Current Rheumatology Reviews - Volume 17, Issue 2, 2021

The new coronavirus infection (Covid-19) is a pandemic that has affected the whole world and progresses with high morbidity and mortality. It has a high contagion rate and a course capable of rapid lung involvement with severe acute respiratory distress syndrome (ARDS) and pulmonary insufficiency. A severe clinical picture develops as a result of a “perfect cytokine storm” which results from possible immunological mechanisms triggered by the viral infection. Immune system dysregulation and possible autoinflammatory and autoimmune mechanisms are responsible for a higher amount of cytokines release from immune cells. Although no clear treatment of Covid-19 infection has emerged yet, it is argued that some disease-modifying anti-rheumatic drugs (DMARDs) may be effective in addition to anti-viral treatments. These drugs (anti-malarial drugs, colchicum dispert, biologics) have been well known to rheumatologists for years because they are used in the treatment of many inflammatory rheumatologic diseases. Another important issue is whether DMARDs, which can cause severe immunosuppression, pose a risk for Covid-19 infection and whether they have been discontinued beforehand. Although there are insufficient data on this subject, considering the risk of disease reactivation, patients may continue their DMARDs treatment under the supervision of a rheumatologist. In this article, the possible immunological mechanisms in the pathogenesis of Covid-19 infection and the efficacy and safety of various DMARDs used in the treatment are discussed from a rheumatologist’s perspective in the light of recent literature data.

Background: Gout, inflammatory arthritis caused by the deposition of monosodium urate crystals into affected joints and other tissues, has become one of the major health problems of today's world. The main risk factor for gout is hyperuricemia, which may be caused by excessive or insufficient excretion of uric acid. The incidence is usually in the age group of 30- 50 years, commonly in males. In developed countries, the incidence of gout ranges from 1 to 4%. Despite effective treatments, there has been an increase in the number of cases over the past few decades. Objective: In recent years, the development of targeted drugs in gout has made significant achievements. The global impact of gout continues to increase, and as a result, the focus of disease-modifying therapies remains elusive. In addition, the characterization of available instrumental compounds is urgently needed to explore the use of novel selective and key protein-ligand interactions for the effective treatment of gout. Xanthine oxidase (XO) is a key target in gout to consider the use of XO inhibitors in patients with mild to moderate condition, however, the costs are high, and no other direct progress has been made. Despite many XO inhibitors, a selective potent inhibitor for XO is limited. Likewise, in recent years, attention has been focused on different strategies for the discovery and development of new selectivity ligands against transforming growth factor beta- activated kinase 1 (TAK1), a potential therapeutic target for gout. Therefore, the insight on human XO structure and TAK1 provides a clue into protein-ligand interactions and provides the basis for molecular modeling and structure-based drug design. Conclusion: In this review, we briefly introduce the clinical characteristics, the development of crystal, inhibitors, and crystal structure of XO and TAK1 protein.

Rheumatoid arthritis is an auto-immune disorder, recognized by cartilage as well as bone destruction, which causes irreversible joint deformities, which further results in functional limitations in the patient. Genes like HLA-DRB1 and PTPN22 are likely implicated in the genetic predisposition of rheumatoid arthritis pathology. The first and foremost clinical manifestation in a person with rheumatoid arthritis is joint destruction followed by cartilage and bone destruction caused by cell-cell interactions. The cell-cell interactions are thought to be initialized through the contact of antigen-presenting cells (APC) with CD4+ cells, leading to the progression of the disease. APC includes a complex of class Ц#134;Ц#134; major histocompatibility complex molecules along with peptide antigens and binds to the receptors present on the surface of T-cells. Further, the activation of macrophages is followed by the release of various pro-inflammatory cytokines such as IL-1 and TNF-α, which lead to the secretion of enzymes that degrade proteoglycan and collagen, which in turn, increase tissue degradation. Biomarkers like IL-6, IL-12, IL-8 and IL-18, 14-3-3η, RANKL, IFN-γ, IFN-β and TGF-β have been designated as key biomarkers in disease development and progression. The study of these biomarkers is very important as they act as a molecular indicator of pathological processes that aggravate the disease.

