Low T3 syndrome and chronic inflammatory rheumatism

For the clarification of pathogenesis and clinical relevance of decreases of the triiodothyronine (T3) level in patients with chronic inflammatory rheumatism in a group of 63 patients with clinically, paraclinically and roentgenologically diagnosed rheumatoid arthritis (59 times) and with SLE (4 times), respectively, parallel were determined parameters of the thyroid gland function and of the rheumatic activity as well as a subtile drug anamnesis for the medication of antirheumatic drugs was established. In 33 of the 63 patients who were included into the study decreases and low normal values, respectively, for the total T3 (TT3 less than 1.5 nmol/l) were found. In comparison to the remaining 30 patients with normal TT3 a typical constellation of paraclinical parameters of the thyroid gland with distinct reduction of TT3 and free T3 (FT3), low normal total T4 (TT4), slight increase of the reverse T3 (rT3), moderate decrease of the basal and stimulated TSH and an only very small restriction of the binding capacity of the thyroid hormone (TBG) were found. A clinically relevant hypothyroidism is thus to be excluded with certainty. Antirheumatic drugs, in particular steroidal ones (glucocorticoids) may on principle also induce such paraclinical constellations, related to the thyroid gland. In our investigations a therapy with antirheumatic drugs is causally scarcely considered, since both in the group of patients with decrease of T3 and without decrease comparable quantities of antirheumatic drugs including glucocorticoids were administered and the cortisol values in the plasma do not differ. The investigations confirm our already formerly expressed supposition that also in rheumatics a "low-T3-syndrome" is existing as it is otherwise described in consumptive extrathyroidal diseases (NTI).(ABSTRACT TRUNCATED AT 250 WORDS)     

Drug treatment of rheumatoid arthritis and osteoarthritis

A review is given about more recent methods for therapy of the rheumatoid arthritis as well as of the osteoarthrosis. Of a large importance in the treatment of the rheumatoid arthritis and of the osteoarthrosis is the method of clinical tests of non-steroidal antirheumatic drugs and of the so-called disease-activity modifying substances. Own experiences and results of controlled, clinical open and double-blind studies were given.     

Cyclosporine and tacrolimus for the treatment of rheumatoid arthritis

PURPOSE OF REVIEW: The calcineurin inhibitors cyclosporine and tacrolimus are important treatments for patients with active rheumatoid arthritis, especially in cases of resistance or intolerance to methotrexate or other disease-modifying antirheumatic drugs. Here, we discuss the mechanism, efficacy and safety of cyclosporine and tacrolimus in the treatment of rheumatoid arthritis. RECENT FINDINGS: Recent clinical trials of cyclosporine have shown the advantages of its combination with methotrexate, glucocorticoids and leflunomide in the treatment of active rheumatoid arthritis. In Japan, tacrolimus monotherapy was found to be quite effective and combination therapy with methotrexate had positive results in an American study. The inhibitory effects of both drugs not only on T lymphocytes, but also on human osteoclast formation, have been demonstrated in basic studies. SUMMARY: Cyclosporine and tacrolimus are clinically available disease-modifying antirheumatic drugs. Numerous clinical studies have shown the usefulness of these calcineurin inhibitors in monotherapy and also when combined with methotrexate. Although these drugs have similar effects, there are some differences in adverse reactions.     

Is there still a role for traditional disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis?

Rheumatoid arthritis is a chronic and debilitating disease, affecting an estimated 1% of the population worldwide. The past decade has witnessed an explosion in our understanding of the pathophysiology of rheumatoid arthritis and therefore in our ability to more effectively target the disease process. Although a cure remains elusive, remission is an approachable goal. There has been a complete remodeling of the traditional "pyramid" by rheumatologists, who now treat rheumatoid arthritis earlier and more aggressively than ever before. Standard single therapy with disease-modifying antirheumatic drugs, which was previously the final step in treating rheumatoid arthritis, is now practically bypassed in the deluge of information suggesting that combinations of disease-modifying antirheumatic drugs or newer biologic therapy is more effective. It is difficult to assimilate all the data and develop a rational approach; however, the bottom line is often the deciding factor: the newer agents are tremendously expensive. The intent of this article is to review recent and relevant trials in the treatment of rheumatoid arthritis, suggest a treatment algorithm, and argue that traditional disease-modifying antirheumatic drugs continue to play a pivotal role.     

