Biological treatments in Behçet's disease: beyond anti-TNF therapy.

Behçet's disease (BD) is universally recognized as a multisystemic inflammatory disease of unknown etiology with chronic course and unpredictable exacerbations: its clinical spectrum varies from pure vasculitic manifestations with thrombotic complications to protean inflammatory involvement of multiple organs and tissues. Treatment has been revolutionized by the progressed knowledge in the pathogenetic mechanisms of BD, involving dysfunction and oversecretion of multiple proinflammatory molecules, chiefly tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1ß, and IL-6. However, although biological treatment with anti-TNF-α agents has been largely demonstrated to be effective in BD, not all patients are definite responders, and this beneficial response might drop off over time. Therefore, additional therapies for a subset of refractory patients with BD are inevitably needed. Different agents targeting various cytokines and their receptors or cell surface molecules have been studied: the IL-1 receptor has been targeted by anakinra, the IL-1 by canakinumab and gevokizumab, the IL-6 receptor by tocilizumab, the IL12/23 receptor by ustekinumab, and the B-lymphocyte antigen CD-20 by rituximab. The aim of this review is to summarize all current experiences and the most recent evidence regarding these novel approaches with biological drugs other than TNF-α blockers in BD, providing a valuable addition to the actually available therapeutic armamentarium.

Untangling the web of systemic autoinflammatory diseases.

The innate immune system is involved in the pathophysiology of systemic autoinflammatory diseases (SAIDs), an enlarging group of disorders caused by dysregulated production of proinflammatory cytokines, such as interleukin-1ß and tumor necrosis factor-α, in which autoreactive T-lymphocytes and autoantibodies are indeed absent. A widely deranged innate immunity leads to overactivity of proinflammatory cytokines and subsequent multisite inflammatory symptoms depicting various conditions, such as hereditary periodic fevers, granulomatous disorders, and pyogenic diseases, collectively described in this review. Further research should enhance our understanding of the genetics behind SAIDs, unearth triggers of inflammatory attacks, and result in improvement for their diagnosis and treatment.

Thalassemic trait prevalence in patients affected by psoriatic arthritis in anti-TNF treatment.

Thalassemic trait (Thal) is associated with rheumatic disease, particularly a mild form of seronegative polyarthritis resembling rheumatoid arthritis (RA), but not with other rheumatic diseases. The aim of this study was to estimate the frequency of Thal in patients with psoriatic arthritis (PsA) and to evaluate the efficacy of anti-tumor necrosis factor alpha (TNF-α) therapy in patients with PsA and Thal. We performed a retrospective study in 321 patients with PsA who started therapy with TNF-α blockers. For all patients included in the study, at baseline and every 3 months for the 1 year of follow up, data concerning PsA activity and ferritin levels were registered. In our group of PsA patients, a total of 27 (8%) with concomitant Thal were identified and included in the study. In patients without Thal, all variables improved significantly after 6 months of therapy, while in patients with Thal, the same variables showed a significant decrease after 12 months.: Our study shows that PsA is significantly associated with Thal, but further studies are needed to address this issue. The presence of Thal could be a negative predictor of achieving remission during treatment with TNF-α-blockers.

Working the endless puzzle of hereditary autoinflammatory disorders.

Hereditary autoinflammatory disorders encompass manifold dysfunctions of innate immunity caused by mutations in genes coding for the main characters of the inflammatory scene: most of these conditions have an early onset, ranging from the first days of life to the first decades, and include hereditary periodic fevers, NLRP-related diseases, granulomatous and pyogenic syndromes, which are basically characterized by upturned inflammasome activity and overproduction of bioactive interleukin (IL)-1ß and other proinflammatory cytokines. The discovery of a causative link between autoinflammation and IL-1ß release has improved our understanding of the intimate mechanisms of innate immunity, and has likewise led to the identification of extraordinary treatments for many of these disorders.

Investigating the Effectiveness of a Carb-Free Oloproteic Diet in Fibromyalgia Treatment.

