Current Rheumatology Reviews - Volume 14, Issue 2, 2018

Osteoarthritis represents the most frequently diagnosed condition of the musculoskeletal system and accounts for a high amount of direct and indirect socioeconomic costs worldwide. While for rheumatoid arthritis much progress has been made in the past decades both in understanding its pathogenesis and in creating novel therapies, the pathophysiology of osteoarthritis still holds several secrets to be unraveled in the near future in order to also allow for the development of effective novel pharmacotherapeutical options. Though first categorized as a joint disorder being primarily non-inflammatory in nature for a long period of time with research focused on biomechanic aspects and imbalanced wear and tear, recent evidence including immunological processes helped to refine disease interpretation. Thus, showing true inflammatory characteristics that clinically emerge as synovitis, osteoarthritis is nowadays recognized to include signs of inflammation that at least histologically may sometimes be indistinguishable from rheumatoid synovial infiltration. Although this was known already more than 25 years ago, efforts made in solving pathophysiologic key issues did not succeed sufficiently. This review is thought to summarize elementary pathogenic aspects including genetic predisposition and epigenetic regulation and highlights important central innate but also putative adaptive immunological mechanisms today generally accepted to drive inflammation and tissue destruction in osteoarthritis.

Osteoarthritis (OA) is the most common joint disease and a leading cause for impaired function and disability with significant treatment costs and socio-economic burden. Despite recent achievements in the knowledge on disease pathogenesis, the treatment is still a challenge and contrary to the inflammatory joint diseases, no disease-modifying drugs are currently available for OA. Different response in different localizations of the disease further complicates the therapeutic choice. The standard pharmacological treatment includes agents for control of pain and inflammation (non-steroidal anti-inflammatory drugs, analgesics including opioids, intraarticular corticosteroids) and the group of the symptomatic slow acting drugs for OA such as glucosamine sulfate, chondroitin sulfate, diacerein, unsaponifiables extract of soybean and avocado administered orally and intrarticular hyaluronic acid. In addition, a number of studies investigate the efficacy of classic disease-modifying drugs used in inflammatory arthritides and antiresoptive agents as potential future therapies that could prevent structural progression of the disease. In a number of small studies, therapeutic efficacy of hydroxychloroquine (HCT) in OA has been suggested, but the results are contradictory. The first results from a multicenter, randomized, double-blind, placebo-controlled trial focused on symptomatic hand OA were recently reported (British HERO study). It has been concluded that HCQ was not superior than placebo as analgesic treatment or for reduction of the radiographic progression in hand OA. Placebo-controlled trial evaluating the efficacy of HCT in inflammatory and erosive hand OA is under way (OA TREAT study). Another field of recent research is the efficacy of TNF-alpha blockers based on the knowledge of their high efficacy in the inflammatory joint diseases and the significant role of TNF-alpha in the pathogenesis of OA. However, current evidence from the available studies does not support the use of TNF-alpha blockers in OA. The benefit of TNF-alpha blockers in specific sub-groups of patients with higher level of inflammation, objective criteria for the expected responders as well as cost-effectiveness of such treatment is a matter of further research and discussion. New biologic agents that target the nerve growth factor-β are other currently investigated drugs as a potential symptomatic therapeutic option in OA. Significant research has been also focused on revealing potential symptomatic or eventually disease-modifying efficacy of drugs that target bone metabolism due to contemporary notion for the crucial role of the subchondral bone in OA pathology and the positive association between the increased subchondral bone turnover and the progressive cartilage loss. A significant delay of joint width narrowing vs. placebo has been observed in patients with symptomatic knee OA after treatment with strontium renelate. The intraarticular administration of platelet-rich plasma is evaluated as potential future therapy and has been tried in knee and hip OA with beneficial effect. Based on the current knowledge about the OA pathogenesis and the undergoing studies, new therapies for OA are awaited both as a safe symptomatic treatment - alternative to the conventional treatment options and as a disease-modifying therapy that would revolutionize the contemporary approach to OA.

Background: In view of the already existing and the expected growing costs due to the pathological osteoarthritic joint alterations and the related consequences, preventive and conservative strategies which can avoid or delay osteoarthritic joint alterations are welcomed from a socioeconomical perspective. Here, it should be mentioned that corresponding primary prevention measures should take place early by already educating children about a healthy diet and motivating them to regular physical exercise. In overt or symptomatic osteoarthritis, a good joint function and reduction of disease-related pain as well as a delay in the progression of osteoarthritis should be the primary goals of non-surgical therapeutic approaches. Objective: The current body of studies is already able to prove the effectiveness of differential indicative physiotherapeutic and physical measures and should be further developed in the future. Nevertheless, the implementation of the available knowledge from the studies under evidencebased medicine criteria proves difficult during the daily routine in clinics. On one hand, an assessment of the effectiveness of physical therapy within the framework of a multimodal treatment approach (e.g. thermotherapy in combination with manual therapy) is difficult to define. Result and Conclusion: On the other hand, an objective assessment of treatment success, owing to the heterogeneity among the patients (above all varied disease activity, functional limitations, accompanying diseases and therapy) will also remain complicated.