Introduction: We performed a systematic review of the literature to determine the value of bronchoalveolar lavage (BAL) in evaluating the pulmonary involvement of systemic sclerosis (SSc). Methods: Articles published between 1980 and 2019 were retrieved from the databases: PubMed and Scielo. The search was restricted to clinical trials published in English, utilizing the keywords “scleroderma, systemic sclerosis, interstitial lung disease, and bronchoalveolar lavage”. Results: Twenty-two papers were analyzed. A positive correlation was observed between increased BAL cellularity (alveolitis) and worsening clinical symptoms, pulmonary function, and radiological pattern in 2, 11, and 15 studies, respectively. The majority of BAL studies that evaluated interleukin levels, including TNF-α, IL-6, IL-7, and IL-8, observed higher levels in patients with impaired pulmonary function and increased lung involvement. Conclusions: Alveolitis and the increase of some cytokines/chemokines in BAL were related to more severe pulmonary disease in SSc in the majority of the studies and seemed to be markers of worse prognosis, but it is unknown whether BAL adds clinical value to the use of the other non-invasive diagnostic procedures.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by progressive swelling and stiffness in the joints. Mavrilimumab is a human monoclonal antibody that may block the autoimmune mechanism of the antibodies causing RA. Objective: We aim to assess the safety and efficacy of Mavrilimumab in treating rheumatoid arthritis. Methods: We conducted an online search using PubMed, Scopus, Web of Science, and Cochrane CENTRAL till June 2019, and updated the search in May 2020, using relevant keywords. We screened studies for eligibility. Data were extracted from eligible studies and pooled as Risk ratio (RR) with a 95% confidence interval (CI), using Review Manager software (ver.3.5). Results: Five studies (with 1145 patients) were eligible to our criteria. Pooled result from three trials showed a significant reduction in Disease Activity Score 28 based on C-reactive protein (DAS28-CRP) remission < 2.6 after 12 weeks (RR = 3.31, 95% CI [1.53, 7.18], P = 0.002), American College of Rheumatology (ACR) 20, after 12 weeks (RR = 2.38, 95% CI [1.80, 3.16], P < 0.00001), ACR 50, after 12 weeks (RR = 2.93, 95% CI [1.67, 5.15], P = 0.0002), ACR 70, after 12 weeks (RR = 4.90, 95% CI [1.60, 15.00], P = 0.005). Mavrilimumab not associated with a significant adverse event (RR = 1.22, 95% CI [0.89, 1.68], P = 0.22). Conclusion: We found that subcutaneous Mavrilimumab was effective and well-tolerating in treating RA patients, with no significant adverse events.

Introduction: Over 4.9 million cases of Coronavirus disease 2019 (COVID-19) have been confirmed since the worldwide pandemic began. Since the emergence of COVID-19, a number of confirmed cases reported autoimmune manifestations. Herein, we reviewed the reported COVID-19 cases with associated autoimmune manifestations. Methods: We searched PubMed database using all available keywords for COVID-19. All related studies between January 1st, 2020 to May 22nd, 2020 were reviewed. Only studies published in English language were considered. Articles were screened based on titles and abstracts. All reports of confirmed COVID-19 patients who have associated clinical evidence of autoimmune disease were selected. Results: Among the 10006 articles, searches yielded thirty-two relevant articles for full-text assessment. Twenty studies has met the eligibility criteria. The twenty eligible articles reported 33 cases of confirmed COVID-19 diagnosis who developed an autoimmune disease after the onset of covid-19 symptoms. Ages of patients varied from a 6 months old infant to 89 years old female (Mean=53.9 years of 28 cases); five cases had no information regarding their age. The time between symptoms of viral illness and onset of autoimmune symptoms ranged from 2 days to 33 days (Mean of the 33 cases=9.8 days). Autoimmune diseases were one case of subacute thyroiditis (3%), two cases of Kawasaki Disease (6.1%), three cases of coagulopathy and antiphospholipid syndrome (9.1%), three cases of immune thrombocytopenic purpura (9.1%), eight cases of autoimmune hemolytic anemia (24.2%), and sixteen cases of Guillain-Barré syndrome (48.5%). Conclusion: COVID-19 has been implicated in the development of a range of autoimmune diseases, which may shed light on the association between autoimmune diseases and infections.

