the onset of metabolic syndrome. In patients affected by chronic arthritis, TNF-α is considered as one of the factors responsible for favouring insulin resistance and dyslipidemia, which are important features of the metabolic syndrome. Even if TNF-α is a single player in the great molecular cauldron of inflammation, the use of TNF-α inhibitors may be an important approach for not only treating articular and cutaneous symptoms but also for ameliorating glucose and lipid metabolism. Nevertheless, further research and clinical trials are needed to better determine the effects of biologic therapies on metabolic components in chronic arthritis patients and to identify the most appropriate strategies on the basis of the comorbidities in these patients.

Golimumab in real-life settings: 2 Years drug survival and predictors of clinical outcomes in rheumatoid arthritis, spondyloarthritis, and psoriatic arthritis

OBJECTIVES To assess the drug survival of golimumab, and predictors thereof, in patients affected with rheumatoid arthritis (RA), spondyloarthritis (SpA), and psoriatic arthritis (PsA) in a prospective observational cohort. METHODS This is a non-interventional, longitudinal study on RA, SpA, and PsA patients starting treatment with golimumab. Endpoints were the 2 years persistence rate of golimumab and predictors of therapy discontinuation. Drug retention was analyzed using Kaplan-Meier and Cox models. Hazard ratios (HR) of golimumab discontinuation were estimated by Cox-regression hazard models. RESULTS Of 416 patients starting golimumab, 171 biologic-naïve and 245 inadequate responders to prior biologic drugs, 88 had RA, 147 SpA, and 181 PsA. Global 2 years drug retention was 70.2%, with no different hazard of discontinuation among diseases or line of biologic treatment. The strongest predictor of golimumab discontinuation was female gender (HR = 1.95). Golimumab monotherapy was associated with higher risk drug interruption (HR = 1.67). Within SpA, predictors of golimumab discontinuation were female sex (HR = 4.19), and absence of extra-articular manifestations (HR = 4.60). In PsA, duration of disease was negatively associated to drug interruption (HR = 0.93), whereas golimumab monotherapy was positively (HR = 2.21) associated. Interestingly, failing to achieve a good EULAR response at 3 months was the only predictor of golimumab discontinuation for RA patients (HR = 3.03). CONCLUSIONS This study provided evidence that golimumab has high retention rate in real-life settings. SpA male patients with extra-articular manifestations, PsA patients on co-therapy with DMARDs, and RA patients attaining an early clinical response had the highest probability to continue golimumab over 2 years.

Why TNF-α inhibition is not sufficient to avoid juxta-articular erosions in chronic arthritis?

There is an emerging interest in the role of anti-TNF-α therapy in reducing bone damage in chronic arthritis with special regard to rheumatoid arthritis. Accumulation of osteoclasts in rheumatoid synovial tissues, and their activation due to osteoclastogenic cytokines and chemokines at cartilage erosion sites suggest that they may advantageously be considered as therapeutic targets. Given that the primary role of TNF-α in osteoclastogenesis, the inhibition of TNF-α represents an important strategy for reducing bone damage in rheumatoid arthritis. In point of fact, there is evidence that treatment with anti-TNF-α agents may avoid or reduce bone damage in rheumatoid arthritis, even if further studies are required to provide a biological explanation and a link for the observation of the advantageous effects of TNF-α inhibitors on the progression of bone damage in chronic arthritis. The existence of factors involved in osteoclast activation, including IL-1, IL-6, IL-7, IL-11, IL-17, M-CSF, TGF-β, MIP-1α, MIP-1β, IP-10, MIG, and OSCAR, indicates that TNF-α is only a single player in the great molecular cauldron of osteoclastogenesis. The presence of mediators behind the TNF-α and RANK-RANKL complex that may be independent in inducing osteoclastogenesis, such as NFATc1, suggests that the anti-TNF-α therapy will not provide a complete reduction of bone damage in chronic arthritis.

Two cases of distal extremity swelling with pitting oedema in psoriatic arthritis: the different pathological mechanisms.