Therapeutic exercises in osteoarthritis (OA) are therapeutic approach with proven efficacy. However, the different disease forms, the lack of established consensus and system for patient education limit the widespread use of therapeutic exercises in clinical practice. The mechanisms of action of therapeutic exercise in OA include the following components e.g. neuromuscular (improvement of proprioception, muscle strength and joint stability), intra-articular (prevention of cartilage degeneration, antiinflammatory effect, improvement of the quality of the joint fluid), periarticular, general health with reduction of cardiovascular risk and psychological components. The main exercises, which are used in OA patients, are stretching exercises, range of motion exercises, analytic exercises for muscle strengthening (isometric and isotonic) and aerobic exercises (walking, cycling, swimming, etc.). The recommended exercise programmes have to be individualized according to patient age, severity of OA and presence of concomitant diseases. The analytic exercises for improvement of muscle strength in hip OA aim to influence the abductors, adductors, flexors and extensors of the hip joint. In knee OA, the target muscle groups are thigh muscles (quadriceps muscle and posterior group of thigh muscles), calf muscles (triceps surae muscle) as well as muscles around the hip joint. There are no established programmes for therapeutic exercises regarding the intensity, frequency, the degree and the interval for increasing of joint load. No significant difference in the efficacy of group vs. individual exercise programmes has been observed. In OARSI recommendations (2010), it is underlined that aerobic exercises and those for muscle strength have a moderate efficacy in knee OA for pain relief e.g. ES (effect size) - 0.52 (for aerobic exercises) and 0.32 (for strengthening exercises). The ES for functional improvement is 0.46 for the aerobic exercises and 0.32 for the strengthening exercises. The data for the role of therapeutic exercises in hip OA are scarce. An effect on pain has been observed (ES-0.38) but without improvement of functional capacity. Therapeutic exercises have low to moderate complex efficacy in patients with OA. They should be an obligatory part in the therapeutic regimens of the patients, which requires close collaboration between rheumatologists, general practitioners and physiotherapists as well as establishment of system for patient education.

The biological drugs have all been successfully used to treat rheumatoid arthritis (RA) and have led to fair rates of clinical remission; however, the possible occurrence of adverse events such as infectious diseases or cancers means that the patients undergoing treatment need to be closely monitored. Anti-TNF agents, first appeared in the pharmacological algorithm of RA in the early 2000s, seem to lead to a higher risk of reactivated tubercular infection than the biological agents with different mechanism of action (abatacept or rituximab). Although the data on anti-TNF agents and cancer are controversial, their use is currently not recommended in neoplastic patients because of their uncertain effects on immune-surveillance. The safety profile of abatacept is similar to that of other biological agents, while rituximab is used to treat non-Hodgkin lymphomas and is also considered in the case of RA patients with previous hematological or non-hematological malignancies. The risk of infections and new-onset cancers during tocilizumab treatment is similar to that associated with other biological therapies. Finally, under particular circumstances, such as in the presence of infections or malignancies, blocking a specific immunological pathway may be simultaneously successful and detrimental. The only thing that can be done at the moment is to continue to look for adverse events in order to discover these complications as soon as possible, and then develop the most appropriate means of treating (and even preventing) them.

Systemic Lupus Erythematosis (SLE) is a heterogeneous and complex disease produced by diverse pathogenic events in the innate and adaptive immune system. Lupus nephritis affects over half of all patients with lupus and leads to substantial morbidity and mortality. This review presents our current understanding of the development of lupus nephritis and examines the role of genetics and epigenetics in further elucidating the pathogenesis of the disease. Advancements in genomics are leading the way to better understanding and novel biologic therapies for SLE.

Background: Systemic Lupus Erythematosus (SLE) is an autoimmune disorder, characterized by producing different auto-antibodies and multiorgan involvements. In this study we aimed to investigate the relationship between SLE activity and persistently positive antiphospholipid antibodies. Objective/Methods: Fifty-nine lupus patients (55 women and 4 men) who were assessed in two consecutive visits with 6 weeks interval were selected. Patients' clinical and laboratory data and serum antiphospholipid antibodies' values, were collected. Serum anticardiolipin antibodies and lupus anticoagulant were measured in two visits. The correlations between these antibodies with SLEDAI and with major organ involvements were assessed. We found that SLEDAI was significantly higher in persistently positive aPLs patients compared with persistently negative aPLs patients. A positive correlation between IgG-aCL antibody titer and SLEDAI at first visit (P=0.049) was also seen. Result and Conclusion: The results showed that disease activity in SLE was associated with increased APAs and persistent positive antiphospholipid antibodies may indicate higher lupus disease activity.