Fibromyalgia (FM), a chronic disease with a high incidence in women, poses a significant challenge for diagnosis and treatment, especially due to the absence of specific biomarkers and the multifaceted nature of its symptoms, which range from neuromuscular pain to mood disorders and intestinal dysbiosis. While diagnosis currently relies on rheumatological clinical evaluations and treatment options mainly focus on symptom management, FM seems to have possible links with systemic metabolic dysfunctions with a common inflammatory root. In this context, a new therapeutic avenue emerges: could a therapeutic nutritional approach be the missing piece of the puzzle? Indeed, diet therapies employed particularly for metabolic syndromes proved recently to be efficacious for correcting systemic dysmetabolism and a high number of chronic inflammation conditions. In particular, the very-low-calorie ketogenic diet (VLCKD) demonstrated therapeutic benefits in many disorders. In the present study, we aimed to investigate the specific effects of two dietary interventions, namely the oloproteic VLCKD and the low-glycemic insulinemic (LOGI) diet, on two groups of female FM patients (FM1 and FM2) over a 45-day period. Utilizing clinical and laboratory tests, as well as non-invasive NMR metabolomic analysis of serum, urine, and saliva samples, we sought to uncover how these dietary regimens impact the metabolic dysfunctions associated with FM.

The occurrence of lower limb enthesopathy in coeliac disease patients without clinical signs of articular involvement.

OBJECTIVE: Coeliac disease (CD) is a systemic autoimmune condition induced by gluten consumption in genetically predisposed people, affecting ∼1% of the general population. In the literature, there are many studies that report the association between CD and different kinds of arthritis. The aim of this study was to investigate the presence of entheseal abnormalities by US in patients with CD without clinical signs of articular involvement as compared with healthy control subjects. METHODS: Sixty patients with CD attending the gastroenterology outpatient clinic of the University Federico II of Naples and 60 healthy control subjects matched for age and sex were enrolled in this study. Coeliac patients and healthy controls underwent clinical and US examination. RESULTS: Among 60 CD patients, 24 (40%) presented at least one entheseal alteration as compared with 6 (10%) control subjects (P < 0.01). In CD patients, the entheseal site more frequently involved was patellar (distal and proximal), while in the healthy controls the enthesopathies were all localized at the Achilles tendon. CONCLUSION: In conclusion, the results of this study underline the ability of US to detect signs of subclinical enthesopathy and indicate the presence of a higher prevalence of subclinical enthesopathies in asymptomatic CD patients.

Osteoporosis and psoriatic arthritis.

Osteoporosis (OP) is a skeletal disorder characterized by compromised bone strength that predisposes to an increased risk of fracture. The prevalence of OP in the general population is very high as established in several studies, and OP represents one of the possible aspects of bone involvement in arthritis. In psoriatic arthritis this involvement is particularly complex because it affects not only mechanisms of bone loss but also of bone formation. We will discuss these aspects and the available epidemiological data.

New developments in magnetic resonance imaging of the nail unit.

The evolution of dedicated magnetic resonance imaging (MRI) musculoskeletal equipment allows new sequences and better images of the nail unit. The use of MRI has modified the imaging strategies used in treating inflammatory arthritis. In the case of psoriatic arthritis (PsA), the MRI study of the nail unit identifies nail involvement, which appears as an initial lesion for the induction of distal phalanx damage and consequently of distal interphalangeal joint arthritis. All patients with psoriasis, even in the absence of a clinically evident onychopathy, show characteristic MRI changes in the nail. This evidence could have a practical diagnostic value, because MRI study of the nail could document diagnosis in patients with undifferentiated spondyloarthropathies who have a barely evident psoriasis. We discuss the advantages and problems related to the use of low-field and high-field MRI in the study of the nail unit of patients with PsA.

Screening and monitoring of latent tubercular infection in patients taking tumor necrosis factor-α blockers for psoriatic arthritis.

Patients with arthritis who need treatment with biologics are carefully screened for possible previous exposure to tuberculosis to detect any latent tubercular infection (LTBI). The traditional method of screening for LTBI is not specific, because positivity could also depend on infection by atypical mycobacteria and bacillus Calmette-Guerin vaccination. In addition, the screening does not show high sensitivity, frequently presenting a false negativity because of immunosuppression caused by drugs used for arthritis. Recently, interferon-γ release assays (IGRA) have been used to screen LTBI with more sensitivity and specificity before treatment with anti-tumor necrosis factor-α drugs. Moreover, in our experience, IGRA are potentially useful in monitoring LTBI during biologic therapy.

