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ID PMID Title PublicationDate abstract
12700082 Osteoclasts, pro-inflammatory cytokines, RANK-L and bone remodeling in rheumatoid arthriti 2003 May 1 Inflammatory joint diseases such as rheumatoid arthritis tend to destroy joint cartilage and bone matrices. Since bone resorption is a common characteristic of rheumatoid arthritis, one of the cell types thought to play a vital role in the destruction of these matrices are the osteoclasts. Osteoclasts and osteoclastogenic factors such as inflammatory cytokines and RANK-L are present within inflamed joints, and osteoclastic bone resorptive activities are also displayed, further suggesting the possibility that osteoclasts are responsible for the joint cartilage and bone matrix damage observed in this joint disease.
14702212 Sleep quality and immune functions in rheumatoid arthritis patients with and without major 2004 Feb The purpose of this study was to determine the discriminative factors between rheumatoid arthritis (RA) patients with and without major depression (MD). We assessed subjective sleep quality, pain, and cell-mediated immune functions in RA patients with (n = 20) and without (n = 20) MD by using Pittsburgh Sleep Quality Index (PSQI), visual analogue scale (VAS), and fluorescein isothiocyanat (FITC) labeled CD3, CD4, CD8, CDI9, CD45, CD56, and HLADR T monoclonal antibodies by flow cytometry. We found that the RA patients with MD had significantly higher pain level, poorer sleep equality, higher HDRS points, and higher HLADR T cell level than those without MD; and that these variables are discriminant factors between patient groups. These findings suggest that the RA patients with MD may be differentiated from those without MD by using VAS, PSQI, and HLADR levels; that these variables correctly classify the depressed and non depressed groups up to an accuracy level of 96.8%.
12233877 Tumor necrosis factor-alpha receptor II polymorphism in patients from southern Europe with 2002 Sep OBJECTIVE: To define the frequency of the exon 6 tumor necrosis factor-alpha (TNF-alpha) receptor II (TNFRII) gene polymorphism in severe and mild-moderate rheumatoid arthritis (RA) and its possible influence on anti-TNF-alpha treatment responsiveness. METHODS: Two cohorts of patients with RA, the first (n = 97) defined as methotrexate responders (MTX-R) with mild-moderate synovitis, and the second (n = 78) defined as nonresponders to combination therapy and receiving anti-TNF-alpha treatment because of their severe and aggressive disease (TNF-T), were studied retrospectively and compared to age, sex, and ethnically matched controls (n = 84). In the prospective study, 66 patients with severe RA were followed over the first 6 months of anti-TNF-alpha therapy and their response was examined according to genotype. RESULTS: We observed a trend towards an increased frequency of the GG genotype in patients with severe RA (6.4%) in comparison with patients with mild-moderate disease (3.1%) and controls (1.2%). When looking at the response to anti-TNF-alpha therapy, we observed that after 12 weeks of treatment, 37.8% of the TT versus 10.7% of the TG/GG patients passed from high to medium-low disease activity (p = 0.03). CONCLUSION: In our cohorts of patients selected by response to the conventional therapy and by disease severity, our preliminary study results showed a trend towards a higher prevalence of the GG genotype for the exon 6 TNFRII polymorphism in the less responsive patients with more aggressive disease. We also found a lower degree of response to anti-TNF-alpha treatments in patients carrying the G allele.
14626629 The relationship between serum ferritin levels and disease activity in systemic lupus eryt 2003 OBJECTIVE: The aim of this study is to investigate the relationship between serum ferritin levels and disease activity in patients with systemic lupus erythematosus (SLE). METHODS: Serum ferritin levels of 72 SLE patients were measured. The SLE patients were subdivided into two groups according to SLE disease activity index (SLEDAI) as < or = 10 and > or = 11. The results were compared with 31 patients with rheumatoid arthritis (RA). 36 patients among 72 with SLE were evaluated before and after treatment. RESULTS: Serum levels of ferritin in SLE patients were higher than RA patients (p < 0.001). There was a significant difference in ferritin levels before and after treatment. The levels of ferritin in SLE were positively correlated with SLEDAI scores. Patients with SLEDAI scores > or = 11 had significantly higher serum ferritin levels. CONCLUSION: Serum ferritin levels may be a useful marker of disease activity in SLE patients.
