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Clinical Rheumatology Apr 2022Myasthenia gravis is an autoimmune disease affecting the neuromuscular junction, often associated with other autoimmune diseases, including rheumatoid arthritis.... (Review)
Review
INTRODUCTION
Myasthenia gravis is an autoimmune disease affecting the neuromuscular junction, often associated with other autoimmune diseases, including rheumatoid arthritis. Patients with rheumatoid arthritis present an increased prevalence of myasthenia gravis compared to the general population. While these two diseases share some therapeutic options, such as glucocorticoids, methotrexate, and rituximab, there are no guidelines for treating concomitant disease. We aim to review the available evidence and to discuss the efficacy and safety of the therapeutic options in patients with rheumatoid arthritis associated with myasthenia gravis.
METHOD
We described three patients with rheumatoid arthritis associated with myasthenia gravis and we performed a systematic review of the associated literature.
RESULTS
A 48-year-old man and two women (48 and 55 years old) with concomitant diagnoses of active rheumatoid arthritis and well-controlled myasthenia gravis are described. They were treated with methotrexate, leflunomide, upadacitinib, and adalimumab. None of them experienced changes in their myasthenic symptoms. We found 9 additional cases from our literature review. Methotrexate, rituximab, upadacitinib, diphenyl sulfone, auranofin, and loxoprofen sodium did not show an impact on the seven patients with previously well-controlled myasthenia. Glucocorticoids, methotrexate, and rituximab proved effective in active myasthenia gravis and arthritis. Conflicting data emerged for Tumor-necrosis factor inhibitors.
CONCLUSIONS
Although the available evidence remains scarce, we consider glucocorticoids, methotrexate, and rituximab as safe and effective options. The role of tumor-necrosis factor inhibitors remains uncertain. Eventually, Janus Kinase inhibitors are a novel interesting option for these patients. Key Points • To date, the only evidence on the treatment of patients with rheumatoid arthritis and concomitant myasthenia gravis derives from case reports. • Based on the review of the available case reports and on the cases we described, we consider glucocorticoids, methotrexate, and rituximab as safe and effective options, while the role of Tumor-necrosis factor inhibitors remains uncertain. • Based on the cases we described, Janus Kinase inhibitors are a novel interesting option for patients with concomitant rheumatoid arthritis and myasthenia gravis.
Topics: Adalimumab; Arthritis, Rheumatoid; Female; Humans; Janus Kinase Inhibitors; Male; Methotrexate; Middle Aged; Myasthenia Gravis
PubMed: 35031874
DOI: 10.1007/s10067-022-06062-w -
The Journal of Rheumatology Mar 2023Nail psoriasis is common, impairs fine motor finger functioning, affects cosmesis, and is associated with a lower quality of life. This review updates the previous Group...
OBJECTIVE
Nail psoriasis is common, impairs fine motor finger functioning, affects cosmesis, and is associated with a lower quality of life. This review updates the previous Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations for nail psoriasis.
METHODS
This systematic literature review of the PubMed, MEDLINE, Embase, and Cochrane databases examined the updated evidence since the last GRAPPA nail psoriasis treatment recommendations published in 2014. Recommendations are based on preformed PICO (Patient/Population - Intervention - Comparison/Comparator - Outcome) questions formulated by an international group of dermatologists, rheumatologists, and patient panel members. Data from this literature review were evaluated in line with Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology.
RESULTS
Overall, there is insufficient evidence to make any recommendation for the use of topical corticosteroids, topical calcipotriol, topical tazarotene, topical cyclosporine, dimethyl fumarates/fumaric acid esters, phototherapy, and alitretinoin. There is a low strength of evidence to support the use of calcipotriol and corticosteroid preparations, topical tacrolimus, oral cyclosporine, oral methotrexate, intralesional corticosteroids, pulsed dye laser, acitretin, Janus kinase inhibitors, and apremilast.
CONCLUSION
The highest strength of supporting evidence is for the recommendation of biologic agents including tumor necrosis factor inhibitors, and interleukin 12/23, 17, and 23 inhibitors.