Rheumatic complaints in women taking aromatase inhibitors for treatment of hormone-dependent breast cancer.

BACKGROUND: The rheumatic adverse effects accompanying treatment with aromatase inhibitors (AIs) in hormone-dependent breast cancer represent an area of clinical relevance and emerging concern. This report describes these rheumatic complaints detailing their clinical pattern. METHODS: During 1-year period, 18 consecutive postmenopausal women (mean age, 58.33 years; range, 52-66 years) in treatment with AIs for hormone-dependent breast cancer (mean duration of therapy, 12.0 months; range, 9.1-17.7 months) were referred for evaluation in the outpatient clinic of the rheumatology unit in relation to rheumatic complaints. According to a routine protocol planned with oncologists, patient evaluations consisted of a complete clinical examination with careful assessment of rheumatic complaints and related physical symptoms, followed by laboratory testing and a bone scintiscan. In no cases were rheumatic complaints present before AI therapy. RESULTS: On the basis of clinical data and investigations and by applying accepted diagnostic criteria, a diagnosis of an undifferentiated spondyloarthropathy was reached in 10 (55.5%) of the 18 patients studied, and an oligoarthritis was shown in 2 more patients (11.1%), whereas a simple arthralgia was found in the remaining 6 patients (33.3%). In the patients meeting criteria as belonging to a spondyloarthritic subset, a family history positive for psoriasis and celiac disease was shown in 2 and 1 instance, respectively, whereas HLA-CW6 and HLA-B27 were detected in 3 and 1 case. A high serum level of anti-cyclic citrullinated peptide antibodies was shown in 1 patient with oligoarthritis. Most of the patients (16/18) were treated with nonsteroidal anti-inflammatory drugs or with corticosteroids. Methotrexate (10 mg weekly) was added in 3 of these patients, nonresponders. Aromatase inhibitor discontinuation was needed in the remaining 2 cases with spontaneous resolution of symptoms over time. CONCLUSIONS: Data from the present study emphasize a previously unsuspected high prevalence of defined arthritides underlying these rheumatic complaints. Therefore, investigative efforts should be addressed to better clarify the clinical and pathogenetic significance of these important consequences of AI therapy. An accurate monitoring of rheumatic complaints has to be suggested to patients taking AI therapy, with a rapid referral to a rheumatologist in the case of consistent suspicion of an inflammatory arthritis.

Switching from infliximab or etanercept to adalimumab in resistant or intolerant patients with spondyloarthritis: a 4-year study.

OBJECTIVE: TNF-alpha antagonists, infliximab (INF), etanercept (ETA) and adalimumab (ADA), have been demonstrated to be effective in controlling symptoms in SpAs. The aim of this study was to investigate the possibility of using ADA as a second or third choice. METHODS: A retrospective study was conducted in patients with SpA treated with TNF-alpha blockers who switched from INF or ETA to ADA, for inefficacy or adverse events. Kaplan-Meier survival curves were plotted to determine the rates of continuation of the first treatment (INF or ETA) as compared with the rates of continuation of the second or third treatment with ADA. RESULTS: A total of 1619 patients with SpA were treated with INF (35.3%), ETA (43.7%) and ADA (20.9%). In this cohort, ADA was started in 38 (2.34%) patients as a second anti-TNF-alpha drug and in 9 (0.56%) as a third anti-TNF-alpha drug. In SpA patients who failed the first anti-TNF-alpha, for whatever reason, survival curves for ADA (as a second anti-TNF-alpha) were significantly better than survival curves for these same patients on their first anti-TNF-alpha (overall: P < 0.0001; INF: P < 0.0011; ETA: P < 0.02). CONCLUSION: Our retrospective study, resulting from real-life experience, showed that SpA patients who fail to respond to a first agent, INF or ETA, respond to ADA as a second-line drug regardless of the reason for switching.

Rehabilitation in psoriatic arthritis.

This article summarizes the state of the art of rehabilitation in psoriatic arthritis (PsA). Very little evidence was available to assess the efficacy of rehabilitation. Some data were borrowed from studies on ankylosing spondylitis. Covering certain aspects of the disease by the standard measure of functioning was difficult. However, rehabilitation was considered by the GRAPPA Group (Group for Research and Assessment of Psoriasis and Psoriatic Arthritis), as part of treatment of axial PsA.

