minocycline and Arthritis--Rheumatoid

Tetracyclines are broad-spectrum antibiotics that act as such at the ribosomal level where they interfere with protein synthesis. They were first widely prescribed by dermatologists in the early 1950s when it was discovered that they were effective as a treatment for acne. More recently, biologic actions affecting inflammation, proteolysis, angiogenesis, apoptosis, metal chelation, ionophoresis, and bone metabolism have been researched. The therapeutic effects of tetracycline and its analogues in various diseases have also been investigated. These include rosacea, bullous dermatoses, neutrophilic diseases, pyoderma gangrenosum, sarcoidosis, aortic aneurysms, cancer metastasis, periodontitis, and autoimmune disorders such as rheumatoid arthritis and scleroderma. We review the nonantibiotic properties of tetracycline and its analogues and their potential for clinical application.

Topics: Acne Vulgaris; Anti-Bacterial Agents; Anti-Inflammatory Agents; Aortic Aneurysm, Abdominal; Apoptosis; Arthritis, Rheumatoid; Doxycycline; Humans; Matrix Metalloproteinases; Minocycline; Neoplasms; Neovascularization, Physiologic; Periodontitis; Rosacea; Sarcoma, Kaposi; Skin Diseases; Skin Diseases, Vesiculobullous; Tetracyclines

From time to time there have been reports of autoimmune disease succumbing to tetracycline antibiotics, but many have assumed this was due to coincidence, or to some ill-defined 'anti-inflammatory property' of the tetracyclines. But now the inflammation of sarcoidosis has succumbed to antibiotics in two independent studies. This review examines the cell wall deficient (antibiotic resistant) bacteria which have been found in tissue from patients with sarcoidosis. It examines how such bacteria can infect the phagocytes of the immune system, and how they may therefore be responsible for not only sarcoid inflammation, but also for other autoimmune disease. Proof positive of a bacterial pathogenesis for Sarcoidosis includes not only the demonstrated ability of these studies to put the disease into remission, but also the severity of Jarisch-Herxheimer shock resulting from endotoxin release as the microbes are killed. Studies delineating the hormone responsible for phagocyte differentiation in the Th1 immune response, 1,25-dihydroxyvitamin D, are discussed, and its utility as a marker of Th1 immune inflammation is reviewed. Finally, data showing that the behavior of this hormone is also aberrant in rheumatoid arthritis, systemic lupus erythematosus, and Parkinson's, raise the possibility that these diseases may also have a CWD bacterial pathogenesis.

Topics: Animals; Anti-Bacterial Agents; Arthritis, Rheumatoid; Autoimmune Diseases; Bacteria; Doxycycline; Forecasting; Humans; Lupus Erythematosus, Systemic; Minocycline; Parkinson Disease; Phagocytes; Sarcoidosis; Secondary Prevention; Tetracyclines; Vitamin D

To compare the effectiveness of tetracycline antibiotics versus control (placebo or conventional treatment) in rheumatoid arthritis (RA) for the reduction of disease activity as defined by American College of Rheumatology criteria.. We searched Medline (1966-February 2002), Embase (1980-February 2002), and the Cochrane Controlled Trials Register (Issue 1, 2002 Cochrane Library). Reference lists of published trials were searched by hand for further identification of published reports and presentations at scientific meetings. Randomized controlled trials comparing tetracyclines to control (placebo or conventional disease modifying antirheumatic therapy) were selected for inclusion if at least one of the following outcomes was reported: tender joint count (TJC), swollen joint count, patient pain score by visual analog scale, patient global assessment of disease activity, physician global assessment of disease activity, eosinophil sedimentation rate (ESR) and C-reactive protein (CRP), joint space narrowing and erosions, adverse events, and quality of life as measured by the Health Assessment Questionnaire. Subjects were required to have RA as defined by the 1987 ARA criteria.. Ten randomized controlled trials including 535 individuals were reviewed. Only 3 trials were considered high quality; elements of bias could not be excluded in the remainder. Tetracyclines, when administered for > or = 3 months, were associated with a significant reduction in disease activity in RA as follows: for TJC, standardized mean difference (SMD) = -0.39, 95% CI -0.74, -0.05; and for acute phase reactants, ESR, SMD = -8.96, 95% CI -14.51, -3.42. The treatment effect was more marked in the subgroup of patients with disease duration < 1 year who were seropositive. There was no absolute increased risk of adverse events associated with tetracyclines: absolute risk difference = 0.10, 95% confidence interval (CI) -0.01, 0.21. No beneficial effect was seen on radiological progression of disease: for erosions, SMD = 0.17, 95% CI -0.29, 0.64. In addition, subgroup analysis excluding trials with doxycycline showed that minocycline alone had a greater effect on reduction of disease activity: for TJC, SMD = -0.69, 95% CI -0.89, -0.49; and for ESR, SMD = -10.14, 95% CI -14.72, -5.57.. Tetracyclines, in particular minocycline, were associated with a clinically significant improvement in disease activity in RA with no absolute increased risk of side effects. Unfortunately, the information available was inadequate to allow a detailed analysis of individual side effects in the studies. Further research is warranted to compare these agents to newer disease modifying drugs for comparable safety, efficacy, and cost-effectiveness.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Arthrography; Doxycycline; Joints; MEDLINE; Minocycline; Pain Measurement; Randomized Controlled Trials as Topic; Severity of Illness Index; Tetracyclines; Treatment Outcome

