Current Rheumatology Reviews - Volume 15, Issue 3, 2019

Background: Accelerated atherosclerosis, responsible for premature cardiovascular disease, has been estimated to develop or progress in 10% of systemic lupus erythematosus (SLE) patients each year and to be 6-fold more frequent in SLE compared with the general population. The mechanisms underlying accelerated atherosclerosis in SLE are complex and involve classical and “non-classical” cardiovascular risk factors. Subclinical and disseminated atherosclerosis is associated with endothelial dysfunction and arterial stiffness. Objective: The aim of this review is to analyze the association between SLE and endothelial dysfunction. Results and Conclusion: Different mechanisms have been proposed to explain the prevalence of endothelial dysfunction in SLE, which are briefly reported in this review: impaired clearance of apoptotic cells, oxidative stress markers, B cell activation with different circulating autoantibodies, different subtypes of T lymphocytes, cytokine cascade. Several studies and meta-analyses show a significant trend towards a prevalence of subclinical accelerated atherosclerosis in patients with SLE compared with healthy controls, since childhood. Based on general considerations, we suggest a multidisciplinary management to assess endothelial dysfunction at the diagnosis of the disease and to periodically search for and treat the traditional cardiovascular risk factors. Prospective studies are needed to confirm the benefits of this management.

The low molecular weight fraction of commercial human serum albumin (LMWF5A) has been shown to successfully relieve pain and inflammation in severe osteoarthritis of the knee (OAK). LMWF5A contains at least three active components that could account for these antiinflammatory and analgesic effects. We summarize in vitro experiments in bone marrow–derived mesenchymal stem cells, monocytic cell lines, chondrocytes, peripheral blood mononuclear cells, fibroblast-like synoviocytes, and endothelial cells on the biochemistry of anti-inflammatory changes induced by LMWF5A. We then look at four of the major pathways that cut across cell-type considerations to examine which biochemical reactions are affected by mTOR, COX-2, CD36, and AhR pathways. All three components show anti-inflammatory activities in at least some of the cell types. The in vitro experiments show that the effects of LMWF5A in chondrocytes and bone marrow– derived stem cells in particular, coupled with recent data from previous clinical trials of single and multiple injections of LMWF5A into OAK patients demonstrated improvements in pain, function, and Patient Global Assessment (PGA), as well as high responder rates that could be attributed to the multiple mechanism of action (MOA) pathways are summarized here. In vitro and in vivo data are highly suggestive of LMWF5A being a disease-modifying drug for OAK.

Immune checkpoint inhibitors are revolutionized drugs for cancer immunotherapy in the last years. The mechanism of action of CPIs including the limitation of the activation of Tcells, and thus enhancing the self-immune response against tumour cells. Checkpointinhibitors( CPIs) may dysregulate the immune system, resulting in some toxicities. These toxicities or side effects are called Immune-related Adverse Events (IRAEs) that can potentially affect any organ and tissue. Rheumatic diseases due to checkpoint inhibitors are also reported in the literature. The spectrum of rheumatic manifestations are quite wide; the most common are arthralgia/arthritis, myalgia/myositis, polimyalgia rheumatica, lupus, rheumatoid arthritis, Sjögren’s syndrome. At the same time, these drugs can also cause an exacerbation of known rheumatologic disease. Treatment approaches for developing rheumatic findings due to checkpoint inhibitors should be multidisciplinary. There should be a close relationship between oncologists who follow-up these patients and rheumatologists. The rheumatic manifestations should be defined and treated early. In general, the musculoskeletal side effects are transient and may regress after stopping CPIs. The most commonly used medications are corticosteroids. Immunosuppressive drugs (HQ, MTX, anti-TNF-alpha, anti-IL-6) should be preferred when treatment is unresponsive or as steroid-sparing agents. The aim of this review was to evaluate the checkpoint inhibitors-related rheumatologic findings and therapeutic strategies in light of recent literature data.