Topics: Humans; Arthritis, Psoriatic; Quality of Life; Psoriasis; Nail Diseases; Adrenal Cortex Hormones; Cyclosporins
PubMed: 36319021
DOI: 10.3899/jrheum.220313 -
PloS One 2022Hematopoietic stem cell transplantation (HSCT) for haematological disorders. Graft-versus-host disease (GVHD), a cause of morbidity and mortality is treated with... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Hematopoietic stem cell transplantation (HSCT) for haematological disorders. Graft-versus-host disease (GVHD), a cause of morbidity and mortality is treated with corticosteroids. However, patients with steroid-refractory GVHD after HSCT have a poor prognosis. Ruxolitinib, a selective Janus kinase inhibitor, is a novel treatment strategy for steroid-refractory GVHD.
OBJECTIVES
To assess the efficacy of ruxolitinib for the treatment of steroid-refractory GVHD and analyse its adverse effects.
STUDY DESIGN
Meta-analysis.
SEARCH METHODS
Randomised controlled trials (RCTs) and non-RCTs of ruxolitinib-based therapy in patients with steroid-refractory GVHD were found in the Cochrane Central Register of Controlled Trials, EMBASE, PubMed, and Web of Science in March 2021. Outcomes included overall response rate, survival, and adverse effects. The Methodological Index for Non-randomised Studies (MINORS) and the Cochrane collaboration risk-of-bias tool were used to assess methodological quality. Funnel plots, Egger's test, and the trim and fill method were used to assess publication bias.
RESULTS
In total, 1470 studies were identified; 19 studies (17 non-RCTs, 2 RCTs) involving 1358 patients met our inclusion criteria. Survival rates at the longest follow-up in non-RCTs, were 57.5% (95% CI 46.9-67.4) and 80.3% (95% CI 69.7-87.9) for acute GVHD (aGVHD) and chronic GVHD (cGVHD), respectively. In non-RCTs, the overall response was 74.9% (95% CI 66.6-81.8, I2 = 49%) in aGVHD and 73.1% (95% CI 62.5-81.6, I2 = 49%) in cGVHD. In aGVHD, the response rates were gastrointestinal, 61.4-90.2%; skin, 52.5-80.6%; and liver, 41.8-71.8%. In cGVHD, the response rates were gastrointestinal, 30.1-70.4%; skin, 30.1-84.4%; lung, 27.0-83.0%; and mouth 3.5-98.1%. In addition, a lower aGVHD grade and moderate cGVHD were associated with a better clinical response. Common adverse events were cytopenia and infectious complications.
CONCLUSIONS
Our systematic review and meta-analysis indicated that ruxolitinib therapy could be a potentially effective and safe treatment for patients with steroid-refractory GVHD.
Topics: Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Nitriles; Pyrazoles; Pyrimidines; Steroids
PubMed: 35905125
DOI: 10.1371/journal.pone.0271979 -
Advances in Therapy Feb 2024Immune-mediated inflammatory diseases including rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), non-radiographic axial... (Review)
Review
Safety of Upadacitinib in Immune-Mediated Inflammatory Diseases: Systematic Literature Review of Indirect and Direct Treatment Comparisons of Randomized Controlled Trials.
INTRODUCTION
Immune-mediated inflammatory diseases including rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), non-radiographic axial spondylarthritis (nr-axSpA), atopic dermatitis (AD), ulcerative colitis (UC), and Crohn's disease (CD) pose a substantial burden on patients and their quality of life. Upadacitinib is an orally administered, selective, and reversible Janus kinase inhibitor indicated for seven conditions, but data on its safety versus other active treatments are limited. A systematic literature review of indirect and direct treatment comparisons of randomized controlled trials (RCTs) was conducted to assess the safety profile of upadacitinib.
METHODS
MEDLINE, Embase, and Cochrane Library databases were searched for indirect and direct treatment comparisons of RCTs that (1) included licensed upadacitinib dosages; (2) studied any of the seven conditions; (3) reported any adverse events (AEs), serious AEs (SAEs), AEs leading to discontinuation, major adverse cardiovascular event, venous thromboembolism, malignancies, infections or serious infections, and death; and (4) were published between January 2018 and August 2022.