Topics: Antibodies, Monoclonal; Antirheumatic Agents; Arthritis, Rheumatoid; Auranofin; Azathioprine; Cyclophosphamide; Cyclosporine; Drug Therapy, Combination; Etanercept; Humans; Hydroxychloroquine; Immunoglobulin G; Infliximab; Isoxazoles; Leflunomide; Methotrexate; Minocycline; Penicillamine; Receptors, Tumor Necrosis Factor; Sulfasalazine

During the past decade, many important changes have occurred in the treatment of rheumatoid arthritis, perhaps the most important of which has been the realization that early diagnosis and early treatment are critical. This has challenged our health-care systems to make sure that patients with early arthritis have access to the appropriate physicians. Additionally, the last decade has also seen many new treatment options become available for patients with rheumatoid arthritis. These new options have included the use of old drugs more effectively; the use of combinations of two or more disease-modifying anti-rheumatic drugs; new evidence to support the use of steroids; the resurrection of tetracyclines; the introduction of leflunomide; and, finally, the tumour necrosis factor inhibitors etanercept and infliximab. The availability of all these new options is clearly excellent news for patients with RA and their physicians. It is hoped that we will, in the next few years, better understand how most effectively to utilize these treatment options for the optimal care of our patients.

Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Etanercept; Humans; Immunoglobulin G; Infliximab; Isoxazoles; Leflunomide; Methotrexate; Minocycline; Prognosis; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha

Topics: Analgesics; Antibodies, Monoclonal; Antirheumatic Agents; Arthritis, Rheumatoid; Azathioprine; Cyclosporine; Etanercept; Glucocorticoids; Humans; Hydroxychloroquine; Immunoglobulin G; Infliximab; Isoxazoles; Leflunomide; Methotrexate; Minocycline; Penicillamine; Receptors, Tumor Necrosis Factor; Sulfasalazine

Radiographic studies of methotrexate (MTX) treated and minocycline treated patients with rheumatoid arthritis (RA) are reviewed. A formal metaanalysis of publications of RA treated with MTX was undertaken at the time when MTX was used for patients with established RA. Thus the conclusions of that metaanalysis may not be applicable to patients treated with MTX earlier in the course of their disease. On the other hand, there are no sufficient data to conduct a formal metaanalysis of patients with RA treated with minocycline.

Topics: Anti-Bacterial Agents; Arthritis, Rheumatoid; Clinical Trials as Topic; Humans; Immunosuppressive Agents; Methotrexate; Minocycline; Radiography; Treatment Outcome