Cardiovascular comorbidity and its risk factors in rheumatoid arthritis

Rheumatoid arthritis (RA) is still associated with an increased mortality mainly due to an increase in cardiovascular risk. This increase is not solely explained by traditional cardiovascular risk factors but also by disease characteristics, e.g. inflammation, positive rheumatoid factor and anti-citrullinated peptide antibodies (ACPA). Control of disease activity with disease-modifying drugs (DMARDs) was shown to reduce cardiovascular risk in RA patients. Use of non-steroidal antirheumatic drugs (NSAIDs) and glucocorticoids might be associated with an increased risk. The EULAR recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis have been established. These recommendations are based on national guidelines regarding control of traditional cardiovascular risk factors.     

Incidence of goiter and thyroiditis in chronic inflammatory rheumatism

In our investigations 201 patients with rheumatoid arthritis show in 127 cases according 63.2% (123 women = 71.1%; 4 women = 14.3%) and 32 patients with collagen diseases in 11 cases according 34.4% (11 women = 43.3%) a goiter. In comparison to a control group with a goiter incidence of 29.5% in women (168 out of 570 women), we found in female patients with rheumatoid arthritis or collagen diseases a clearly higher prevalence of goiter. But there was no difference of goiter frequency between the small groups of men. A second aim of our study was to investigate, whether an increased occurrence of the hypertrophic kind of Hashimoto's thyroiditis is to find in patients with rheumatic diseases, because of a possible association of two immunological induced affections. The results of sonographical, immunological and cytological examinations of the thyroid gland suggested no high responsibility of Hashimoto's thyroiditis for the goiter frequency in rheumatism. Only in three out of 201 investigated patients with rheumatoid arthritis (1.5%) we were able to diagnose this disease. In comparison to a rheumatologically healthy population out of the same catchment area (HT-frequency less than 0.5%), indeed the morbidity rate in rheumatic patients seems to be 3 times higher. But for a goiter frequency of altogether 63.2% in this disease the Hashimoto's thyroiditis is only of very small importance. Other causes such as pharmacotherapy with goitrogenic antirheumatic drugs, conditions of iodine deficiency, disposition and probably also an increase of thyroid growth stimulating immunoglobulins may be alone or in combination or a much higher degree responsible for goiter development in patients with rheumatoid arthritis or collagen diseases.     

Non-steroidal anti-inflammatory drug (NSAID)-induced colonic strictures and perforation: A case report

Although non-steroidal anti-inflammatory drug-induced colopathy is well described, colonic perforations complicating non-steroidal anti-inflammatory drug intake are rare. We report a patient with rheumatoid arthritis who was on long-term diclofenac and presented with early colonic stricture formation and a caecal perforation, which to the best of our knowledge, has only been reported once before. It is important to suspect this diagnosis in patients on non-steroidal anti-inflammatory drug therapy who present with an acute abdomen.     

Helicobacter pylori colonization of the gastric mucosa in rheumatic patients]

This study examines whether infections with Helicobacter pylori are more frequent in patients suffering from rheumatoid arthritis than in patients with non-inflammatory rheumatic diseases. The study furthermore examines whether the colonisation by H. pylori is favoured by antiphlogistic-antirheumatic treatment. For this purpose gastric biopsies obtained by endoscopy from 123 patients were histologically evaluated for the presence of H. pylori. 85 patients with rheumatoid arthritis were compared with 38 patients with non-inflammatory rheumatic diseases. Although an increased susceptibility for infections can be expected in persons with rheumatoid arthritis undergoing long-term antirheumatic treatment, this could not be confirmed by our results for the colonisation of the stomach by H. pylori. It is therefore statistically confirmed that rheumatoid arthritis itself and treatment with short-term effective antirheumatic drugs has no significant influence on the colonisation rate. Still it is doubtful whether any lesion associated with NSAR and H. pylori must necessarily be considered an NSAR-"induced". Future studies will have to elaborate whether NSAR in H. pylori infected mucosa will lead to higher incidence of damage.     