14618373 Lack of evidence for inhibition of angiogenesis as a central mechanism of the antiarthriti 2005 Mar OBJECTIVES: The aim of this study was to investigate whether methotrexate (MTX) has an antiangiogenic effect and whether this property plays a role in the control of rheumatoid arthritis (RA). METHODS: A human placenta angiogenesis assay was used to examine the antiangiogenic effects of MTX in vitro. In addition, DBA/1 mice were used to compare the antiarthritic effect of MTX in collagen-induced arthritis (CIA) and its antiangiogenic effect in a murine in vivo matrigel model for angiogenesis. RESULTS: The spreading of microvessels from placental vessel fragments was not significantly inhibited by MTX. Treatment with MTX reduced significantly the incidence of CIA in DBA/1 mice in a dose-dependent manner. However, treatment with the same doses of MTX did not significantly reduce vessel growth in subcutaneous depots of bFGF-enriched matrigel. CONCLUSION: These data support the hypothesis that inhibition of angiogenesis does not significantly contribute to the antiarthritic effect of MTX seen in patients and animal models for RA. Therefore, the combination of MTX with antiangiogenic drugs appears to be a rational strategy in the treatment of RA.
15559549 [Focus on biological agents in rheumatoid arthritis: newer treatments and therapeutic stra 2004 Jul Tumour necrosis factor (TNF)-alpha and interleukin (IL)-1 are major regulators of inflammation. TNFalpha inhibitors have been shown to be effective in treating some inflammatory diseases such as rheumatoid arthritis. TNFalpha inhibitors include soluble receptor antagonists (etanercept) and monoclonal antibodies (infliximab, adalimumab). IL-1 inhibitors (anakinra) were also developed, used in therapeutics and licensed in France. TNFalpha inhibitors can be added to background regimens of methotrexate in second-line treatments. Etanercept and adalimumab can be administered alone, especially to patients who have experienced methotrexate toxicity or who do not show clinical and/or radiological improvement. The use of these new agents may optimise rheumatoid arthritis treatment and delay disease progression, particularly when first-line treatments are disappointing. This paper reviews recent data on biological therapies for rheumatoid arthritis: tolerance and their ability to modify the course of disease and prevent radiological damage.
15235579 A phase II study of Rituximab in rheumatoid arthritis patients with recurrent disease foll 2004 Aug Haematopoietic stem cell transplantation (HSCT) has been used recently as an effective therapy in patients with resistant rheumatoid arthritis (RA). Although disease control occurs in the majority of cases, recurrence is common, often coinciding with B-cell reconstitution. We hypothesized that Rituximab, a monoclonal anti-CD20 antibody, would have activity in this group of patients. We treated 10 RA patients (8F:2M, median age 46.5 years), who had recurrent disease post HSCT. All patients received two doses of Rituximab 1 g, 2 weeks apart with no major adverse sequelae and were followed for 12 months. A total of eight out of 10 patients experienced major clinical responses as measured by the American College of Rheumatology (ACR) criteria, with 50-70% improvement in disease parameters. Responses were equivalent to previous responses attained with HSCT. Disease responses were maximal at 4-8 months post Rituximab and correlated with B-cell lymphopenia and a reduction of rheumatoid factor titre. Disease recurrence occurred in 6/9 responders within 12 months and four patients were subsequently retreated, with major responses again attained. This study provides further evidence that B-cell depletion leads to a significant improvement in disease activity in patients with severe RA and provides data for future trials of HSCT and Rituximab therapy.
11908552 Dynamic T cell receptor clonotype changes in synovial tissue of patients with early rheuma 2002 Mar OBJECTIVE: To study T cell receptor (TCR) repertoire changes in synovial membrane over a 16 week period in patients with early rheumatoid arthritis (RA); and to study the influence of cyclosporin A (CSA) on TCR repertoire in a subgroup of these patients. METHODS: Synovial tissue biopsies and paired blood samples were obtained from 12 patients with early RA at 2 time points. Seven patients were treated with CSA (Neoral-Sandimmun, 3 mg/kg/day) and 5 patients with placebo for 16 weeks. TCR V gene repertoires were analyzed by semiquantitative PCR-ELISA. CDR3 spectratyping and sequence analysis was used to compare TCR clonotype distributions. RESULTS: TCR-specific mRNA was detected in all synovial tissue biopsies at the first sampling, but in only 8/12 biopsies 16 weeks later (4/7 CSA group, 4/5 placebo group). Overrepresented TCR BV genes were found in biopsies of 10/12 patients at the first time point, and in 7/12 patients after 16 weeks (3/7 CSA, 4/5 placebo). CDR3 sequence analysis revealed dynamic repertoire changes with only a few persisting clonotypes in the synovial tissue of placebo controls. Persisting T cell clonotypes were more frequently found in the synovial tissue of CSA treated patients compared to the placebo group. CONCLUSION: These data suggest a dynamic process of T cell recruitment in the joints of RA patients. This process, possibly due to activation and subsequent infiltration of new T cell clones, apparently is influenced by CSA treatment. Synovial tissue T cells were no longer detected after 16 weeks' CSA treatment in 3 patients. In the other CSA treated patients, new T cell clones infiltrated, while other clones were persistently represented in the joints. These data may have important consequences for the design of T cell targeted therapies for RA.