Rheumatoid arthritis is a chronic inflammatory disease affecting about 1% of the adult population. The pathophysiology of rheumatoid arthritis remains incompletely understood. An infectious aetiology of the disease has long been postulated, but not proved. Despite insufficient evidence for the infectious nature of this disorder, several antibacterials, such as sulfa compounds, tetracyclines and rifampicin, have been investigated in the treatment of rheumatoid arthritis. In the last few years, minocycline, a semi-synthetic derivative of tetracycline, has been extensively studied as a therapeutic agent for rheumatoid arthritis. The antirheumatic effect of minocycline can be related to its immunomodulatory and anti-inflammatory, rather than to its antibacterial properties. Its efficacy in rheumatoid arthritis has been reported in 2 open trials and in 3 double-blind controlled studies. The first 2 double-blind studies, 1 in The Netherlands and 1 in the US, were performed in patients with advanced disease. Both studies showed a modest, but statistically significant improvement in the clinical parameters of disease activity and in the erythrocyte sedimentation rate in the minocycline-treated patients. The US study also reported that patients in the minocycline group developed fewer erosions than those in the placebo group. This finding supports the role of minocycline as a disease modifying agent. The common adverse effects of minocycline reported in these 2 studies included gastrointestinal adverse effects, dizziness, rash and headaches. Less common adverse effects were intracranial hypertension, pneumonitis, persistent skin and mucosal hyperpigmentation, lupus-like syndrome and acute hepatic injury. The third double-blind study enrolled only seropositive rheumatoid arthritis patients with early disease (less than 1 year duration), and showed very encouraging results of significant improvement in the disease activity parameters in the minocycline treated group of patients. The same authors later reported that about half of these patients were in or near remission after 3 years of follow up. No adverse effects were reported in this study. Summarising the data of these 3 double-blind studies, we may conclude that minocycline may be beneficial in patients with rheumatoid arthritis, especially when given early in the disease course or in patients with a mild disease.

Topics: Animals; Anti-Bacterial Agents; Arthritis, Rheumatoid; Humans; Minocycline; Risk Assessment

Despite many advances in the understanding and treatment of rheumatoid arthritis, its pathophysiology remains incompletely understood. An infectious aetiology of rheumatoid arthritis has long been postulated but, even though many continue to believe that there is a 'triggering agent for rheumatoid arthritis', none has been identified. Currently, both sulfasalazine and minocycline have been shown to be effective treatments for rheumatoid arthritis and are being used increasingly. In the case of minocycline, it appears that its ability to inhibit metalloproteases is an important characteristic that may account for some or part of its action against rheumatoid arthritis. Whether the antibacterial effects of these drugs or others are important in the treatment of rheumatoid arthritis continues to be investigated.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Minocycline; Sulfasalazine

Rheumatoid arthritis is a painful, chronic disease that affects an estimated 2 million Americans. Although no single pharmacologic agent is completely effective against the disease, some patients have shown significant improvement when treated with minocycline. Dr Alarcón summarizes the outcomes of studies to date and offers her recommendations.

Topics: Anti-Bacterial Agents; Arthritis, Rheumatoid; Humans; Minocycline

Minocycline is the most widely prescribed systemic antibiotic for the management of acne. In the past several years, increasing attention has been paid to the drug, both for its potential use as a disease-modifying antirheumatic agent and for its propensity to engender untoward autoimmune reactions, including serum sickness-like disease, drug-induced lupus, and autoimmune hepatitis. This paper reviews the evidence for minocycline as an anti-inflammatory and immunomodulatory agent, its utility in the treatment of rheumatoid arthritis, and the spectrum of adverse reactions that have been ascribed to the drug in the past 5 years.

Topics: Acne Vulgaris; Animals; Anti-Bacterial Agents; Arthritis; Arthritis, Rheumatoid; Autoimmune Diseases; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Female; Humans; Lupus Erythematosus, Systemic; Male; Minocycline; Vasculitis

The scientific basis for the use of antibiotics (with special emphasis on tetracycline and its derivatives) in the treatment of RA is discussed. The data on efficacy and toxicity are presented. The possible place of tetracycline derivatives within the overall strategy of RA treatment is also presented.

Topics: Anti-Bacterial Agents; Arthritis, Rheumatoid; Humans; Minocycline; Severity of Illness Index; Treatment Outcome

The author presents a review of contemporary knowledge on the treatment of rheumatoid arthritis with minocycline. He analyzes the assumed mechanism of action, dosage and the most frequently encountered undesirable effects of treatment. He informs the reader on the results of the most important studies with minocycline.