Inhibition of in vivo leucocyte migration by NSAIDs

Leucocyte migration was studied in vivo using a skin window technique, and in vitro by migration under agarose. No difference was found between 28 patients with rheumatoid arthritis (RA), 10 patients with psoriatic arthritis (PA) and 30 healthy controls. Most patients were under treatment with anti-rheumatic drugs. Patients treated with non-steroidal anti-inflammatory drugs (NSAIDs) had significantly lower values (p less than 0.01) than untreated patients. In vivo but not in vitro migration decreased during short-term treatment with diclofenac and naproxen, an effect observed both in patients and in healthy individuals. After pre-incubation of normal polymorphonuclear leucocytes with diclofenac, in vitro migration was diminished only at concentrations of 50 micrograms/ml and above, which are at least 10 times higher than those attained clinically. The in vivo effect of NSAIDs on leucocyte migration may imply a long-term disease modifying influence in chronic arthritides.     

Is retardation of radiologic progression of ankylosing spondylitis possible?

In the introduction is the author dealing with problems of early diagnosis of ankylosing spondylitis and he is explaining the advantages of new ASAS/EULAR criteria for diagnosis of axial spondylarthritis. Than he continues with discussion about new "Recommendations for treatment of ankylosing spondylitis", stressing the modification of recommendations for anti-TNF therapy. Despite the fact, that high symptomatic efficacy of anti-TNF therapy was confirmed, there is no clear evidence that anti-TNF drugs delay radiologic progression. On the contrary, study with nonsteroidal antirheumatic drugs in duration 24 months was performed and have documented that patients treated continuously by celecoxib had smaller radiographic progression than patients treated with celecoxib on demand. Anti-TNF therapy delays radiographic progression in rheumatoid arthritis, but not NSAID, in ankylosing spondylitis it is opposite. The differences may be caused by different pathophysiology of rheumatoid arthritis and ankylosing spondylitis as it is explained in the next part of publication. Combination therapy of AS with anti-TNF and continuous celecoxib therapy could be very interesting.     

Evaluation of analgesic action and efficacy of antirheumatic drugs. Study of 10 drugs in 684 patients with rheumatoid arthritis.

A single-blind non-crossover method for assessing the potential effectiveness of antirheumatic drugs has been described. The method employs entirely subjective indices and incorporates a daily pain chart for measuring the pain response over the duration of the trial. In addition, the mean number of days withdrawn and patients' satisfaction rating are measured. The statistical method can correct for initial imbalances between groups and allows for the valid comparison of drugs from separate trials. Ten antirheumatic medications were evaluated using this technique in 684 patients with rheumatoid arthritis, and the results are in agreement with those of previous studies using standard clinical methods. The new method is simple, rapid in performance, economical in terms of cost and time, and has been shown to be sensitive and reproducible. The results indicate that there are no significant differences in efficacy between the currently available non-steroidal, anti-inflammatory analgesic drugs, in the treatment of rheumatoid arthritis.     

Serum level of oxidative stress marker is dramatically low in patients with rheumatoid arthritis treated with tocilizumab

Regarding the pathobiology of rheumatoid arthritis, oxidative stress induced by reactive oxygen species is an important mechanism that underlies destructive and proliferative synovitis. Abundant amounts of reactive oxygen species have been detected in the synovial fluid of inflamed rheumatoid joints. It is reported that drugs that block tumor necrosis factor-?? reduce the oxidative stress marker levels in patients with rheumatoid arthritis. In this study, we measured reactive oxygen species using a free radical analytical system in patients with rheumatoid arthritis treated with disease-modifying antirheumatic drugs, tumor necrosis factor-??-blocking drugs (infliximab, etanercept), and an interleukin-6-blocking drug (tocilizumab). The serum level of oxidative stress was drastically low in patients with rheumatoid arthritis treated with tocilizumab, suggesting that interleukin-6 blocking therapy reduces not only joint damage, but also vascular degeneration in patients with rheumatoid arthritis. We believe that such a drastic effect would reduce the incidence of cardiovascular events and mortality in patients with rheumatoid arthritis.     