11838837 Susceptibility for and clinical manifestations of rheumatoid arthritis are associated with 2002 Feb OBJECTIVE: To analyze the association of genetic polymorphisms of pro-inflammatory cytokines with rheumatoid arthritis (RA) in comparison with healthy controls from Northern Sweden and the potential contribution of these genetic variants for disease severity and development of cardiovascular complications. METHODS: Polymerase chain reaction amplification was used for analysis of TaqI restriction fragment length polymorphism (RFLP) of interleukin-1 beta (IL-1beta), variable tandem repeat polymorphism of IL-I receptor antagonist (IL-1Ra) gene and NcoI RFLP at position -308 of tumor necrosis factor-alpha (TNF-alpha) gene. One hundred and fifty-four patients with RA, 42 men and 112 women, were consecutively recruited into the study through the Department of Rheumatology. RESULTS: The allele A1 of TNF-alpha was more common in the patient group (p < 0.01; OR = 1.62). Patients having the genotype A1A2 seemed to develop more severe disease compared with patients with A1A1 genotype: they were younger at disease onset (p < 0.05), had a higher accumulated disease activity (p < 0.05) and worse functional class (p < 0.05). Patients with genotype A2A2 of IL- 1beta had higher accumulated disease activity score than patients with A1A1 and A1A2 (p < 0.05). The allelic combination Al IL-1beta/A2 IL-1Ra was less prevalent in RA patients who developed cardiovascular complications (p < 0.005; OR = 0.20). CONCLUSIONS: The Al allele of TNF-alpha associates with RA. Genotypes A1A2 of TNF-alpha and A2A2 of IL-1beta are associated with more severe disease. The allelic combination A1IL-1beta/A2 IL-1Ra is less often present in RA patients who developed cardiovascular complications.
15494900 Cytomegalovirus retinitis in a patient treated with anti-tumor necrosis factor alpha antib 2004 Nov 1 BACKGROUND: Anti-tumor necrosis factor alpha (anti-TNF- alpha ) antibodies have been used for the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA) and psoriasis arthritis. Such antibody therapies result in a severe interference with the patient's immune system. Increased rates of upper respiratory tract infection, reactivation of latent tuberculosis, and other systemic infectious diseases have been reported among patients receiving anti-TNF- alpha antibodies. METHODS: As a note of caution, we describe a 57-year-old woman who received therapy with anti-TNF- alpha antibodies for RA refractory to methotrexate. After almost 2 years of treatment, she developed a severe cytomegalovirus (CMV) retinitis of the right eye. RESULTS: Laboratory assays revealed an immune status with nearly total loss of the cellular immune response and partial reduction of the humoral immune response. Intravenous treatment with ganciclovir, followed by oral administration of valganciclovir, resulted in an ophthalmological remission. Cessation of immunosuppressive therapy led to partial immunological reconstitution in the patient. Six months after discontinuation of immunosuppressive therapy, CMV retinitis of the left eye occurred but was treated successfully with a second course of oral valganciclovir. CONCLUSION: In the light of this first reported case of a serious CMV infection following therapy with anti-TNF- alpha antibodies, CMV infection should be considered in symptomatic patients.