RESULTS
A total of 25 studies were eligible for inclusion. SAEs, AEs leading to discontinuation, and any AEs were commonly studied. RA was the most studied condition, followed by AD and UC. Most studies (16/25, 64%) reported no statistically significant difference in the studied safety outcomes between upadacitinib and other active treatments (e.g., tumor necrosis factor blockers, interleukin receptor antagonists, integrin receptor antagonists, T cell co-stimulation modulator), or placebo (placebo ± methotrexate or topical corticosteroids). Other studies (9/25, 36%) reported mixed results of no statistically significant difference and either statistically higher (8/25, 32%) or lower rates (1/25, 4%) on upadacitinib.
CONCLUSION
Most studies suggested that upadacitinib has no statistically significant difference in the studied safety outcomes compared to active treatments or placebo in patients with RA, PsA, AS, AD, UC, and CD. A few studies reported higher rates, but findings were inconsistent with limited interpretation.
Topics: Humans; Arthritis, Psoriatic; Arthritis, Rheumatoid; Colitis, Ulcerative; Heterocyclic Compounds, 3-Ring; Methotrexate; Randomized Controlled Trials as Topic; Spondylitis, Ankylosing
PubMed: 38169057
DOI: 10.1007/s12325-023-02732-6 -
Clinical, Cosmetic and Investigational... 2024Upadacitinib is a selective Janus kinase inhibitor approved for the treatment of severe atopic dermatitis (AD). This systematic review aims to summarize the most recent... (Review)
Review
Upadacitinib is a selective Janus kinase inhibitor approved for the treatment of severe atopic dermatitis (AD). This systematic review aims to summarize the most recent data in terms of effectiveness and safety of upadacitinib in the treatment of severe AD in a real-world setting. The review included a comprehensive search of databases, including PubMed, Google Scholar and Web of Science, according to Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. The literature search initially identified 242 studies. Of these, 214 were excluded after reviewing their titles and abstracts. We then conducted a full-text review of 25 studies, of which 17 met our inclusion criteria and were therefore included in our systematic review. The analysis of real-world studies showed high effectiveness of upadacitinib, in terms of both clinical signs and subjective symptoms, in different patient populations, including those resistant to other treatments. No new significant safety concerns have emerged as compared to randomized clinical trials.
PubMed: 38495913
DOI: 10.2147/CCID.S329442 -
Infectious Diseases and Therapy Feb 2022Many immunomodulators have been studied in clinical trials for the treatment of coronavirus disease 2019 (COVID-19). However, data identifying the most effective and...
INTRODUCTION
Many immunomodulators have been studied in clinical trials for the treatment of coronavirus disease 2019 (COVID-19). However, data identifying the most effective and safest treatment are lacking. We conducted a systematic review and network meta-analysis to rank immunomodulators in the treatment of COVID-19 according to their efficacy and safety.
METHODS
Published and peer-reviewed randomized controlled trials assessing the efficacy of immunomodulators in hospitalized patients with COVID-19 were searched up to June 30, 2021. Direct and network meta-analyses were applied to assess the outcomes. The probability of efficacy and safety was estimated, and the drugs were awarded a numerical ranking.
RESULTS
Twenty-six studies were eligible. Compared with standard of care, dexamethasone and tocilizumab had significantly lower mortality rates with pooled risk ratios (RRs) of 0.91 (95% confidence interval [CI] 0.84-0.99) and 0.88 (95% CI 0.82-0.96), respectively. Meanwhile, the most effective corticosteroid, interleukin-6 antagonist, and Janus kinase (JAK) inhibitor were hydrocortisone, sarilumab, and ruxolitinib, respectively. However, when superimposed infection was considered, ruxolitinib was the best treatment followed by baricitinib. Moreover, methylprednisolone had the worst combined efficacy and safety among the examined treatments.
CONCLUSIONS
Overall, immunomodulators were more effective than standard of care. Important differences exist among immunomodulators regarding both efficacy and safety in favor of ruxolitinib and baricitinib. Further well-conducted randomized controlled trials should focus on JAK inhibitors. Methylprednisolone use should be discouraged because of its poor efficacy and high risk of superimposed infection. TRIAL REGISTRATION: PROSPERO registration identifier CRD 42021257421.
PubMed: 34757578
DOI: 10.1007/s40121-021-00545-0 -
The Journal of Rheumatology Jan 2020Understanding the placebo response is critical to interpreting treatment efficacy, particularly for agents with a ceiling to their therapeutic effect, where an...