Background: Neuropsychiatric symptoms have been well documented in several systemic inflammatory conditions, for example, systemic lupus erythematosus (SLE). Increased prevalence of cognitive decline and psychiatric issues has been reported in patients with rheumatoid arthritis (RA). However, there is limited evidence of which exact cognitive domains are affected and to what degree. Aim: To test the performance of cognition in the domain of ideational fluency (Thing Categories Test in particular) in patients with RA and compare the results with the general population and to the results with cognitive and depression screening scores in both groups. Methods: Patient Health Questionnaire 9 (PHQ-9), Generalized Anxiety Disorder 7 (GAD-7) assessment, Montreal Cognitive Assessment (MoCA), and Thing Categories Test (TCT) were used to evaluate patients with RA, as well as the control group. Results: Twenty patients with RA and 20 controls were tested, with 7 and 4 men, and 13 and 16 women in the study and control group, respectively. Average scores in TCT at three minutes were 7.50 (IQR6.0-10.0) and 6.0 (IQR3.0-8.0) for category “blue”; 17.50 (IQR15.0-19.0) and 16.0 (10.0-18.0) for category “round” in the control and study group, respectively. A statistically significant difference was established between the study and the control group in TCT for the category “blue” (p<0.025). The average score for GAD7 was 2.0 (IQR 0.0-5.75) and 3.0 (IQR0.50-6.00) in the control and study group, respectively. The average score for PHQ-9 was 2.0 (IQR0.25-4.75) and 4.0 (IQR2.00-5.50) in the control and study group, respectively. Finally, the average score for the MoCA scale was 27.0 (IQR25.25-28.00) and 26.0 (IQR23.50-28.00) in the control and study group, respectively. Conclusion: Preliminary evidence suggests that RA at least partially affects the cognitive domain of ideational fluency. However, further research with larger experimental groups is needed to provide more conclusive evidence.

Background: Lupus nephritis (LN) represents 40%-50% of all systemic lupus erythematosus (SLE) patients, and rapidly progressive glomerulonephritis is associated with significant morbidity and mortality. Antineutrophil cytoplasmic antibody (ANCA) might be involved in the pathogenesis of LN. Objective: We evaluated the role of myeloperoxidase (MPO)-ANCA, proteinase 3 (PR3)-ANCA, and anti-glomerular basement membrane autoantibodies (anti-GBM autoAb) for the diagnosis of LN. Methods: In this cross-sectional study, 95 SLE patients were divided into 2 subgroups: LN group (n = 60) and non-LN group (n = 35). For further analysis, we subclassified the LN group into ANCA- positive (n = 16) and ANCA-negative (n = 44) LN patients. The entire Non-LN group was ANCA- negative. The SLE disease activity index (SLEDAI) was reported for each patient. Determination of MPO-ANCA, PR3-ANCA, and anti-GBM autoAb was performed using a novel multiplex bead-based technology in all patients. Data analyses were done using SPSS, version 20. Approval was obtained from the institutional review board of Zagazig University (ZU-IRB#6000). Results: Of 95 patients with SLE, 16 patients (16.84%) had ANCA-positive LN, all of which were MPO-ANCA. There was a positive correlation between MPO-ANCA and SLEDAI, as well as with class IV LN. Receiver operating characteristic analyses revealed that the sensitivity and specificity of MPO-ANCA were 81.3% and 99.8%, respectively, in discriminating LN from systemic lupus without nephritis. Conclusion: MPO-ANCA level was significantly correlated with SLEDAI, inflammatory markers, kidney function tests, and LN class IV.

Background: Systemic lupus erythematosus (SLE) has a variable natural history and clinical characteristics. Objectives: This study aims to evaluate the clinical and immunological characteristics, and assess the disease accrual of an Egyptian SLE cohort. Methods: The study included 569 SLE patients who were collected from three different centers; demographic, laboratory data, cumulative manifestations, and comorbidities were assessed (characteristics at the time of diagnosis were recorded retrospectively, while current clinical data were recorded cross-sectionally). Evaluation of disease activity was done using Systemic Lupus Erythematosus Disease Activity Index score (SLEDAI) and damage by Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index (SDI). Results: The median age of patients at disease onset was 25.0±10.5 years, the median disease duration was 4.0 (6.5) years, the female to male ratio was (12.5:1), and the median SLEDAI was 12.0±14.0. Family history of SLE was noticed in 4%. Antinuclear antibody was positive in all patients and 86% had positive anti-double-stranded DNA. Arthritis/arthralgia was the most frequent presenting symptom (44%) followed by fever (39%). Along the disease course; alopecia was the most common clinical manifestation (76.1%), followed by constitutional symptoms (75.9%), and nephritis (65.7%). Three hundred and five patients encountered organ damage (SDI >1); kidney damage was the most frequent (32%), followed by cardiovascular damage (24.3%). Neutropenia, hypocomplementemia, arthritis, hypertension, longer disease duration, and higher disease activity were found to be independent risk factors for disease damage. Conclusions: There are some diversities and similarities in our findings compared to the previously reported data. Arthritis is the most common presenting symptom, while alopecia is the most frequent clinical finding, and a higher prevalence of nephritis was reported. Renal damage is the most frequent outcome.

