COVID-19 and reported mortality cases among rheumatic disease patients in Kuwait: Data from the Global Rheumatology Alliance registry.

Mycophenolate mofetil and rituximab have been shown to be considerably associated with poorer outcomes following SARS-CoV-2 infection. Such agents were associated with longer hospital stay as well as severe COVID-19 outcomes (infection-related complications, intensive care unit admission, and mortality). Using the data of the COVID-19 Global Rheumatology Alliance (GRA) registry of inflammatory rheumatic disease (IRD) patients in Kuwait, who had COVID-19 from March 2020 to March 2021, revealed 4 mortality cases (3 cases used CD-20 inhibitors as monotherapy and 1 case used mycophenolate mofetil/mycophenolic acid as monotherapy). This article describes the characteristics and course of disease among 4 patients with IRD who died following COVID-19 infection at Jaber Al Ahmed Hospital, Kuwait. The current series raises the intriguing prospect that IRD patients may have a varying risk of unfavorable clinical outcomes depending on the type of biological agents they were given. Rituximab and mycophenolate mofetil should be used with caution in IRD patients, particularly if they have concomitant comorbidities that put them at a high likelihood of developing severe COVID-19 outcomes.

Is Serum Uric Acid Level Associated with Disease Activity in Rheumatoid Arthritis Patients.

Background: An association between serum uric acid (UA) and disease activity in rheumatoid arthritis (RA) patients has not been well studied. We describe RA patients with high and normal UA and study its association with RA activity. Methods: Adult RA patients from the Kuwait Registry for Rheumatic Diseases (KRRD) were studied from February 2012 through March 2022. Patients with documented UA levels were included. UA of >357 µmol/L (6mg/dL) was considered high. Statistical comparison and correlation were made using multivariate logistic regression. Results: Overall, 1054 patients with documented UA. A total of 158 patients (15%) had high UA level with a mean of 409± 44.4µmol/L. The mean age for the high UA group and low UA group were 59.3 ± 10.7 years and 54.5 ± 12.4 years, respectively (p<0.001). 49.4% were female in high UA group, and 62.2% were female in low UA group, respectively (p<0.05). Logistic analysis showed an inverse relation between DAS28 and UA, as lower DAS28 score was associated with higher UA level (p=0.032) OR 1.39. There was a direct relation with HAQ, creatinine and UA. A higher HAQ is associated with a higher UA level (p=0.019) OR 0.78. High creatinine level is also associated with high UA level (p<0.001) OR 0.24. The use of antirheumatic drugs was similar among patients with high and normal UA. Conclusion: RA patients with a higher UA had a lower disease activity despite using similar antirheumatic drugs. The reasons behind this association need to be further studied.

COVID-19 outcomes among rheumatic disease patients in Kuwait: Data from the COVID-19 Global Rheumatology Alliance (C19-GRA) physician registry.

PURPOSE: We aimed to assess the characteristics of inflammatory rheumatic disease (IRD) patients in Kuwait diagnosed with COVID-19 and the factors linked with hospitalization, complications, and mortality. METHODS: Data of IRD patients from Kuwait diagnosed with COVID-19 between March 2020 and March 2021, submitted to the COVID-19 Global Rheumatology Alliance physician-reported registry, were included in our analysis. Data on patients' age, gender, smoking, diagnosis, IRD activity, and other comorbidities were collected. Statistical Package for the Social Sciences (SPSS), version 25, was used for statistical analysis. RESULTS: A total of 52 patients were included, with a mean age of 55 years (±14). The majority of patients were ≤65 years (77%), female (77%), non-smokers (80.8%), and diagnosed with rheumatoid arthritis (67.0%). Of the included patients, 19.2%, 9.6%, and 7.7% reported having methotrexate monotherapy, antimalarials monotherapy, and interleukin-6 inhibitors monotherapy immediately before COVID-19, respectively. Most of the included patients (92.3%) were either in remission or had minimal/low disease activity, while others (7.7%) had moderate disease activity. Forty-three patients (82.7%) were hospitalized, while 11 patients (25.6%) required ventilation (invasive or non-invasive). Ten of the ventilated patients (90.9%) received glucocorticoids as part of the local protocol to treat severe COVID symptoms, and 4 patients (7.69%) died. The duration till symptom-free ranged between 0 to 30 days, with a mean value of 10 days (±6.5). CONCLUSION: The current study provides timely real-world evidence regarding characteristics and potential risk factors linked to poor COVID-19-related outcomes in the IRD population in Kuwait.

Therapeutic role of immunomodulators during the COVID-19 pandemic- a narrative review.