OBJECTIVE
Understanding the placebo response is critical to interpreting treatment efficacy, particularly for agents with a ceiling to their therapeutic effect, where an increasing placebo response makes it harder to detect potential benefit. The objective of this study is to assess the change in placebo responses over time in rheumatoid arthritis (RA) randomized placebo-controlled trials (RCT) for drug licensing authorization.
METHODS
The Cochrane Controlled Trials Register database was searched to identify RCT of biological or targeted synthetic disease-modifying antirheumatic drugs (DMARD) in RA. Studies were excluded if patients were conventional synthetic DMARD (csDMARD)-naive, not receiving background csDMARD therapy, or were biologic experienced. Metaregression model was used to evaluate changes in American College of Rheumatology (ACR) 20, ACR50, and ACR70 treatment response over time.
RESULTS
There were 32 trials in total: anti-tumor necrosis factor therapy (n = 15), tocilizumab (n = 4), abatacept (n = 2), rituximab (n = 2), and Janus kinase inhibitors (n = 9). From 1999 to 2018, there was no significant trend in the age or sex of patients in the placebo arm. Disease duration, swollen joint count, and 28-joint count Disease Activity Score using erythrocyte sedimentation rate at baseline all significantly declined over time. There was a statistically significant increase in placebo ACR50 and ACR70 responses (ACR50 β = 0.41, 95% CI 0.09-0.74, p = 0.01; ACR70 β = 0.18, 95% CI 0.04-0.31, p = 0.01) that remained significant after controlling for potential confounders.
CONCLUSION
There has been a rise in the placebo response in RA clinical trials over the last 2 decades. Shifting RA phenotype, changes in trial design, and expectation bias are possible explanations for this phenomenon. This observation has important implications when evaluating newer novel agents against established therapies.
Topics: Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Rheumatoid; Biological Products; Female; Humans; Janus Kinase Inhibitors; Male; Middle Aged; Patient Outcome Assessment; Placebo Effect; Randomized Controlled Trials as Topic; Treatment Outcome; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha
PubMed: 31043548
DOI: 10.3899/jrheum.190008 -
American Journal of Hematology Mar 2018Ruxolitinib exerts immunosuppressive activity that may increase the risk of infectious complications. We performed a systematic review of the literature with the aim of... (Meta-Analysis)
Meta-Analysis
Ruxolitinib exerts immunosuppressive activity that may increase the risk of infectious complications. We performed a systematic review of the literature with the aim of estimating the risk of infections in patients treated with ruxolitinib. Studies were identified by electronic search of MEDLINE and EMBASE database. Differences in the incidence of infectious events between ruxolitinib and comparison groups were expressed as odds ratios (ORs) and 95% confidence intervals (95% CI). Five phase III randomized clinical trials (RCTs) (3 phase IIIa with their extended phase and 2 phase IIIb), 6 phase IV studies and 28 case reports were included in this systematic review. Ruxolitinib was associated with a statistically significant increased risk of herpes zoster infection compared to control group in 3 RCTs including patients with polycythemia vera (OR 7.39 [1.33, 41.07]) and in a pooled analysis of the extended phase IIIa RCTs (OR 5.20 [95%CI 1.27, 21.18]). In the larger phase IV post-marketing study, the incidence of the most frequent infections was 8% for herpes zoster, 6.1% for bronchitis and 6% for urinary tract infections. In the published case reports, the most frequent infections were tuberculosis (N = 10), hepatitis B reactivation (N = 5) and pneumocystis jeroveci infection (N = 2). Evidence is not solid enough to accurately estimate the risk of infection in ruxolitinib-treated patients. However, published data clearly suggest that the infection risk may be clinically relevant. Well-designed studies are warranted to evaluate the risk of ruxolitinib-associated infection, in order to identify the most appropriate antimicrobial prophylactic strategy.
Topics: Antibiotic Prophylaxis; Bacterial Infections; Clinical Trials, Phase III as Topic; Confidence Intervals; Disease Susceptibility; Herpes Zoster; Humans; Immunocompromised Host; Immunosuppressive Agents; Incidence; Infections; Janus Kinase 1; Janus Kinase 2; Mycoses; Nitriles; Odds Ratio; Product Surveillance, Postmarketing; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Risk
PubMed: 29150886
DOI: 10.1002/ajh.24976 -
MedRxiv : the Preprint Server For... Aug 2020Background Novel coronavirus (SARS-CoV-2) has infected over 17 million. Novel therapies are urgently needed. Janus-kinase (JAK) inhibitors and Type I interferons have...
