Carmen Pizzorni

Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis

Methotrexate (MTX) is a folate analogue originally synthesised in the 1940s and designed to inhibit dihydrofolate reductase.1 Reduced folate (tetrahydrofolate) is the proximal single carbon donor in several reactions involved in the de novo synthetic pathways for purine and pyrimidine precursors of DNA and RNA required for cell proliferation. Furthermore, tetrahydrofolate plays a part in a second important biochemical step: the methionine-homocysteine cycle, which is necessary to provide a methyl group for several downstream reactions such as methylation of DNA, RNA proteins, and others. Therefore, MTX has been used extensively for treatment of neoplastic diseases. In 1951 the rationale for the introduction of MTX for the treatment of rheumatoid arthritis (RA) was that it inhibited proliferation of the lymphocytes and other cells responsible for inflammation in the joint.2 No further studies on clinical experience with MTX in RA were published until the early 1980s, when several uncontrolled trials were reported.3-8 Finally, four well designed, blinded, placebo controlled studies published in 1984 and 1985 introduced the use of MTX in the treatment of RA.9-12 The early indications for MTX use in the rheumatic diseases were first reported in a large review in 1984.13 From the considerable experience obtained over the past 15 years, several lines of evidence clearly suggest that MTX does not act simply as a cytotoxic (antiproliferative) agent for the cells responsible for the joint inflammation in RA.14 As a matter of fact, it would be difficult to understand how a drug that diminishes inflammation by preventing proliferation of immune cells might work at effective concentrations for only a very short time and once a week. In addition, the rapid clinical remission and the short term effect on the acute phase reactants, as seen with low dose MTX administration in most patients with …

Androgens and estrogens modulate the immune and inflammatory responses in rheumatoid arthritis.

Abstract: Generally, androgens exert suppressive effects on both humoral and cellular immune responses and seem to represent natural anti‐inflammatory hormones; in contrast, estrogens exert immunoenhancing activities, at least on humoral immune response. Low levels of gonadal androgens (testosterone/dihydrotestosterone) and adrenal androgens (dehydroepiandrosterone and its sulfate), as well as lower androgen/estrogen ratios, have been detected in body fluids (that is, blood, synovial fluid, smears, salivary) of both male and female rheumatoid arthritis patients, supporting the possibility of a pathogenic role for the decreased levels of the immune‐suppressive androgens. Several physiological, pathological, and therapeutic conditions may change the sex hormone milieu and/or peripheral conversion, including the menstrual cycle, pregnancy, the postpartum period, menopause, chronic stress, and inflammatory cytokines, as well as use of corticosteroids, oral contraceptives, and steroid hormonal replacements, inducing altered androgen/estrogen ratios and related effects. Therefore, sex hormone balance is still a crucial factor in the regulation of immune and inflammatory responses, and the therapeutical modulation of this balance should represent part of advanced biological treatments for rheumatoid arthritis and other autoimmune rheumatic diseases.

Scoring the nailfold microvascular changes during the capillaroscopic analysis in systemic sclerosis patients

Background: Longitudinal study to define a scoring system to quantify the specific capillary abnormalities, as observed by capillary microscopy in systemic sclerosis (SSc). Methods: Ninety patients with SSc were evaluated by nailfold videocapillaroscopy for an average of 72 (SD 23) months. Enlarged and giant capillaries, haemorrhages, loss of capillaries, disorganisation of the microvascular array, and capillary ramifications were the evaluated parameters identifying the “scleroderma patterns”. A semiquantitative rating scale to score these altered microvascular parameters was adopted (score 0–3). A “microangiopathy evolution score” (sum of three scores: loss of capillaries, disorganisation of the microvascular array and capillary ramifications) was also selected to assess the progression of the vascular damage. Results: At the end of the follow-up, the score for each nailfold videocapillaroscopy parameter significantly changed. The microangiopathy evolution score significantly increased in 53 of 90 patients (59%) indicating a worsening of the microangiopathy. On the contrary, 22 patients (24%) showed a significant decrease of the evolution score suggesting an improvement of the microangiopathy and no changes were detected in 15 patients with SSc (17%). Conclusions: The capillaroscopic score was found to be a sensitive tool to quantify and monitor the SSc microvascular damage. Furthermore, the microangiopathy evolution score might be used to survey the evolution of the microvascular damage, as the relative scores increase during the progression of the SSc.