Topics: Anti-Bacterial Agents; Arthritis, Rheumatoid; Humans; Minocycline

Rheumatoid arthritis was considered for centuries to be a nuisance condition, limiting in its effects on an individual's range of motion and the source of considerable distress, but not a life-threatening disease. Recently, however, it has become apparent that patients with severe rheumatoid arthritis may have a decreased life span. Current pharmacologic therapies for patients with rheumatoid arthritis, which include nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, methotrexate, and corticosteroids, have been moderately successful in alleviating the discomforts associated with swollen, painful joints. Many practitioners have sought to improve use of these agents and slow joint destruction by challenging traditional treatment paradigms, altering the sequence in which drugs are given. Nevertheless, most standard medical approaches to treatment have had little or no impact on the course of rheumatoid disease. Innovative strategies, particularly those based on new concepts in the immunobiology of rheumatoid arthritis, are being developed to target cellular inflammatory mechanisms and actually prevent disease progression. Some agents, such as inhibitors of 5-lipoxygenase-omega-3 fatty acid and zileuton-may be most useful in treatment of milder disease manifestations such as moderate synovitis. Other agents, such as oral type II collagen, minocycline, subcutaneous interleukin-1ra, and anti-CD4 monoclonal antibodies, have produced such inconsistent results that substantial additional research will be required before any conclusions may be drawn about their value. Among the most promising agents, and the most extensively studied, are tumor necrosis factor-alpha monoclonal antibodies, immunosuppressive drugs such as cyclosporine and mycophenolate mofetil, and the novel compound tenidap, which has both cytokine-modulating and anti-inflammatory properties.

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Antibodies; Antirheumatic Agents; Arthritis, Rheumatoid; CD4 Antigens; Collagen; Cyclosporine; Humans; Hydroxyurea; Immunosuppressive Agents; Interleukin-1; Minocycline; Mycophenolic Acid; Tumor Necrosis Factor-alpha

Topics: Anti-Bacterial Agents; Arthritis, Rheumatoid; Collagenases; Humans; Immunity, Cellular; Minocycline; Phospholipases A; Treatment Outcome

Topics: Anti-Bacterial Agents; Arthritis, Rheumatoid; Clinical Trials as Topic; Follow-Up Studies; Humans; Minocycline; Prognosis

Minocycline is arguably the most interesting new drug for rheumatoid arthritis since the development of methotrexate. Tetracycline compounds have long been used by rheumatologists who were considered mavericks by their peers, and recent controlled studies have demonstrated their antirheumatic activity. The reason that minocycline works is unclear, and their niche in the treatment of rheumatoid arthritis remains to be established. Nonetheless, it is clear that some patients with rheumatoid arthritis respond favorably to this form of treatment.

Topics: Anti-Bacterial Agents; Arthritis, Rheumatoid; Clinical Trials as Topic; Minocycline

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that occurs two to four times as often in women as in men and increases in incidence with advancing age. It affects synovial-lined joints and can also affect the pulmonary, cardiac, nervous, integumentary, and reticuloendothelial systems. RA is manifested clinically by malaise and fatigue, followed by a symmetric pattern of joint inflammation characterized by pain and stiffness. RA most likely occurs in the setting of a genetically predisposed individual, triggered by infectious agents or endogenous antigens. Many of the newer treatments being studied involve blocking cytokine-mediated interactions between cells of the synovium.

Topics: Aged; Antibodies, Monoclonal; Arthritis, Rheumatoid; Cyclohexanes; Diphtheria Toxin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Herpesvirus 4, Human; Humans; Interferon-gamma; Interleukin 1 Receptor Antagonist Protein; Interleukin-2; Lymphocyte Activation; Male; Methotrexate; Minocycline; Neoplasm Proteins; O-(Chloroacetylcarbamoyl)fumagillol; Parvoviridae; Receptors, Tumor Necrosis Factor, Type II; Recombinant Fusion Proteins; Sesquiterpenes; Sialoglycoproteins; Synovitis; Tumor Necrosis Factor Decoy Receptors

To compare the efficacy of minocycline with that of a conventional disease-modifying antirheumatic drug (DMARD), hydroxychloroquine, in patients with early seropositive rheumatoid arthritis (RA).. Sixty patients with seropositive RA of <1 year's duration who had not been previously treated with DMARDs were randomized to receive minocycline, 100 mg twice per day, or hydroxychloroquine, 200 mg twice per day, in a 2-year, double-blind protocol. All patients also received low-dose prednisone. The primary end points of the study were 1) the percentage of patients with an American College of Rheumatology (ACR) 50% improvement (ACR50) response at 2 years, and 2) the dosage of prednisone at 2 years.. Minocycline-treated patients were more likely to achieve an ACR50 response at 2 years compared with hydroxychloroquine-treated patients (60% compared with 33%, respectively; P = 0.04). Minocycline-treated patients were also receiving less prednisone at 2 years compared with the hydroxychloroquine group (mean 0.81 mg/day compared with 3.21 mg/day, respectively; P < 0.01). In addition, patients treated with minocycline were more likely to have been completely tapered off prednisone (P = 0.03). Trends favoring the minocycline treatment group were seen when outcomes were assessed according to components of the ACR core criteria set, with the differences reaching statistical significance for patient's global assessment of disease activity (P = 0.004).. Minocycline is an effective DMARD in patients with early seropositive RA. Patients treated with minocycline were more likely to achieve an ACR50 response and did so while receiving less prednisone. In addition, minocycline-treated patients were more likely to have discontinued treatment with prednisone at 2 years.