Early psoriatic arthritis.

Early detection of psoriatic arthritis (PsA) can effectively help in reducing the risk of joint damage and disability. Accordingly, the authors offer diagnostic insights in order to improve the approach to the patient's medical history, clinical examination, and the imaging modalities. Early PsA is a condition with a consistent risk of clinical progression. Marked entheseal involvement is a distinctive clinical aspect that helps discriminate early PsA from other conditions observed at their onset, in particular rheumatoid arthritis.

Prevention of tuberculosis in patients taking tumor necrosis factor-alpha blockers.

Treatment with tumor necrosis factor-alpha (TNF-alpha) inhibitors increases the risk of tuberculosis (TB) due to reactivation of latent Mycobacterium tuberculosis infection (LTBI). Screening for LTBI is based mainly on the tuberculin skin test (TST), which has several limitations in any patient who is immunosuppressed due to drugs or autoimmune disease. T cell interferon-gamma release assays (IGRA) have been shown to be more specific than TST in immunocompetent patients and potentially represent a new approach for the management of patients taking TNF-alpha blockers. Even if there is no evidence-based literature of IGRA superiority versus TST in this specific clinical setting, some studies suggest blood assays may be helpful in clinical management of these patients, in addition to currently recommended clinical screening for risk factors for LTBI.

Magnetic resonance imaging of nail unit in psoriatic arthritis.

The use of magnetic resonance imaging (MRI) has modified the imaging strategies of inflammatory arthritides. In psoriatic arthritis (PsA), MRI study of the nail unit identifies nail involvement that appears as the initial lesion for induction of distal phalanx damage and consequently of distal interphalangeal joint arthritis. All psoriatic patients, also in the absence of a clinically evident onychopathy, show characteristic MRI changes of the nail. This evidence could have practical diagnostic value because MRI study of the nail could document diagnosis in patients with undifferentiated spondyloarthropathies who have barely evident psoriasis. We discuss the advantages and problems related to the use of low- and high-field MRI in the study of the nail unit of patients with PsA.

The effectiveness of a traditional therapeutical approach in early psoriatic arthritis: results of a pilot randomised 6-month trial with methotrexate.

Thirty-five patients with Early Psoriatic Arthritis (EPA) (17 female and 18 male; mean age 25.6 years) entered this randomised 6-month study. At the enrolment, all patients were on non-steroidal anti-inflammatory drug (NSAID) therapy on demand and were divided in two matched groups (A and B). Group A continued NSAID therapy at full dosage in the following 3 months and then added methotrexate (MTX) for another 3 months. Group B was under the combination of NSAID and MTX for the entire 6-month period. Clinical and laboratory assessment included the count of tender joints and/or entheses (TJC), the count of swollen joints and/or entheses (SJC), patient's global assessment (PGA), physician's global assessment (PhGA), patient's assessment of pain (VAS), erythrocyte sedimentation rate (ESR) and serum concentration of C-reactive protein (CRP). All variables were done at baseline (T0), at 3 (T3) and at 6 months (T6). In both group A and in group B, there was a significant improvement of all variables at T3 and T6. However, in comparison to the patients of group A, patients included in group B showed a more rapid and marked improvement of TJC and SJC, which was statistically significant at T3 (p < 0.05). In contrast, the improvement of PGA, PhGA, VAS, ESR and CRP was not significantly different between groups. The early use of MTX in EPA patients markedly improves TJC and SJC. In fact, at T3, other markers used to quantify EPA disease activity, in particular PGA, PhGA, VAS, ESR and CRP, did not show significant differences in EPA patients treated with either NSAIDs or MTX. This finding suggests an incomplete control under MTX of the pathogenetic process and stimulates further interest on early use of other therapeutical approaches capable of modifying the course of disease.

Is the involvement of the distal interphalangeal joint in psoriatic patients related to nail psoriasis?