Objectives: To study the utility of gray scale and power Doppler ultrasonography in assessing the disease activity and correlation of ultrasonographic findings with disease activity parameters in Rheumatoid Arthritis (RA). Materials and Methods: This cross-sectional study was conducted on 100 RA patients diagnosed as per 2010 classification criteria. Rheumatoid Factor (RF), serum Anti-cyclic Citrullinated Peptide Antibodies (ACPA), Erythrocyte Sedimentation Rate (ESR), C-reactive Protein (CRP), disease activity score with 28-joint counts and ESR (DAS28-ESR), Visual Analogue Scale (VAS) for global disease activity and Gray Scale Ultrasonography (GSUS) and Power Doppler Ultrsonography (PDUS) scores in hands and wrists were determined. Results: Of 100 RA patients with clinically active arthritis, GSUS detected disease activity in all and PDUS in 95 (95%) patients. Of total 2200 joints assessed, disease activity was seen by clinical assessment in 51.31% (1116/2200), GSUS in 57.36% (1262/2200) and PDUS in 48.36% (1064/2200) joints. For detecting active arthritis, clinical assessment showed 79.5% sensitivity and 76.2% specificity while GSUS showed 100% sensitivity and 82.5% specificity using PDUS as a gold standard. GSUS findings of synovitis, joint effusion and bone erosions and PDUS score showed significant correlations with the swollen joint count, tender joint count, ESR and DAS28- ESR (p<0.05 each) but not with VAS, CRP, RF and ACPA (p>0.05 each). Multivariate analysis showed that swollen joint count was independently associated with synovitis (p=0.029) and tender joint count with PDUS score (p=0.036). Conclusions: GSUS and PDUS findings are useful in ascertaining the disease activity and correlate with clinical disease activity in joints in RA.

Background: Juvenile Idiopathic Arthritis (JIA) is the most common inflammatory joint disease in children. JIA and autoimmune inflammatory Gastrointestinal (GI) diseases share common etiologic mechanisms, including genetic predisposition and environmental influences. Objective: To Investigate association between gastrointestinal, rheumatologic clinical variables and the presence of autoantibodies in patients with JIA in treatment. Methodology: In a cross-sectional study of patients with JIA according to diagnostic criteria and the ILAR classification. GI symptoms and autoantibody expression were evaluated with respect to their association with JIA clinical variables. Anti-Saccharomyces Cerevisiae IgG/IgA (ASCA), 6 antigen associated with anti polymorphonuclear neutrophil (ANCA), anti Transglutaminase (tTG) IgG/IgA, anti deaminated gliadin peptide (DGP) IgG/IgA autoantibodies, ANAS and IgA were measured in all patients. The association between clinical variables and auto-antibodies were evaluated using the Fisher test with significant value of p <0.05. The study was approved by the ethics committee of the all institutions. Results: Samples were collected from ninety-seven patients, 63% of whom were female. The average age was 14 years. The JIA subtype associated with the most common GI symptoms was enthesitis- related arthritis. Of these patients, 44.3% and 14% reported abdominal pain and diarrhea, respectively. Anti-DPG and anti-tTG antibodies were found in 9.28% and 7.22%, respectively and 11.34% were positive for p-ANCA, and 2% were positive for ASCA. Conclusion: GI symptoms and autoantibodies associated with inflammation of the GI mucosa were detected in JIA patients but were not associated with autoantibodies or clinical variables. However, it is the monitoring of these patients diagnosis is important.

Introduction: Systemic Sclerosis is known to involve the gastrointestinal system and can lead to multitude of problems predominantly affecting the GI motility. Methods: It was a prospective, observational, single centre study of fifty consecutive patients with SSc who presented to rheumatology clinic. Gut score was assessed using UCLA SCTC GIT 2.0 questionnaire. 35 patients underwent esophago- gastro duodenoscopy(UGIE), 31 underwent esophageal manometry, 37 underwent lactulose breath test to assess orocaecal transit time (OCTT) and glucose breath test for detecting small intestinal bacterial overgrowth (SIBO) and 36 underwent gastric emptying scintigraphy to measure gastric emptying time. Results: GI involvement was seen in 98% of patients, with most common symptom being regurgitation (78%). Mean T score of the GUT score was 0.60±0.27. In UGIE, esophagitis was seen in 30, of which 3 had candidiasis and 1 had HSV esophagitis. Hiatus hernia was noted in 10 patients. Mean lower esophageal sphincter pressure was 16.1± 12.7 mmHg with hypotensive sphincture in twelve patients. Esophageal peristaltic abnormalities were observed in 28(90%) patients. Gastric emptying was delayed in10/36 patients. OCTT was prolonged in 23/ 37 patients whereas SIBO was noted in 7/37. Conclusion: GI involvement is common in SSc with esophagus being most commonly affected. Motility abnormalities make them prone for super added infections especially infectious esophagitis and SIBO and should be investigated for early detection and treatment.