11954881 Global functional status in rheumatoid arthritis: disease duration and patient age. 2002 Feb With the aim of clarifying whether patient age could be an additional explanation for the differences in the clinical expression of rheumatoid arthritis (RA) found in different populations, we evaluated the possibility of patient age being a significant factor associated with global functional status, independent from disease duration. Our present results suggest that both disease duration and patient age are major factors in the global functional status of patients with RA, and that patient age is particularly important when a subgroup of patients with more than 60 years of age and more than 20 years of disease duration is considered. These data are relevant when comparing two different RA groups: not only should we have a similar mean age and mean disease duration, but also the subgroups of patients more than 60 years of age and with more than 20 years of disease duration should correspond to equivalent proportions in the populations studied.
15478158 A crossover trial of custom-made and commercially available wrist splints in adults with i 2004 Oct 15 OBJECTIVE: To compare the effect of 3 wrist splints (2 prefabricated commercial splints and 1 custom made) on perceived wrist pain, hand function, and perceived upper extremity function in adults with inflammatory arthritis. METHODS: Subjects (n = 45, mean age 49 years, mean disease duration 8.6 years) were randomly assigned to treatment order in a 3-phase crossover trial. Splints were worn for 4 weeks, separated by 1-week washouts. Outcomes were assessed at baseline, after each splint phase and washout period, and at 6 months' followup using a pain visual analog scale (VAS), the Arthritis Hand Function Test, and McMaster-Toronto Arthritis Patient Function Preference questionnaire. Data were analyzed with multivariate analyses of variance (MANOVAs), t-tests, and chi-square tests. RESULTS: There did not appear to be order or carryover effects. MANOVA indicated that wrist splints significantly reduced pain (P = 0.007). The custom leather splint was most effective in reducing pain, from 4.1 cm to 2.8 cm on the VAS (P = 0.001). All splints improved hand strength, and the commercial Rolyan splint provided significantly stronger grip than the Anatech commercial splint (P = 0.04). In contrast to previous studies, splints did not compromise dexterity. There were several significant differences among splints, depending on the outcome measure. Improvements were maintained at 6 months. CONCLUSION: After 4 weeks' use, wrist splints reduce pain, improve strength, and do not compromise dexterity. Similar improvements were achieved with the custom leather splint and Rolyan commercial splint, which were superior to the Anatech commercial splint.
15024484 [Extraintestinal manifestations of inflammatory bowel disease]. 2004 Mar 15 Extraintestinal manifestations of Crohn's disease and ulcerative colitis are found in > 50% of all patients. These extraintestinal manifestations sometimes impair the overall life quality much more than the bowel-related symptoms. Extraintestinal manifestations need to be distinguished from secondary diseases or complications of inflammatory bowel diseases, as they require a different and specific therapy. Complications of the intestinal disease, such as vitamin deficiency or osteoporosis, can be treated specifically by substitution of vitamin D, calcium, or other vitamins. However, extraintestinal manifestations of Crohn's disease and ulcerative colitis, such as primary sclerosing cholangitis, arthritis or granulomatous inflammation of the skin, lung, or liver, are much more difficult to treat sufficiently. Almost every organ can be a localization of extraintestinal symptoms of inflammatory bowel diseases. It is important to acquire knowledge on these extraintestinal manifestations of Crohn's disease and ulcerative colitis to start the respective treatment early. Perhaps even more important, these extraintestinal symptoms can be the primary manifestation of Crohn's disease and ulcerative colitis. Therefore, they have to be recognized as extraintestinal manifestations to adequately treat the intestinal disease.
15553211 Rare case of pulmonary joint, cardiac and mediastinal involvement in rheumatoid arthritis 2004 Jul It is extremely uncommon to find a patient with rheumatoid arthritis with pulmonary and cardiac manifestations together with co-existent intrathoracic lymphadenopathy. We report the case of a 40-year-old female with rheumatoid arthritis with rheumatoid lung disease with severe aortic regurgitation, congestive heart failure, bronchial asthma and allergic rhinitis.