The emergency state caused by COVID-19 saw the use of immunomodulators despite the absence of robust research. To date, the results of relatively few randomized controlled trials have been published, and methodological approaches are riddled with bias and heterogeneity. Anti-SARS-CoV-2 antibodies, convalescent plasma and the JAK inhibitor baricitinib have gained Emergency Use Authorizations and tentative recommendations for their use in clinical practice alone or in combination with other therapies. Anti-SARS-CoV-2 antibodies are predominating the management of non-hospitalized patients, while the inpatient setting is seeing the use of convalescent plasma, baricitinib, tofacitinib, tocilizumab, sarilumab, and corticosteroids, as applicable. Available clinical data also suggest the potential clinical benefit of the early administration of blood-derived products (e.g. convalescent plasma, non-SARS-CoV-2-specific immunoglobins) and the blockade of factors implicated in the hyperinflammatory state of severe COVID-19 (Interleukin 1 and 6; Janus Kinase). Immune therapies seem to have a protective effect and using immunomodulators alone or in combination with viral replication inhibitors and other treatment modalities might prevent progression into severe COVID-19 disease, cytokine storm and death. Future trials should address existing gaps and reshape the landscape of COVID-19 management.

Accessibility to biologics and its impact on disease activity and quality of life in patients with rheumatoid arthritis in Kuwait.

OBJECTIVE: Biologics are indicated in rheumatoid arthritis (RA) in case of persistent high disease activity despite conventional disease-modifying anti-rheumatic drugs (cDMARDs) or patients with contraindications to cDMARDs or poor prognostic factors. The purpose of this study was to compare the prescription rates of biologics in Kuwaiti and non-Kuwaiti patients and to assess whether this had an impact on disease activity and quality of life in RA patients. METHODS: Data were extracted from the Kuwait Registry for Rheumatic Diseases. Adult patients who satisfied the ACR classification criteria for RA from four major hospitals in Kuwait were evaluated from February 2013 through May 2018. The treatment agents, disease activity, and quality of life of Kuwaiti patients were compared with non-Kuwaiti patients. RESULTS: A total of 1651 RA patients were included; 806 (48.8%) were Kuwaiti patients. Among Kuwaiti patients, 62.5% were on biologic drugs in comparison with 14% of non-Kuwaiti patients. In comparison with non-Kuwaiti patients, Kuwaiti patients had significantly lower numbers of swollen joints (p < 0.001) and disease activity score-28 scores (p = 0.02) and less steroid use (p < 0.001) yet a significantly higher health assessment questionnaire-disability index (p < 0.001). Regression analysis showed that DAS-28 scores were significantly associated with the treatment type (p < 0.001) and that nationality was significantly predictive of the treatment type (p < 0.001). CONCLUSION: In the setting of easy accessibility to treatment for Kuwaiti patients, biologics were prescribed by rheumatologists at a higher rate than for non-Kuwaitis. This may explain the lower disease activity and the lower rate of steroid use in Kuwaiti patients than non-Kuwaitis. KEY POINTS: • Significant discrepancies in the rates of prescribing biologic therapies between KP and NKP in Kuwait were observed. • Several treatment outcomes were significantly better in the KP group than in the NKP group even after adjustment of confounding factors. • The poor access to biologic therapies was suggested to limit the effectiveness of RA treatments in the NKP group.

Recommendation for the Management of Spondyloarthritis Patients in Kuwait.

OBJECTIVE: In 2016, ASAS and EULAR made joint recommendations for the management of patients with spondyloarthritis. Although Global and European perspectives are important, they cannot accurately reflect the situation for all patients in all countries and regions. As such, the group worked to tailor the existing international recommendations to suit the specific demographic needs of local populations in the Gulf region, with a specific focus on Kuwait. METHODS: Recommendations drafted following a PubMed search for relevant literature were reviewed and then underwent Delphi vote to reach consensus on those to be included. Advice for newly approved agents, including targeted synthetic disease-modifying anti-rheumatic drugs, was included based on the group's clinical experience. RESULTS: The resulting 41 recommendations are grouped into five categories covering key definitions and principles for the management and treatment of both axial and peripheral forms of spondyloarthritis. CONCLUSION: Through adaptation of existing guidelines and incorporating the current evidence and clinical experience of the members of the group, these recommendations have been developed to reflect the unique situation in Kuwait with regard to differing patient profiles, local culture and approved therapeutic approaches, and are designed to aid in clinical decision-making.

Kuwait association of rheumatology 2018 treatment recommendations for patients with rheumatoid arthritis.