Circadian rhythms in RA

Possible roles of cortisol and melatonin It is well known that some clinical signs and symptoms of rheumatoid arthritis (RA) vary within a day and between days, and the morning stiffness seen in patients with RA has become one of the diagnostic criteria of the disease (fig 1).1 Figure 1 Clinical signs and symptoms of articular inflammation in patients with RA change consistently as a function of the hours of the day: pain and joint stiffness are greater after waking up in the morning than in the afternoon or evening. Among the clinical signs of joint inflammation in patients with RA, the intensity of pain changes consistently as a function of the hours of the day: pain is greater after waking up in the morning than in the afternoon or evening.2 In patients with RA circadian variations are also found in joint swelling and finger size and these symptoms are in phase with the circadian rhythm of pain. The RA rhythms differ in phase by about 12 hours from the circadian changes of left and right hand grip strength: a greater grip strength is seen when joint circumferences and the subjective ratings of stiffness and pain are least and vice versa.3 “Clinical signs and symptoms in RA depend on the time of day” Therefore, clinical signs and symptoms in RA show a rhythm that seems driven by a biological clock. Biological rhythms have been seen in different models of inflammation, and maximal inflammation occurred during the activity period of the animals—that is, between midnight and 8 00 am.4 Biological rhythms with a periodicity longer than 24 hours have also been detected, and a circaseptan rhythm (almost seven days) of paw oedema, over a period of 30 days, was observed, with peak of inflammation every 6–7 days.5 Furthermore, …

Vitamin D endocrine system involvement in autoimmune rheumatic diseases

Vitamin D is synthesized from cholesterol in the skin (80-90%) under the sunlight and then metabolized into an active D hormone in liver, kidney and peripheral immune/inflammatory cells. These endocrine-immune effects include also the coordinated activities of the vitamin D-activating enzyme, 1alpha-hydroxylase (CYP27B1), and the vitamin D receptor (VDR) on cells of the immune system in mediating intracrine and paracrine actions. Vitamin D is implicated in prevention and protection from chronic infections (i.e. tubercolosis), cancer (i.e. breast cancer) and autoimmune rheumatic diseases since regulates both innate and adaptive immunity potentiating the innate response (monocytes/macrophages with antimicrobial activity and antigen presentation), but suppressing the adaptive immunity (T and B lymphocyte functions). Vitamin D has modulatory effects on B lymphocytes and Ig production and recent reports have demonstrated that 1,25(OH)2D3 does indeed exert direct effects on B cell homeostasis. A circannual rhythm of trough vitamin D levels in winter and peaks in summer time showed negative correlation with clinical status at least in rheumatoid arthritis and systemic lupus erythematosus. Recently, the onset of symptoms of early arthritis during winter or spring have been associated with greater radiographic evidence of disease progression at 12 months possibly are also related to seasonal lower vitamin D serum levels.

Nailfold capillaroscopy for day-to-day clinical use: construction of a simple scoring modality as a clinical prognostic index for digital trophic lesions

Objective Construction of a simple nailfold videocapillaroscopic (NVC) scoring modality as a prognostic index for digital trophic lesions for day-to-day clinical use. Methods An association with a single simple (semi)-quantitatively scored NVC parameter, mean score of capillary loss, was explored in 71 consecutive patients with systemic sclerosis (SSc), and reliable reduction in the number of investigated fields (F32–F16–F8–F4). The cut-off value of the prognostic index (mean score of capillary loss calculated over a reduced number of fields) for present/future digital trophic lesions was selected by receiver operating curve (ROC) analysis. Results Reduction in the number of fields for mean score of capillary loss was reliable from F32 to F8 (intraclass correlation coefficient of F16/F32: 0.97; F8/F32: 0.90). Based on ROC analysis, a prognostic index (mean score of capillary loss as calculated over F8) with a cut-off value of 1.67 is proposed. This value has a sensitivity of 72.22/70.00, specificity of 70.59/69.77, positive likelihood ratio of 2.46/2.32 and a negative likelihood ratio of 0.39/0.43 for present/future digital trophic lesions. Conclusions A simple prognostic index for digital trophic lesions for daily use in SSc clinics is proposed, limited to the mean score of capillary loss as calculated over eight fields (8 fingers, 1 field per finger).