12209040 Does active treatment of rheumatoid arthritis limit disease-associated bone loss? 2002 Sep OBJECTIVE: Generalized bone loss in rheumatoid arthritis (RA) is multi-factorial, with the inflammatory disease itself thought to contribute to bone loss. To study the extent to which control of disease activity affects bone turnover in RA and whether treatment with disease-modifying anti-rheumatic drugs (DMARDs) reduces bone turnover and loss of bone mass, we measured bone density and biochemical markers of bone resorption in a group of patients with active RA starting on DMARDS. METHODS: Patients with active RA were enrolled on starting a new DMARD. Patients were mobile and none took steroids or any treatment for osteoporosis. Clinical and laboratory measures of disease activity were made at 3-monthly intervals and an index of disease activity (DAS) calculated. Bone density was assessed at 0, 1 and 2 yr (Hologic QDR 4500c). Urinary deoxypyridinoline (D-PYR) and pyridinoline (PYR) were measured by ELISA at 0, 3, 6, 9 and 12 months. RESULTS: Forty patients were enrolled, mean age 59.5 (range 31-76), 26 female, 14 male, 25 had established RA, 15 had RA for <2 yr. Baseline D-PYR was elevated (8.4+/-4.55 nmol/mmol creatinine) and correlated with ESR (r=0.6, P<0.01) and DAS (r=0.4, P<0.05). On treatment ESR and DAS fell by 38.5 and 29.3%, respectively. D-PYR was reduced by 12.3% by 9 months (P<0.01). Spearman rank order correlation showed ESR to be the most significant determinant of D-PYR over 1 yr (r=0.43, P<0.001). Serial bone density was available on 21 patients. There was no significant change in BMD over the 2 yr. The change in DAS over 0-3 months showed an inverse relationship with the percent change in spine over 1 yr (r=-0.5, P=0.05). The change in D-PYR over 0-3 months was not closely related to the change in BMD at hip or spine at 1 yr. CONCLUSION: Disease activity is a significant determinant of bone turnover in RA. Bone resorption markers fall on treatment of RA with DMARDs and no change in BMD was demonstrated at 2 yr. This study suggests the need to control disease activity in RA in order to prevent systemic bone loss.
15529378 Prognostic importance of low body mass index in relation to cardiovascular mortality in rh 2004 Nov OBJECTIVE: Various etiologic mechanisms have been implicated in the observed increase in cardiovascular mortality in rheumatoid arthritis (RA). Body mass index (BMI) is associated with cardiovascular mortality in the general population. This study compared the effect of BMI on cardiovascular mortality in a population-based cohort of subjects with RA with that in a cohort of individuals without RA from the same population. METHODS: The RA cohort comprised all members of an incidence cohort of Rochester, Minnesota residents ages > or =18 years who were first diagnosed with RA (by the American College of Rheumatology 1987 criteria) from 1955 through 1994. An age- and sex-matched comparison cohort of subjects without RA was assembled. Both cohorts were followed up longitudinally through their complete (inpatient, outpatient) medical records beginning at age 18 years and continuing until death, migration, or January 1, 2001, and the details of weight and height changes during this period were recorded. High BMI was defined as a BMI >30 kg/m(2) and low BMI as <20 kg/m(2). Cox regression models were used to estimate the effect of BMI on cardiovascular mortality after accounting for traditional cardiac risk factors and malignancies. RESULTS: RA subjects with low BMI at incidence had a significantly higher risk of cardiovascular death (hazard ratio [HR] 3.34, 95% confidence interval [95% CI] 2.23-4.99) compared with non-RA subjects with normal BMI, after adjusting for age, sex, personal cardiac history, smoking status, and presence of diabetes, hypertension, and malignancies. RA subjects with normal BMI at incidence who experienced low BMI during followup also had a higher risk of cardiovascular death (HR 2.09, 95% CI 1.50-2.92) when compared with non-RA subjects who maintained normal BMI throughout followup. CONCLUSION: Among patients with RA, low BMI is associated with a significantly increased risk of cardiovascular death.
15466401 Overexpression of human matrix metalloproteinase-12 enhances the development of inflammato 2004 Oct Increased proteolytic activity of matrix metalloproteinases (MMPs) may promote articular destruction such as occurs in rheumatoid arthritis and osteoarthritis. Recently, we reported that synovial tissue and fluid obtained from patients with rheumatoid arthritis contained higher activity of macrophage elastase (MMP-12). To examine the hypothesis that MMP-12 may potentially enhance the progression of arthritis, we investigated the effects of overexpression of MMP-12 on inflammatory arthritis in transgenic rabbits that express the human MMP-12 transgene in the macrophage lineage. Inflammatory arthritis was produced by articular injection of carrageenan solution and the degree of inflammatory arthritis in transgenic rabbits was compared with that in control rabbits. We found that overexpression of MMP-12 in transgenic rabbits significantly enhanced the arthritic lesions, resulting in severe synovial thickening, pannus formation, and prominent macrophage infiltration at an early stage and a marked destruction of articular cartilage associated with loss of proteoglycan at a later stage. These results demonstrate that excessive MMP-12 expression exacerbates articular connective tissue and cartilage degradation and thus plays a critical role in the development of inflammatory joint disease.