Background: Rheumatoid arthritis is a systemic autoimmune disease, considered the most common inflammatory articular disease among the general population. However, not only the joints are affected; rheumatoid arthritis also has an extra-articular manifestation. As for many other chronic diseases, rheumatoid arthritis may be exacerbated by poorer lifestyle choices. In fact, recent studies emphasize the role of nutrition and physical activity in this disease. Aim: In the current paper, we aim to describe lifestyle modifications based on diet and physical activity and other recommendations that seem to improve the clinical management and the disease outcome of Rheumatoid arthritis. Results: A three-component lifestyle modification programme has been considered based on: (i) A low-fat low-sodium Mediterranean diet rich in fruits, vegetables, whole grains and nuts and poor in sugar-sweetened beverages, red and processed meat and trans fats, and the supplementation with omega-3 fatty acids, non-essential amino acids and probiotics, (ii) An appropriate physical activity programme based on an active daily lifestyle, aerobic exercise and resistance training and (iii) Adequate sleep hygiene and smoking reduction/cessation, that seems to have positive effects in terms of disease progression and related outcomes. Conclusion: Lifestyle modification programme should be considered as the basis of any treatment, (i.e., pharmacological treatment), in patients with rheumatoid arthritis.

Aim: To investigate the impact of body mass index (BMI) on clinical disease activity indices and clinical and sonographic remission rates in patients with rheumatoid arthritis (RA). Patients and Methods: Sixty-three patients with RA were categorized according to BMI score into three groups: normal (BMI<25), overweight (BMI 25-30) and obese (BMI≥30). Thirty-three of them were treated with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), and 30 with biologic DMARDs (bDMARDs). Patients underwent clinical and laboratory assessment and musculoskeletal ultrasound examination (MSUS) at baseline and at 6 months after initiation of therapy. We evaluated the rate of clinical and sonographic remission (defined as Power Doppler score (PD) = 0) and its correlation with BMI score. Results: In the csDMARDs group, 60% of the normal weight patients reached DAS28 remission; 33.3% of the overweight; and 0% of the obese patients. In the bDMARDs group, the percentage of remission was as follows: 60% in the normal weight subgroup, 33.3% in the overweight; and 15.8% in the obese. Within the csDMARDs treatment group, two significant correlations were found: BMI score–DAS 28 at 6th month, rs = .372, p = .033; BMI score–DAS 28 categories, rs = .447, p = .014. Within the bDMARDs group, three significant correlations were identified: BMI score–PDUS at sixth month, rs = .506, p =.004; BMI score–DAS 28, rs = .511, p = .004; BMI score–DAS 28 categories, rs = .592, p = .001. Sonographic remission rates at 6 months were significantly higher in the normal BMI category in both treatment groups. Conclusion: BMI influences the treatment response, clinical disease activity indices and the rates of clinical and sonographic remission in patients with RA. Obesity and overweight are associated with lower remission rates regardless of the type of treatment.

Background: It is unclear whether patients with Anti-Glomerular Basement Membrane (GBM) disease and Anti-Neutrophil Cytoplasmic Antibodies (ANCA), so called “Double-Positive” (DP), have a different clinical presentation and outcome compared to patients with anti-GBM antibody disease alone. This study describes the clinical and histologic characteristics as well as the patient and renal outcomes of DP patients at the University of Washington compared to patients with anti-GBM antibody disease alone. Methods: Adults admitted to the University of Washington and Harborview Medical Centers from 2000 to 2016 who had a kidney biopsy showing anti-GBM disease characterized by crescentic glomerulonephritis with strong linear staining of glomerular basement membranes for IgG by immunofluorescence were included. Subjects were classified into anti-GBM or DP based on serologic testing. Information on demographics, clinical presentation, biopsy findings, initial treatment, and rates of relapse and patient and renal survival were collected. Continuous and categorical variables were analyzed using the Mann-Whitney U and Fisher’s exact tests, respectively. Results: There were 6 anti-GBM and 7 DP patients. Two patients were lost to follow-up after one year. There was no significant difference in clinical presentation or outcomes between the two groups. Two DP patients had greater than 50% global glomerulosclerosis. All the subjects developed ESRD. Two DP patients had a relapse while off immunosuppression. Two patients in each group died within 5 years of diagnosis. Conclusion: Two DP patients in our cohort had a relapse within 5 years of diagnosis. Multicenter studies are needed to determine whether DP patients have a higher relapse rate and need prolonged immunosuppression.