Background: Among rheumatoid arthritis patients (RA), general disease activity is well regulated by disease-modifying anti-rheumatic medications (DMARDS), but sometimes local inflammation still persists among a few joints. Adjuvant modern molecular interventions as Platelet Rich Plasma (PRP) with a suggested down regulating effect on inflammatory mediators has a proven effect in the management of RA. We aim to evaluate the therapeutic effect of intra-articular PRP versus steroid in RA patients and their impact on inflammatory cytokines IL1B, TNF α, local joint inflammation, disease activity and quality of life (QL). Methods: Open-labeled parallel randomized control clinical trial was carried out on 60 RA patients randomly divided into 2 groups, Group 1: included 30 patients received 3 intra-articular injections of PRP at a monthly interval, Group 2: included 30 patients received single intra-articular injection of steroid. They were subjected to clinical, laboratory, serum IL1B and TNF α assessment at baseline and at 3, and 6 months post injection. Results: Patients of both groups showed improvements in their scores of evaluating tools at 3months post injection and this improvement was persistent in the PRP group up to 6 months post injection while it was continued only for 3 months in the steroid group. Conclusion: PRP is a safe, effective and useful therapy in treating RA patients who had an insufficient response and persistent pain and inflammation in just one or two joints through its down regulating effect on inflammatory cytokines IL1B, TNF α with subsequent improvement of local joint inflammation, disease activity and QL.

Background: Juvenile idiopathic arthritis (JIA) could be disabling if left untreated. Methotrexate (MTX) is well known as a cornerstone in management. However, its adverse effects may limit treatment. Objective: The objective of this study was to evaluate the frequency of hepatotoxicity based on liver chemistry in JIA children receiving MTX. Methods: An observational case-control study of children with JIA who attend the Pediatric Rheumatology Unit, Cairo University Pediatric Hospital, Egypt, from January 2018 to December 2018 was carried out. Data were retrieved for 80 children; 50 (62.5%) were prescribed MTX. Their demographic, clinical characteristics, mean dose, duration of MTX therapy and other medications were described. Hepatotoxicity was defined as at least one value above the normal laboratory range of either ALT or AST during the study period. Results: Fourteen patients developed hepatotoxicity, giving an incidence of 28%. Children receiving MTX had higher alanine aminotransferase (ALT) interquartile range (IQR) (26 [21-359] vs. 23[20-32]; p =0.003), higher aspartate aminotransferase (AST) interquartile range (IQR) (31 [22-267] vs. 28[2-35] IU/L; p <0.001), and lower alkaline phosphatase (ALP) mean (±SD) (98±35.5 vs. 256 ± 39.5 IU/L; p <0.001). However, there were no significant differences in age, sex, weight, type of JIA, and duration of MTX treatment (p< 0.05). Conclusion: Hepatotoxicity due to MTX, based on liver chemistry, is common among children with JIA.

Aim: To assess the probable role of +49AG polymorphism in susceptibility to SLE in an Egyptian population. Background: Systemic lupus erythematosus (SLE) is a compound inflammatory chronic disease distinguished through the release of autoantibodies. Cytotoxic T lymphocyte associated antigen-4 is a main down controller of T-cell response; its dysregulation could affect SLE pathogenesis by altered T cells activation to self-antigens. Objectives: To evaluate the CTLA-4 +49AG allelic and genotype frequency in a sample of the Egyptian population and correlate them with disease susceptibility and clinical severity. Materials and methods: Including 100 patients with SLE and 100 healthy controls (age and gender matched), CTLA-4 exon 1 49 A>G Genotyping was done using Real-Time PCR. Results: No difference was noticed in genotype or allele distributions of the studied polymorphism between both groups. Similar genotypes and allele frequencies were established for the 2 groups after their stratification by the age of disease onset, clinical course, or severity. Conclusion: CTLA-4 +49AG gene polymorphism is not linked with the liability to develop SLE in the studied Egyptian population. Yet it is significantly related to disease severity.