12382304 The rheumatoid hand: a predictable disease with unpredictable surgical practice patterns. 2002 Oct 15 OBJECTIVES: To evaluate variation in fusion, arthroplasty, and tenosynovectomy rates among rheumatoid arthritis (RA) patients across states; to evaluate associations between surgery rates and the density of hand surgeons; and to evaluate differences in treatment by sex of the patient. METHODS: Data were obtained from the 1996 and 1997 Healthcare Cost and Utilization Project database. The procedure codes for fusion, arthroplasty, and tenosynovectomy were matched to patients with the diagnostic code of RA, which provided the total number of procedures performed in each state. The smoothed estimates of the RA population for each state were derived from age/sex strata in the 1995 US census using age/sex-adjusted RA prevalence data from the Third National Health and Nutrition Examination Survey. The number of hand surgeons was from the 1996 American Society for Surgery of the Hand. RESULTS: Procedure rates across states varied from 9-fold to 12-fold for all 3 procedures. The rates of the reconstructive procedures-fusion and arthroplasty-were highly correlated in each state, but these 2 procedures were only moderately correlated with tenosynovectomy. Surgeon density and procedure rates were minimally correlated. Procedure rates differed by patient sex, with significantly more arthroplasty and fusion procedures performed in women. More tenosynovectomy procedures were performed in men, and they were also performed at a younger age in men. CONCLUSIONS: Significant large area variations are present in the surgical management of the rheumatoid hand, but the correlations between reconstructive and early intervention procedures are modest. These rate differences are not explained by the number of hand surgeons, disease prevalence, or demographic composition of the states. However, men are more likely to receive more aggressive early surgical interventions, and women are more likely to receive end-stage reconstructive surgery.
12707580 Laboratory changes on anti-tumor necrosis factor treatment in rheumatoid arthritis. 2003 May Tumor necrosis factor-alpha, acting through its receptors expressed on all cells of the body, is a key mediator of inflammation and immunity. However, its overproduction may also lead to pathologic changes. The latter situation occurs often in chronic inflammatory diseases such as rheumatoid arthritis. The concept suggesting tumor necrosis factor-alpha as a potential target emerged from experiments showing its key role in inducing many cytokines and mediators of inflammation. Several clinical trials targeting this cytokine in rheumatoid arthritis patients with a novel group of anti-tumor necrosis factor agents demonstrated reduced synovial inflammation and inhibition of bone and cartilage degradation. In addition to the therapeutic value of anti-tumor necrosis factor, analysis of laboratory changes not only proved the concept but provided new data, continuously expanding our understanding of the role of tumor necrosis factor-alpha in the pathogenesis of many diseases. These laboratory measures may also help the earlier identification of rheumatoid arthritis patients who have a less satisfactory response to this therapy.
12114284 Melatonin serum levels in rheumatoid arthritis. 2002 Jun The pineal hormone melatonin (MLT) exerts a variety of effects on the immune system. MLT activates immune cells and enhances inflammatory cytokine and nitric oxide production. Cytokines are strongly involved in the synovial immune and inflammatory response in rheumatoid arthritis (RA) and reach the peak of concentration in the early morning, when MLT serum level is higher. Nocturnal MLT serum levels were evaluated in 10 RA patients and in 6 healthy controls. Blood samples were obtained at 8 and 12 p.m., as well as at 2, 4, 6, and 8 a.m. MLT serum levels at 8 p.m. and 8 a.m. were found to be higher in RA patients than in controls (p < 0.05). In both RA patients and healthy subjects, MLT progressively increased from 8 p.m. to the first hours of the morning, when the peak level was reached (p < 0.02). However, MLT serum level reached the peak at least two hours before in RA patients than in controls (p < 0.05). Subsequently, in RA patients, MLT concentration showed a plateau level lasting two to three hours, an effect not observed in healthy controls. After 2 a.m., MLT levels decreased similarly in both RA patients and healthy subjects. Several clinical symptoms of RA, such as morning gelling, stiffness, and swelling, which are more evident in the early morning, might be related to the neuroimmunomodulatory effects exerted by MLT on synovitis and might be explained by the imbalance between cortisol serum levels (lower in RA patients) and MLT serum levels (higher in RA patients).