The Kuwait Association of Rheumatology (KAR) aimed to develop a set of recommendations for the treatment of patients with rheumatoid arthritis (RA), tailored to the unique patient population and healthcare system of Kuwait. Each recommendation was developed based on expert opinion and evaluation of clinical practice guidelines from other international and national rheumatology societies. Online surveys were conducted to collate feedback on each KAR member's level of agreement (LoA) with definitions of disease-/treatment-related terms used and the draft recommendations. Definitions/recommendations achieving a pre-defined cut-off value of ≥ 70% agreement were accepted for inclusion. Remaining statements were discussed and revised at a face-to-face meeting, with further modifications until consensus was reached. A final online survey was used to collect feedback on each KAR member's LoA with the final set of recommendation statements on a scale of 0 (complete disagreement) to 10 (complete agreement). Group consensus was achieved on 66 recommendation statements, including 3 overarching principles addressing the pharmacological treatment and management of RA. Recommendations focused on treatment of early RA, established RA, patients with high-risk comorbidities, women during pregnancy and breastfeeding, and screening and treatment of opportunistic infections. The KAR 2018 Treatment Recommendations for RA reported here are based on a synthesis of other national/international guidelines, supporting literature, and expert consensus considering the Kuwaiti healthcare system and RA patient population. These recommendations aim to inform the clinical decisions of rheumatologists treating patients in Kuwait, and to promote best practices, enhance alignment and improve the treatment experience for patients.

Kuwait Recommendations on Vaccine Use in People with Inflammatory Rheumatic Diseases.

People with IRD are at increased risk of infection, and in 2011 EULAR made general recommendations for vaccination in these patients. Global and European perspectives are important, but they cannot accurately reflect the individual situations of patients in different countries and regions. Based on our clinical experience and opinions, we have sought to tailor the original EULAR recommendations to include advice for vaccination with new agents approved in the intervening years-including the new class of targeted synthetic disease-modifying antirheumatic drugs. We have also considered the specific demographic needs of patients in local populations in the Gulf region. The resulting 16 recommendations are grouped into four main categories covering general vaccination guidelines and best-practice for all patients with IRD, followed by a set of recommended vaccines against specific pathogens. The last two categories include recommendations for certain patient subgroups with defined risks and for patients who wish to travel.

Disease activity and cytokine production in mitogen-stimulated peripheral blood mononuclear cells from patients with rheumatoid arthritis.

OBJECTIVE: To test whether there are differences in the levels and ratios of 6 pro- and 3 anti-inflammatory cytokines produced by mitogen-stimulated peripheral blood mononuclear cells (PBMCs) in rheumatoid arthritis (RA) subjects compared to controls. SUBJECTS AND METHODS: 79 participants (42 seropositive RA patients and 37 healthy controls) were enrolled in this study. The production levels in mitogen-stimulated PBMCs of the 6 proinflammatory cytokines (IFN-gamma, TNF-alpha, TNF-beta, IL-8, IL-17, IL-18) and 3 anti-inflammatory cytokines (IL-4, IL-10, IL-13) were assayed by ELISA using kits obtained from Immunotech SA. The ratios of pro- to anti-inflammatory cytokines were calculated for all participants. RESULTS: There were significantly elevated levels of IL-8 and IL-10, and reduced levels of IFN-gamma, IL-4, and IL-17 in mitogen-stimulated PBMC culture supernatants of RA subjects compared to controls. Of the 18 pro-/anti-inflammatory cytokine ratios, 3 ratios (TNF-alpha/IL13, IL-8/IL-4 and IL-8/IL-13) were significantly higher in RA patients compared to controls; and 6 were higher in controls (IFN-gamma/IL-4; IFN-gamma/IL-10; IFN-gamma/IL-13; TNF-beta/IL10; IL-17/IL-10; IL-18/IL-10). CONCLUSIONS: Activated PBMCs of RA patients, regardless of disease activity, showed higher-level production of IL-8 and IL-10 compared to controls; lower-level production of IFN-gamma, IL-4, and IL-17; and elevated ratios of TNF-alpha/IL-13, IL-8/IL-4 and IL-8/IL-13.

Patient demographics and disease variables correlate with distinct cytokine patterns in mitogen-stimulated peripheral blood mononuclear cells from rheumatoid arthritis patients.

There is paucity of literature on the association of peripheral blood cytokine patterns with patient demographics and disease variables in rheumatoid arthritis (RA). We test the hypothesis that there may be differences in peripheral blood levels of inflammatory cytokines in RA subjects according to various disease variables. In this case, we could identify peripheral blood cytokine markers that correlate with different disease variables. Forty-two seropositive RA patients were characterized according to the age at onset, gender, disease duration, severity, activity and ACR functional class. The production levels in mitogen-stimulated PBMCs of five pro-inflammatory cytokines (IFNgamma, TNFalpha, TNFbeta, IL-8, IL-18) and three anti-inflammatory cytokines (IL-4, IL-10, IL-13) were evaluated in these patients and in healthy controls. Several new findings emerge: (1) higher levels of IL-4 correlate with female gender, milder disease, non-erosive disease, and earlier age at onset; (2) higher levels of IL-10 correlate with the requirement of < or =2 DMARDs; (3) higher levels of IL-18 correlate with non-erosive disease and younger age at onset; (4) higher TNFbeta levels correlate with older present age of patients; and (5) higher IL-8 levels correlate with established/late disease. There are several interesting differences in cytokine patterns with respect to age at onset, current age, disease severity, and the number of DMARDs the patients require.