Background: Atherosclerosis, inflammation and coronary plaque destabilization are linked to each other. Infections due to various microbes may trigger Acute Coronary Syndrome (ACS) by systemic inflammation cascade. Methods: We have evaluated the prevalence of Post Chikungunya Chronic Arthritis (PCCA) among 400 consecutive ACS patients (Case group) and compared with control group subjected to elective surgery by the prospective case-control observational study. Cases were excluded if standard criteria of ACS were not satisfied and in the control group if the patient suffered a Myocardial Infarction (MI) within 28 days of elective surgery. PCCA duration more than two years or serum IgM anti-CCP positive patients were also excluded from the case as well as a control group. Results: The case and control groups were similar except, less number of heart failure (O.R.7.3, 95% C.I. 3.3-15.9) and chronic kidney injury patients (O.R. 0.5, 95% C.I. 0.3-0.9) in the elective surgery (control) group. PCCA was present in 24 out of 400 ACS cases and 8 out of 400 control group. Among ACS case-patients, those suffering from PCCA tended to be younger and more often women, with more diabetes, hypertension, chronic kidney injury and high mean CRP. In unadjusted analysis PCCA was three times more common in the case versus control (O.R. 3.0, 95% C.I. 1.4- 6.4); results were indistinguishable after multidiscipline adjustment (O.R. 3.0, 95% C.I. 1.3-6.8). Conclusion: PCCA is common among patients with ACS and post-infective systemic inflammation of PCCA may trigger plaque destabilization.

Introduction: Psoriasis is a chronic immune-medicated inflammatory condition that affects 2-3% of the population, which can lead to psoriatic arthritis. There are multiple regimens for the treatment of psoriasis including disease- modifying anti rheumatic drugs (DMARDS) and biologic agent, phototherapy and apremilast. While monotherapy with biologic agents is effective for many patients with psoriasis some patients are not satisfied by the outcome and require combination therapy. No data exist on the safety of apremilast as a component of combination therapy with biological therapies. Objective: The aim of the study was to determine the safety of apremilast in combination of biologic therapies in the treatment of plaque psoriasis and psoriatic arthritis. Methods: This was retrospective study, open label study carried out at a single community Rheumatology center. Twenty-two patients diagnosed with plaque psoriasis and psoriatic arthritis according to American college of Rheumatology criteria-participated. Apremilast was added to their current biologic agent. Patients were permitted to their current biologic treatment. Results: Out of 22 patients, six patients developed side effects, none of which caused discontinuation of therapy. Out of the six patients who developed side effects, two patients developed nausea and two patients developed diarrhea. One patient developed weight loss and one patient developed abdominal pain. Conclusion: Apremilast can be safely combined with all biologic agents in patients with plaque psoriasis or psoriatic arthritis not responding adequately to biologics alone.

Background and Aim: Lymphoid cell infiltration and destruction of exocrine glands, specifically lacrimal and salivary glands are characteristics of Sjogren’s syndrome (SS). An etiological role has been proposed for Helicobacter pylori (H. pylori), interacting in the clinical course and complications of SS (including gastric cancer and lymphoma). The aim of this study was to identify the probable correlation between H. pylori infection and Sjogren’s syndrome (SS). Methods: In this case-control study, ELISA method was used to determine serum level of IgA and IgM anti H. pylori antibody in 43 subjects with SS according to the international criteria and 95 healthy subjects as control. SPSS-17 was used to analyze data with t-test. P value <0.05 were considered significant. Results: Serum level of IgM (34.9% vs. 10.5%, p-value= 0.001) and IgA (67.4% vs. 46.3% p value= 0.021) anti H. pylori antibody were significantly higher in SS patients compared to the control group. There was a positive correlation between age and H. pylori infection (r=0.2, Pvalue= 0.05). Conclusion: Patients with SS had a higher prevalence of H. pylori infection compared to the normal population. Eradication of H. pylori is recommended particularly in older patients with SS.