Background Novel coronavirus (SARS-CoV-2) has infected over 17 million. Novel therapies are urgently needed. Janus-kinase (JAK) inhibitors and Type I interferons have emerged as potential antiviral candidates for COVID-19 patients for their proven efficacy against diseases with excessive cytokine release and by their ability to promote viral clearance in past coronaviruses, respectively. We conducted a systemic review and meta-analysis to evaluate role of these therapies in COVID-19 patients. Methods MEDLINE and MedRxiv were searched until July 30th, 2020, including studies that compared treatment outcomes of humans treated with JAK-inhibitor or Type I interferon against controls. Inclusion necessitated data with clear risk estimates or those that permitted back-calculation. Results We searched 733 studies, ultimately including four randomized and eleven non-randomized clinical trials. JAK-inhibitor recipients had significantly reduced odds of mortality (OR, 0.12; 95%CI, 0.03-0.39, p=0.0005) and ICU admission (OR, 0.05; 95%CI, 0.01-0.26, p=0.0005), and had significantly increased odds of hospital discharge (OR, 22.76; 95%CI, 10.68-48.54, p<0.00001), when compared to standard treatment group. Type I interferon recipients had significantly reduced odds of mortality (OR, 0.19; 95%CI, 0.04-0.85, p=0.03), and increased odds of discharge bordering significance (OR, 1.89; 95%CI, 1.00-3.59, p=0.05). Conclusions JAK-inhibitor treatment is significantly associated with positive clinical outcomes regarding mortality, ICU admission, and discharge. Type I interferon treatment is associated with positive clinical outcomes regarding mortality and discharge. While these data show promise, additional randomized clinical trials are needed to further elucidate the efficacy of JAK-inhibitors and Type I interferons and clinical outcomes in COVID-19.
PubMed: 32817985
DOI: 10.1101/2020.08.10.20172189 -
Rheumatology and Therapy Jun 2021Peficitinib, a Janus kinase (JAK) inhibitor, is approved for clinical use in Japan, Korea, and Taiwan, but head-to-head comparisons versus other JAK inhibitors are...
INTRODUCTION
Peficitinib, a Janus kinase (JAK) inhibitor, is approved for clinical use in Japan, Korea, and Taiwan, but head-to-head comparisons versus other JAK inhibitors are lacking. We indirectly compared peficitinib, tofacitinib, and baricitinib for rheumatoid arthritis treatment.
METHODS
We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and congress archives up until February 12, 2019, for randomized controlled trials of peficitinib, tofacitinib, and baricitinib. Efficacy (American College of Rheumatology responses, disease activity scores, modified total Sharp score, Simplified Disease Activity Index [SDAI]) and safety outcomes were compared using a Bayesian network meta-analysis. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) consensus was followed for reporting results. A network meta-regression assessed the impact on outcomes of proportions of patients receiving concomitant methotrexate or of Asian ethnicity.
RESULTS
The network meta-analysis included 21 randomized controlled trials. At 12 weeks, all evaluable efficacy outcomes were comparable or improved with peficitinib 150 mg and 100 mg once daily, versus baricitinib 2 and 4 mg once daily and tofacitinib 5 mg twice daily. At 24 weeks, efficacy outcomes were comparable or improved for each peficitinib dose versus baricitinib and tofacitinib. Risk of adverse events and serious adverse events at 12 weeks were similar with peficitinib 100 and 150 mg versus baricitinib and tofacitinib. The proportion of patients receiving concomitant methotrexate had no effect on any outcome analyzed, but Asian ethnicity had a positive effect on multiple efficacy outcomes.
CONCLUSIONS
Peficitinib had comparable efficacy versus tofacitinib and baricitinib for reduction in disease activity as measured by SDAI, and for reduction in progression of joint damage as measured radiographically. No notable differences in safety outcomes were observed. Further studies are required to better characterize the impact of ethnicity on the efficacy of JAK inhibitors.
PubMed: 33725321
DOI: 10.1007/s40744-021-00284-1