Background: ConclusionFibromyalgia is a chronic pain disorder characterized by diffuse musculoskeletal pain, fatigue, sleep disturbance and cognitive impairment. Objective: A significant number of fibromyalgia patients do not respond adequately to the current drugs approved by the Food and Drug Administration (FDA) for fibromyalgia treatment including pregabalin, milnacipran, duloxetine. Thus, there is still a need for adjunctive therapies. Method: Naltrexone is an opioid receptor antagonist used to treat alcohol and opioid dependence. It is hypothesized that low dose naltrexone causes transient blockade of opioid receptors centrally resulting in a rebound of endorphin function which may attenuate pain in fibromyalgia. Results: Two small prospective pilot studies have previously shown that treatment with low dose naltrexone may be an effective, safe, and inexpensive treatment for fibromyalgia. Conclusion: This prospective study lends further support to the preliminary body of evidence that naltrexone is a well tolerated and likely effective treatment option in the community setting. Further large prospective controlled trials are still needed.

Background: Knee osteoarthritis is a common pathology, characterized by a prevalence that increases with age. Absence of anatomo-clinical correlation is a complex management, particularly in a geriatric setting where it is not well studied. Objective: The aim of the present study is to investigate the epidemio-clinical profile, functional impairment and radiographic features of knee osteoarthritis in the old patients versus younger patients (<65 years). Methods: Cross-sectional study includes patients who were monitored for 6 months at a rheumatology department for knee osteoarthritis. Epidemio-clinical, anthropometric and radiographic data were gathered. A comparison was made of these various characteristics between patients of over 65 years of age (group1; n=56) and those under 65 (group2; n=56). Results: The mean age of the group 1 patients was 71±5 with a clear feminine predominance. Comorbidity was observed in two thirds of cases. More than half of them were overweight. Gonalgia had been evolving for approximately 8.4±9.2 years and was bilateral in 82.6% of the cases and of mechanical type in 94.6% of the cases. The patients experienced an average pain scale of 65.2mm. Pain had an anterior site in major of cases. An axial deviation of the lower limbs were observed in 60.7% of the cases and a limited mobility of the knees in 48.2% of the cases. The mean value of Lequesne index was 11.02±4.8. The walking distance was not limited in 37.5% of the cases. Radiographically, knee osteoarthritis was bilateral in all cases and stage 4 was observed in 50% of the cases. Comparative study showed that elderly patients had a smaller waist size (p=0.003), a longer course of gonalgia (p<0.0001), a widespread site of pain (p=0.004), and a more frequent limitation of walking distance (p<0.0001) as well as more axial deviation (p<0.0001) and joint mobility limitation (p=0.005). Gonalgia manifesting during rest was more frequent in elderly patients (p=0.001). In addition, impaired functioning (p=0.001) and the stage of radiographic damage (p=0.02) were more advanced in elderly patients. Conclusion: The present study shows that knee osteoarthritis is more severe in the elderly patients in terms of clinical presentation and functional impairment.

Objective: Joint involvement is common among patients with systemic lupus erythematosus (SLE). Aim of this work was to evaluate the correlation between the presence of joint involvement and patient-reported pain, perception of disease activity, general health and quality of life. Methods: Fifty consecutive SLE patients were enrolled in the study. All patients underwent a complete clinical evaluation including a 44-joint count; in addition, an ultrasound evaluation of joint involvement of hands and wrists was performed. The following patients reported outcomes (PROs) were completed: Visual Analog Scales 0-100 mm (VAS) evaluating patients reported pain, patient's perception of global disease activity and general health (GH) and a validated Italian version of the Health Assessment Questionnaire (HAQ). Results: Fourteen patients (28%) reported a significant morning stiffness lasting for more than 30 minutes; hand or wrist arthritis was clinically detectable in 10 (20%) patients, while the US evaluation exhibited at least one joint or tendon pathology in 18 patients (36%). The mean VAS score for pain and disease activity perception was 27 (±27.7) mm and 25.3 (±25.2) mm, respectively, the mean of GH score was 33.2 (±24.3) mm, and the mean HAQ score was 0.34 (±0.5). A significant correlation was observed between VAS score for pain, patient's perception of disease activity and GH and the presence of arthritis. Conclusion: PROs may play an important role in guiding therapeutic decisions and suggest the utility of ultrasound evaluation in patients reporting articular symptoms.