Reliability of the qualitative and semiquantitative nailfold videocapillaroscopy assessment in a systemic sclerosis cohort: a two-centre study

Objective Investigation of the reliability of the qualitative and semiquantitative scoring of nailfold videocapillaroscopy (NVC) assessment between two raters in a systemic sclerosis (SSc) cohort. Methods Two raters from different centres blindly assessed the NVC images of 71 consecutive patients with SSc qualitatively as belonging to the scleroderma spectrum (SDS) category (‘early’, ‘active’, ‘late’ scleroderma pattern or ‘scleroderma-like’ pattern) or to the ‘normal’ category and semiquantitatively by calculating the mean score for capillary loss, giant capillaries, microhaemorrhages and capillary ramifications. Inter-rater/intrarater agreement was assessed by calculation of the proportion of agreement and by κ coefficients. Rater agreement of mean score values of hallmark parameters was assessed by intraclass correlation coefficients. Results The inter-rater/intrarater proportion of agreement to qualitatively assess an image as belonging to the SDS category or not was 90% and 96%, whereas the agreement to distinguish between only ‘early’, ‘active’ and ‘late’ scleroderma NVC patterns was 62% and 81%. The agreement of the semiquantitative scoring, as assessed by intraclass correlation coefficient, was 0.96 and 0.95 for capillary loss, 0.84 and 0.95 for giant capillaries, 0.90 and 0.95 for microhaemorrhages and 0.64 and 0.95 for capillary ramifications. Conclusions This is the first study to demonstrate reliability of the qualitative and semiquantitative NVC assessment in an SSc cohort between raters at different centres. Reliability of NVC assessment is essential for use of this tool in multicentre SSc trials.

Melatonin serum levels in rheumatoid arthritis.

Abstract: 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).

Use of glucocorticoids and risk of infections.

Glucocorticoids (GC) exert many complex quantitative and qualitative immunosuppressive effects that induce cellular immunodeficiency and consequently might increase host susceptibility to various viral, bacterial, fungal, and parasitic infections. In chronic immune/inflammatory conditions cortisol is secreted at inadequate levels and GC therapy today is devoted in substituting this hormone in adequate doses (low) to compensate just for this; therefore, the correct timing of GC administration, such as given during the turning-on phase of TNF secretion (night), can be of major importance. Consequently, the use of the lowest possible GC dose, at the night time and even for the shortest possible time, should decrease dramatically the risk of infections.

Sex hormones and rheumatoid arthritis.

Sex hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone as natural immune-suppressors. In male rheumatoid arthritis (RA) patients, androgen replacement seems to ameliorate the disease and supports their involvement in the pathophysiology of the disease. The combination of androgens with cyclosporin A or methotrexate has been found to potentiate the apoptosis of monocytic inflammatory cells as well as to reduce the cell growth at least in vitro. Considerable interest has been devoted in the last years as to whether the use of oral contraceptive pills (OCs) may have a protective effect on the risk of RA. The results of many controlled studies have been found contradictory. At the present time, no consensus has been achieved regarding OCs administration and its relationship to the prevention or development of RA. In addition, an association of estrogen receptor gene polymorphism with age at onset of RA has been observed and might further explain inter-individual clinical and therapeutical-response variations. Local increased estrogen concentrations and decreased androgen levels have been observed in RA synovial fluids and seem to play a more important role in the immune/inflammatory local response.