Atherosclerotic cardiovascular disease in rheumatoid arthritis

The past 3 years have seen a remarkable growth in the inter-est of cardiovascular disease in rheumatoid arthritis. There have been studies published documenting an increased inci-dence and prevalence of cardiovascular conditions in patients with rheumatoid arthritis compared with individuals without rheumatoid arthritis. There has also been interest in the occurrence of cardiovascular risk factors in rheumatoid arthritis and in the role of antirheumatic therapy, including cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs, methotrexate, corticosteroids, and tumor necrosis fac-tor inhibitors. A number of studies using noninvasive means to detect atherosclerosis have shown that patients with rheu-matoid arthritis may be prone to atherosclerosis. This infor-mation should be important to physicians who provide care to patients with rheumatoid arthritis, given the difficulty of recognizing cardiovascular signs and symptoms among patients with the disease.     

Methylprednisolone pulse therapy in conjunction with azathioprine in rheumatoid arthritis

In the management of rheumatoid arthritis two potentially useful roles for methylprednisolone (MP) pulse therapy are presently recognised: in patients in whom second line drugs have not led to a satisfactory remission or have caused side effects, and in bridging the gap between the start and the delayed onset of effect of a slow-acting antirheumatic drug. Recently it was shown that MP-pulse therapy was effective in accelerating the response to sulphasalazine and D-penicillamine. Nineteen patients with a persistently active rheumatoid arthritis, who had failed to respond to at least two slow-acting antirheumatic drugs, were treated with MP-pulse therapy in conjunction with azathioprine. Twelve patients continued this treatment for 6 months and 8 for 12 months. MP-pulse therapy resulted in an immediate improvement in Ritchie articular index, grip strength, ESR and CRP. However, this improvement lasted less than six weeks. After 6 months some improvement due to the effect of azathioprine became apparent. Some rather serious side effects were noted. It is concluded that MP-pulse therapy has a (short lasting) beneficial effect in persistently active rheumatoid arthritis. However MP-pulse therapy is not suitable to bridge the gap between the introduction of azathioprine-treatment and the delayed response to this drug.     

Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease-modifying properties, and side effects: a randomized, double-blind, placebo-controlled clinical trial

BACKGROUND: Oral glucocorticoids combined with disease-modifying antirheumatic drugs are beneficial and retard radiologic joint damage in rheumatoid arthritis. OBJECTIVE: To investigate the clinical efficacy, disease-modifying properties, and side effects of low-dose glucocorticoids as monotherapy for previously untreated patients with early active rheumatoid arthritis. DESIGN: 2-year randomized, double-blind, placebo-controlled clinical trial. SETTING: 2 outpatient rheumatology clinics. PATIENTS: 81 patients with early active rheumatoid arthritis who had not been treated with disease-modifying antirheumatic drugs. INTERVENTION: 41 patients were assigned to 10 mg of oral prednisone per day, and 40 were assigned to placebo. Nonsteroidal anti-inflammatory drugs were allowed in both groups. After 6 months, sulfasalazine (2 g/d) could be prescribed as rescue medication. MEASUREMENTS: Clinical variables were assessed at baseline and every 3 months; radiologic studies were performed every 6 months. Adverse effects were documented every 3 months. RESULTS: In the first 6 months, the prednisone group showed more clinical improvement than the placebo group. This effect was not seen after 6 months except in grip strength and the 28-joint score for tenderness. Use of additional therapies was significantly less common in the prednisone group, particularly in the first 6 months. More than 65% of those who completed the study were not taking sulfasalazine. After month 6, radiologic scores showed significantly less progression in the prednisone group than in the placebo group. No clinically relevant adverse effects were observed, except for a higher incidence of osteoporotic fractures in the prednisone group. CONCLUSIONS: Prednisone, 10 mg/d, provides clinical benefit, particularly in the first 6 months, and substantially inhibits progression of radiologic joint damage in patients with early active rheumatoid arthritis and no previous treatment with disease-modifying antirheumatic drugs. Because of their limited disease-modifying effects, glucocorticoids should be combined with disease-modifying antirheumatic drugs in patients with rheumatoid arthritis.     