Background: Patients with rheumatologic disorders often have comorbidities that complicate their psychological well-being. In this study, we looked at 216 patients with rheumatoid arthritis (RA), systemic lupus erythematous (SLE), psoriatic arthritis (PsA), and Sjogren’s syndrome (SS) to determine the prevalence of anxiety, depression, sleep disturbance, fibromyalgia (FM), obesity (BMI greater than 23), and gastroesophageal disease (GERD) and the correlation between FM, BMI, disease activity measure, known as Routine Assessment of Patient Index Data 3 (RAPID3). Methods: Study participants were 216 rheumatology patients seen at the UCF Pegasus Health Clinic from November 2011 to May 2014 with one or more of the following diseases: RA, SS, SLE, or PsA. 116 had rheumatoid arthritis, 27 with systemic lupus erythematous, 22 with psoriatic arthritis, 20 with Sjogren’s syndrome, and 31 with more than one diagnosis. Variables that were collected from patients’ charts included RAPID3 scores, patient demographics (age, sex), BMI, presence of GERD, and presence of FM. Each patient was randomly assigned, unique and had an unidentifiable study number. Results: Anxiety, depression, sleep disturbance and obesity were found to be more prevalent in patients with Sjogren’s syndrome, and fibromyalgia was noted to be more prevalent in patients with more than 1 diagnosis. The presence of fibromyalgia was significantly correlated with higher RAPID3 scores in all patients except those with PsA. Significant correlation among higher BMI and greater RAPID3 scores was found for patients with rheumatoid arthritis and for patients with Sjogren’s syndrome. Conclusion: Our study showed an increased prevalence of anxiety in patients with Sjogren’s syndrome. Fibromyalgia was found to be related to higher disease activity scores. In RA and SS patients, BMI was significantly correlated with higher RAPID3 scores. These results provide a basis for future studies to evaluate these correlations in more detail.

Objective: This is a secondary analysis of a randomized controlled trial that aimed to assess subclinical atherosclerosis in patients with rheumatoid arthritis (RA) by measuring carotid artery intima-media thickness (CIMT) and correlating it with disease activity and inflammatory markers (including levels of matrix metalloproteinase-3(MMP-3) and matrix metalloproteinase-9 (MMP-9)) and to detect the effectiveness of agents that inhibit matrix metalloproteinases (MMPs) as doxycycline in RA therapy. Methods: One hundred and sixty RA patients were assigned in a randomized clinical trial (clinicaltrial. gov NCT03194204). Disease activity score 28(DAS28), laboratory markers, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), MMP-3, and MMP-9 were evaluated and mean CIMT was measured. Subjects were allocated randomly into one of two treatment arms, either methotrexate (MTX) alone or MTX with doxycycline 200mg per day orally. Follow up ESR, CRP, DAS28, MMP-3, and MMP-9 levels were re-evaluated after 3 months. Results: There were positive significant correlations between CIMT and disease duration (r = 0.461, p = 0.001), age (r=0.459, p= 0.001), DAS28 score (r= 0.547, p = 0.001), ESR (r =0.413, p = 0.001), CRP (r = 0.281, p = 0.001), MMP-3 (r = 0.476, p = 0.001), and MMP-9 (r = 0.593, p =0.001). Patients treated with MTX and doxycycline showed lower levels of DAS28, ESR, CRP, MMP-3, and MMP-9 and this was statistically significant. Conclusion: CIMT seems to be the ultimate method to screen for subclinical atherosclerosis in RA patients. MMP-3 and 9 play a key role in both RA synovitis and cardiovascular changes, making them important therapeutic targets, especially with safe and cost-effective agents like doxycycline. This clinical trial was carried out in Assiut University Hospital (AUH), Assiut, Egypt (Clinical Trial Registration No. clinicaltrial.gov NCT03194204).

Background: Psoriasis (Pso) is a common chronic inflammatory disease affecting the skin, both sexes, and all ages. It can be associated with other chronic inflammatory musculoskeletal disorders and certain drugs, including tumor necrosis factor α (TNFα) antagonists. Case Presentation: A 64-year-old man with seronegative rheumatoid arthritis (RA) refractory to leflunomide and prednisone was treated with SB-4 (Benepali), an etanercept biosimilar 50mg/week subcutaneously. He responded well to the treatment, but a year later, he developed erythematous skin eruptions affecting mainly in the palms of both hands. Skin biopsy showed a picture compatible with Pso. SB-4 was discontinued, and the skin lesions disappeared with the addition of topical steroid therapy. This is the only case of psoriatic skin lesions associated with SB-4 treatment. Conclusion: Thus, we review and discuss the relevant literature of Pso cases related to SB-4 and other anti-TNFα biosimilars. Rheumatologists dealing with patients on anti-TNFα biosimilars should be aware of and recognize these complications.