The aim of this study was to investigate the relationship between onychopathy and distal interphalangeal (DIP) joint involvement in psoriatic patients. Twenty-five consecutive unselected, unrelated patients with psoriatic onychopathy and 25 consecutive unselected, unrelated patients with psoriatic arthritis without onychopathy, were enrolled in the study. X-ray films of the hands were taken to identify DIP arthritic involvement and/or bone changes of the distal phalanx, which were categorized into five classes (0: no lesions; 1: tuftal minimal erosions; 2: tuftal bone resorption; 3: tuftal periosteal osteitis; 4: overlap of erosive and osteitic changes). Ten psoriatic patients with onychopathy and 8 without showed DIP arthritis, with no statistical differences in this distribution ( p=0.556). Bone changes of the distal phalanx were found in all 25 psoriatic patients with onychopathy and in 18 without. The distribution of patients in different categories of involvement of the distal phalanx showed that patients without onychopathy were markedly distributed in the categories with no or minimal lesions, whereas patients with onychopathy had structural changes prevailing included in categories with more severe bone changes (osteitis and overlap of erosive and osteitic changes) ( p=0.002). Onychopathic patients with DIP arthritis were older than those without ( p<0.0001) and showed a longer duration of onychopathy ( p<0.0001). Although the occurrence of DIP arthritis seems to depend on the duration of nail involvement, no statistical difference has been found in the distribution of DIP arthritis in psoriatic patients with or without onychopathy. In contrast, a topographical association between bone changes of the distal phalanx and dystrophy of the adjacent nail may be advanced.

Biological therapies for spondyloarthritis.

Biological therapies and new imaging techniques have changed the therapeutic and diagnostic approach to spondyloarthritis. In patients with axial spondyloarthritis, tumor necrosis factor α (TNFα) inhibitor treatment is currently the only effective therapy in patients for whom conventional therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) has failed. TNFα inhibitor treatment is more effective in preventing articular damage in peripheral joints than in axial ones. It is important to treat patients at an early stage of disease to reduce disease progression; moreover it is necessary to identify causes of therapy inefficacy in preventing joint damage in the axial subset.

Efficacy of tocilizumab in a patient with refractory psoriatic arthritis.

Psoriatic arthritis (PsA) is an inflammatory arthropathy, associated with skin and/or nail psoriasis and other possible systemic features. In the last years, PsA therapy has been revolutionized by the increasing knowledge in the pathogenetic mechanisms of the disease, involving dysfunction and oversecretion of multiple proinflammatory molecules, in particular tumor necrosis factor (TNF)-α. Hence, therapy of PsA refractory to disease-modifying antirheumatic drugs (DMARDs) relies mainly on the use of anti-TNF-α agents. However, since PsA can often be refractory also to these therapies, use of agents acting on other cytokines, such as interleukin (IL)-1 receptor targeted by anakinra, the IL-12/23 receptor by ustekinumab, the IL-17A by secukinumab, and the IL-6 receptor by tocilizumab, has been reported successfully. Herein we report a case of a refractory PsA patient successfully treated with the IL-6 receptor agent, tocilizumab. A review of the literature on the use of tocilizumab in PsA has been performed.

Simple clinical indicators for early psoriatic arthritis detection.

BACKGROUND: Diagnosis of psoriatic arthritis (PsA), in a period of 12 months from the onset of the first articular episode, permits of identifying the early form defined as "early PsA". The recognition of the disease in this phase leads to better outcome. The aim of this study was to identify peculiar clinical and/or laboratory findings that could be useful for the diagnosis of "early PsA". FINDINGS: Thirty-five patients with early onset of arthritis were observed. The following data were collected for each patient: family and personal history, physical examination, tender and swollen joint counts (TJC, SJC), tender entheseal count, presence of dactylitis and low back pain (LBP), and laboratory tests. Among the 35 total patients, 24 showed skin and/or nail psoriasis or a family history of psoriasis. The remaining 11 patients showed absence of concomitant or previous psoriasis and/or familiarity for psoriasis. The comparison between the two groups showed that patients with psoriasis had a significant presence of LBP, dactylitis and enthesitis than patients with psoriasis. CONCLUSIONS: The study confirms that the distinctive clinical findings of PsA is psoriasis, but also LBP, dactylitis and enthesitis have a relevant role in early identification. A low number of SJC and TJC are frequently observed in early phases of PsA than in other forms of early arthritis. These aspects could be mostly helpful when psoriasis is not detected or can follow arthritis in absence of familiar positivity, making difficult PsA diagnosis. In conclusion, careful medical history, clinical examination and first-level laboratory investigations are useful to characterize early phases of PsA.