Disease-modifying antirheumatic drugs other than methotrexate in rheumatoid arthritis and seronegative arthritis

PURPOSE OF REVIEW: To outline recent research findings with nonmethotrexate disease-modifying antirheumatic drugs in rheumatoid arthritis and seronegative arthritis spanning systematic reviews, randomized controlled trials, observational clinical practice trials and assessments of adverse effects. RECENT FINDINGS: Systematic reviews show no important differences between methotrexate, leflunomide and sulfasalazine monotherapies; early disease-modifying antirheumatic drug therapy reduces erosive progression. Observational studies show that nonmethotrexate disease-modifying antirheumatic drugs are widely prescribed; their usage has increased in the biologic era. A systemic review also showed patients who failed monotherapy benefited from disease-modifying antirheumatic drug combinations without excess toxicity. Randomized controlled trials of intensive initial disease-modifying antirheumatic drug combinations showed they reduce synovitis and erosive damage, especially when used with steroids. The subsequent sequence of disease-modifying antirheumatic drugs and the value of changing disease-modifying antirheumatic drug monotherapies or stepping-up to combination disease-modifying antirheumatic drugs are, however, unresolved. The adverse risks of nonmethotrexate disease-modifying antirheumatic drugs have been evaluated, including infections and lung disease; patient-related risks seem more important than drug-related risks, though several disease-modifying antirheumatic drugs increase both types of adverse reactions. Two limitations of nonmethotrexate disease-modifying antirheumatic drugs are reduced impact on comorbidities like cardiovascular disease and reduced patient and clinician preferences for these treatments. SUMMARY: Nonmethotrexate disease-modifying antirheumatic drugs are effective, relatively well tolerated and widely used. Their role in intensive treatment strategies in early rheumatoid arthritis appears of crucial importance.     

Biologic therapy for early rheumatoid arthritis: the latest evidence

PURPOSE OF REVIEW: To describe current therapeutic trials with biologic agents for early rheumatoid arthritis, analyzing clinical and radiographic outcomes. RECENT FINDINGS: The use of tumor necrosis factor-alpha inhibitors in combination with disease-modifying antirheumatic drugs early after the diagnosis of aggressive rheumatoid arthritis seems to provide increased clinical benefit over methotrexate or tumor necrosis factor-alpha inhibitors as monotherapy, with better outcomes in terms of faster and more extensive clinical improvement. There also seems to be an increased likelihood of low-disease activity in some cases even after tapering therapy. Control of radiographic progression appears to be most effective among early rheumatoid arthritis patients treated with combination tumor necrosis factor-alpha inhibitors and methotrexate, although radiographic outcomes are better with tumor necrosis factor-alpha inhibitor monotherapy than with methotrexate alone. SUMMARY: The addition of antitumor necrosis factor-alpha agents to traditional disease-modifying antirheumatic drugs in early rheumatoid arthritis is a novel strategy which follows the principle of early and aggressive therapeutic intervention. Results from recent trials show greater levels of disease control. The impact on long-term safety and cost-efficacy are factors which will need to be better characterized over time.     

Effectiveness of plasma exchange therapy in patients with rheumatoid arthritis and systemic manifestations

For the advantage of the therapeutic plasma exchange in the active rheumatoid arthritis there exist at present contradictory opinions. Three patients with rheumatoid arthritis and systemic manifestation as well as high activity of the disease, in whom the conventional therapy with antirheumatic drugs showed only little effectiveness and which was stopped due to severe side effects, respectively, underwent 6 plasma exchange treatments within 14 days. The subjective condition as well as standardized clinical and laboratory-chemical activity parameters quickly ameliorated. A positive therapeutic effect was to be proved still after 6 to 12 months. In 2 patients a proposed synovectomy could be renounced. The reasonable indication for the plasma exchange will be given when there is an acute immunological reaction which can be shortened by a rapid reduction of pathogenic protein fractions before irreversible morphological injuries occur.     

Disease-modifying antirheumatic drugs.

Rheumatologists now seem to accept that early treatment of patients with rheumatoid arthritis with disease-modifying antirheumatic drugs is required if erosions are to be prevented. Methotrexate remains the most popular disease-modifying antirheumatic drug and is used in the most popular combination treatments, although the dose needs to be reduced in the elderly and those with renal dysfunction. The combination of sulfasalazine, methotrexate with reducing high-dose prednisolone, is demonstrated to be cost-effective in patients with rheumatoid arthritis, but although several other combinations have been reported effective in patients with rheumatoid arthritis, most trials do not have the power to provide a definitive answer as to the best combination available, if one exists.