Objective: To determine the frequency of new-onset hypertension in patients with Rheumatoid arthritis taking leflunomide, in comparison with methotrexate in Asian setting. Material and Methods: Perspective case-control study was conducted in 2014 in a tertiary care hospital located in Karachi, Pakistan. Adult patients, having rheumatoid arthritis were randomly prescribed leflunomide or methotrexate. Patients having chronic hypertension, proteinuria and chronic kidney disease were excluded. Patients were monthly followed for blood pressure and heart rate measurements. Hypertension was defined using JNC 7 criteria. Results: Out of 144 patients enrolled, 80 patients received Leflunomide while 64 were started on methotrexate. Mean systolic blood pressure in leflunomide group at the start and at the end of study was 108.5 and 135.4mmHg, respectively while in methotrexate group, mean systolic BP was 109.8 and 110.5 mmhg, respectively. After one year follow up, 33 out of 80 (41%) patients were receiving leflunomide had pre-hypertension or hypertension, while only 3 out of 64 patients (4.7%) were receiving methotrexate had hypertension. Conclusion: Risk of developing hypertension in patient receiving Leflunomide is much higher in Asian population like Pakistan as compared to western population.

Background: Rheumatoid Arthritis (RA) is a common inflammatory disease of the joints. Due to the importance of inflammation and oxidative stress in the pathogenesis of RA, drugs that have anti-oxidant and anti-inflammatory properties, such as N-acetyl Cysteine (NAC), can be used as adjunctive therapy in patients with RA. Aims: The aim of this study was to evaluate the effects of oral NAC on inflammatory cytokines and oxidative stress in patients with RA. Methods: Adjunct to standard treatment, the NAC group (23 patients) received 600 mg of NAC twice daily and the placebo group (19 patients) received identical placebo twice daily for 12 weeks. Serum levels of Total Oxidant Status (TOS), Total Antioxidant Capacity (TAC), nitric oxide (NO), Total Thiol Groups (TTG), Malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), interleukin- 6 (IL-6), C-reactive Protein (CRP), and Erythrocyte Sedimentation Rate (ESR) were measured at baseline and at the end of the study. Results: Results showed that in the NAC group, the serum levels of MDA, NO, IL-6, TNF-α, ESR and CRP were significantly lower than the baseline. Also, the serum level of TAC and TTG, as antioxidant parameters, increased significantly. However, only NO, MDA and TTG showed a significant difference in the NAC group as compared to the placebo group at the end of study. Conclusion: According to the results of this study, oral NAC can significantly reduce the several oxidative stress factors and inflammatory cytokines. These results need to be confirmed in larger studies while considering clinical outcomes of RA patients.

Background: Sjögren's syndrome is an autoimmune disease characterised by exocrinopathy mainly involving the salivary and lacrimal glands. In addition, it is a multisystemic condition (i.e., affecting multiple organs and systems). Neurological involvement has been reported in ~20% of cases, with peripheral manifestations being the most frequent. Methods: We analysed four cases in which neurological manifestations were the first symptoms of Sjögren's syndrome. Results: In all four cases, neurological symptoms preceded sicca symptoms. In addition, immunosuppressive treatment with steroids and, in some cases, cyclophosphamide showed improvement. Conclusion: Neurological involvement in Sjögren's syndrome is common and often occurs as the first clinical manifestation. Since evidence is limited, more studies are required in order to determine appropriate diagnostic methods and treatments for each manifestation of Sjögren's syndrome.