Significant association of insertion/deletion polymorphism of the angiotensin-converting enzyme gene with rheumatoid arthritis.

OBJECTIVE: Only 30% of the genetic contribution to rheumatoid arthritis (RA) can be attributed to HLA genes, and other non-HLA genes may play a role in RA susceptibility. Angiotensin-converting enzyme (ACE) has been reported to be involved in pathogenesis of RA, and high levels of ACE have been documented in RA synovial fluid and pleural effusions. Since plasma and tissue levels of ACE are determined at the transcriptional level, we test the hypothesis that the genotype of ACE in RA patients may be a determining factor in pathogenesis. METHODS: Sixty patients with RA were recruited and clinically characterized according to disease duration, disease severity, disease activity, and American College of Rheumatology functional classes. ACE gene I/D polymorphism genotypes were determined in patients and healthy controls, using polymerase chain reaction. RESULTS: We found a significant overrepresentation of the DD genotype and the D allele in patients with RA; and we found that men with RA exhibited a higher frequency of the DD genotype and D allele compared to male controls. By logistic regression analysis the DD genotype confers a relative risk for development of RA of 3. CONCLUSION: Our study found an association between ACE deletion polymorphism and RA.

Therapeutic efficacy and safety profile of infliximab in active systemic lupus erythematosus.

Since levels of the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) are significantly increased in systemic lupus erythematosus (SLE) and may be involved in the disease pathogenesis, we report on the safety and efficacy of infliximab, a chimeric monoclonal antibody directed against TNFalpha, given to a patient with difficult-to-treat active nonrenal SLE. This patient, who failed to remit with full doses of glucocorticoids, hydroxychloroquine, methotrexate, and azathioprine, went into sustained remission with the addition of infliximab infusions. Glucocorticoids could be tapered off completely.

Safety and efficacy of infliximab in a patient with active WHO class IV lupus nephritis.

Because disease activity in systemic lupus erythematosus correlates well with increased serum levels and activity of the cytokine tumor necrosis factor alpha (TNF-alpha), we report on the safety and efficacy of infliximab, a chimeric monoclonal antibody directed against TNF-alpha, given to a patient with active lupus with diffuse proliferative nephritis (WHO Class IV). This patient who failed to remit with a combination of full-dose steroids, mycophenolate mofetil, and cyclosporine, went into sustained remission with the addition of infliximab infusions.

Ten years of clinical experience with adult onset Still's disease: is the outcome improving?

This study aims to report on the clinical and laboratory picture and the disease course and outcome in patients having adult onset Still's disease (AOSD), to briefly review existing literature on the subject, and to compare our findings with those previously reported. Results are reported for 28 patients with AOSD satisfying the preliminary criteria of Yamaguchi et al. seen in a teaching hospital over the last 10 years. A high percent of the patients with AOSD were women. The mean (+SD) age at disease onset was 27.8 (+8.4) years. We found fever in 100%, rash in 85%, arthritis in 64%, lymphadenopathy in 60%, splenomegaly in 57%, hepatomegaly in 35%, pleural effusion in 17.9%, and pericardial effusion in 3.6% of our patients. Leukocytosis was present in 96% of the patients, a normochromic, normocytic anemia in 54%, and an elevated erythrocyte sedimentation rate (ESR) in all. Serum ferritin levels were raised in 89% of the patients. The mean follow-up of the patients was 3.72 + 2.46 years. The mean delay in diagnosis was 7.32 + 18.0 months. The mean time to enter remission was 9.7 months. Self-limited, intermittent, and chronic disease course was seen in 14.3, 57.1, and 28.6% of patients, respectively. The outcome was good in about 89% of patients, and mortality was nil. No particular clinical or laboratory variable was found to predict the subsequent disease course and outcome in our patients. On comparing our data with important previous series, we found a higher percentage of women and of patients presenting in the age group 16-35 years, a lower frequency of arthritis and pericardial effusion, and some other notable differences. Importantly, the disease course was benign, probably as an outcome of heightened awareness and less diagnostic delay than in the past, allowing for early, aggressive, and appropriate treatment. It is concluded that AOSD is now a relatively benign disease if diagnosed early and treated appropriately.