In psoriatic arthritis, swelling and pitting oedema may be caused by different pathogenic mechanisms: on one hand, the involvement of tenosynovial structures; on the other hand, the involvement of lymphatic vessels, which may be rarely implicated by the inflammatory process. This different involvement is responsible for a different response to therapy and a different clinical outcome. In fact, patients with inflammation of the tenosynovial structures and normal lymphatic drainage have a more favourable clinical outcome and response to pharmacologic treatment, whilst patients affected by psoriatic arthritis with chronic lymphatic vascular damage are characterized usually by resistance of oedema to therapy. In this study, we report two cases of psoriatic arthritis with distal extremity swelling and pitting oedema. In the first patient, the swelling and pitting oedema were associated with lymphatic obstruction, as detected by lymphoscintigraphy. In the second, the predominant involvement of the tenosynovial structures, as shown by magnetic resonance, with normal lymphatic flow, may have been the cause of arthritis with oedema. These different pathogenetic mechanisms were associated with different response to therapy. Nevertheless, oedema was resistant to therapy in both patients probably because of other unknown factors, which influence therapy and clinical outcome.

Cervical myelopathy caused by periodontoid synovial pannus in a patient with psoriatic arthritis: a case report

The atlantoaxial subluxation and the formation of a synovial periodontoid pannus are associated with rheumatoid arthritis causing mechanical compression of the spinal cord and cervical myelopathy. Atlantoaxial subluxation is very rare in psoriatic arthritis (PsA). Even more rare is the formation of a periodontoid synovial pannus associated with PsA and signs of myelopathy. In this report, cervical myelopathy caused by periodontoid synovial pannus in PsA is described.

Psoriatic arthritis and Klinefelter syndrome : case report

Psoriatic arthritis (PsA) is a well-known disease characterized by psoriasis and inflammatory joint disease, with distinct clinical and radiological features to differentiate it from other arthropathies. Whereas many cases of coexistence of arthritis and other autoimmune disorders with chromosomal abnormalities have been reported, the occurrence of PsA and Klinefelter syndrome has not been reported previously. A case of Klinefelter syndrome and PsA was reported. This case report emphasizes the role played by sex hormones and chromosomal abnormalities in the pathogenesis of autoimmune disorder, and to our knowledge, this is an uncommon case of a patient with Klinefelter syndrome who developed PsA.

Combined effect of Neridronate and specific antibiotic therapy in a case of tuberculous spondylodiscitis

Because of the increased incidence of tuberculosis (TB) in recent years, infective spondylitis is still a major problem in the world. In skeletal TB the spine is the most often involved and lumbosacral spine involvement is rare. Nowadays early diagnosis and new medical treatment can reduce the incidence of the serious skeletal sequelae and the number of surgery procedures in spinal TB. We present a case of TB spondylodiscitis characterized by a rapid and progressive clinical and radiological improvement after treatment with Neridronate and chemotherapic drugs. Our data suggest that in the treatment of the TB spondylodiscitis the combined use of these drugs is a good alternative to stimulate bone reparative process to the chemotherapy alone. To our knowledge this is first case of a patient with TB discitis treated with Neridronate. Further studies are necessary to confirm the effectiveness of Neridronate treatment added to antiTB drugs in spondylodiscitis

Anti-TNF-α effects on anemia in rheumatoid and psoriatic arthritis

A key role in the pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) is played by inflammatory cytokines, including tumor necrosis factor-α (TNF-α), which are also involved in inducing inflammatory anemia. We have followed 67 RA patients and 64 PsA patients for 1 year to evaluate the effects of TNF-α inhibitors on disease activity and on inflammatory anemia. Patients were divided into three different treatment groups, according to a randomized assignment to receive therapy with etanercept, adalimumab, or infliximab. Treatment with anti-TNF-α resulted in a significant reduction in disease activity score-28 (DAS28) values both in RA and PsA patients, already from the third month of treatment (P = 0.01). In both populations, there was an increase in hemoglobin (HB) levels already after 3 months of treatment (P = 0.001), and HB levels were inversely proportional to the disease activity, regardless of the type of medication used. The increased HB values and the reduction of DAS28 values during the observation period suggest the existence of a negative correlation between them both in RA and PsA, regardless of the type of anti-TNF-α used. Our data suggest a pleiotropic action of anti-TNF-α, such as the well-known action on the activity of the disease, and the improvement in inflammatory anemia.