Topics: Adult; Aged; Anti-Bacterial Agents; Antirheumatic Agents; Arthritis, Rheumatoid; Double-Blind Method; Female; Humans; Hydroxychloroquine; Male; Middle Aged; Minocycline; Serologic Tests; Treatment Outcome

Rheumatoid arthritis (RA) causes substantial morbidity and mortality, and current treatments are suboptimal. Recent studies have demonstrated the short-term efficacy of minocycline in the treatment of patients with early RA. This study was undertaken to compare patients treated with conventional therapy in the early phase of their RA and those treated with minocycline, after 4 years of followup.. Forty-six patients with seropositive RA of <1 year's duration had been enrolled in a double-blind study of minocycline (100 mg twice daily) versus placebo. After the blinded portion of the study (3-6 months, depending upon response), all patients were treated with conventional therapy. This report compares those patients randomized to receive placebo for 3 months and then conventional therapy for the duration of 4 years versus those originally randomized to receive minocycline.. Twenty of the 23 original minocycline-treated patients and 18 of the 23 original placebo-treated patients were available for followup (mean 4 years). At followup, RA was in remission (American College of Rheumatology criteria) without disease-modifying antirheumatic drug (DMARD) or steroid therapy in 8 of the patients originally treated with minocycline compared with 1 patient in the placebo group (P = 0.02). Ten patients in the minocycline group versus 16 in the original placebo group currently require DMARD therapy (P = 0.02).. Among patients with seropositive RA, remissions are more frequent and the need for DMARD therapy is less in those treated early in the disease course with minocycline compared with those treated with conventional therapy delayed by an average of only 3 months. Minocycline appears to be an effective therapy for early RA; further investigation into its mechanism of action is needed.

Topics: Anti-Bacterial Agents; Arthritis, Rheumatoid; Double-Blind Method; Female; Follow-Up Studies; Gastrointestinal Hemorrhage; Humans; Male; Minocycline; Placebos; Time Factors

We report a local experience with minocycline (100 mg b.i.d.) in treating Chinese patients with rheumatoid arthritis (RA) who were resistant to the conventional disease-modifying antirheumatic drug (DMARD) treatment. In contrast to a preliminary observation in seven patients with rheumatoid arthritis, minocycline was effective and safe in treating our patients when added to the previous, relatively ineffective DMARD regimen. The antirheumatic effect of minocycline was impressive early in the first month. Drug compliance was fair; all patients continued to receive the study drugs, with no obvious adverse drug reactions. The reason why minocycline showed dramatic effects in reducing disease activity remains to be determined; however, minocycline-associated immune modulation, as indicated in this study, may be one of the important mechanisms in its antiarthritic effects.

Topics: Adult; Aged; Anti-Bacterial Agents; Antirheumatic Agents; Arthritis, Rheumatoid; Asian People; Drug Resistance; Female; Humans; Joints; Male; Middle Aged; Minocycline; Severity of Illness Index; Treatment Outcome

The efficacy and safety of minocycline was investigated in Japanese patients with rheumatoid arthritis (RA) who had already received more than three disease modifying anti-rheumatic drugs (DMARDs). Minocycline was administered at 100 mg twice a day to fifteen patients with active RA. The drug efficacy was evaluated by the clinical variables including the number of painful and/or swollen joints, the duration of morning stiffness, grip strength, the erythrocyte sedimentation rate, serum concentrations of C-reactive protein, and the titer of rheumatoid factor. Three patients experienced adverse effects such as dizziness and abdominal pain or discomfort, but only one patient with abdominal pain and dizziness was discontinued. Fourteen RA patients, who had taken minocycline for at least 6 months, were subjected to the clinical evaluation. Among them, 8 patients (54%) showed a significant improvement of clinical valuables for disease activity, beginning even at 4 weeks of the therapy. The continued effects were observed in 8 patients with over 1 year-minocycline therapy. Intriguingly, an active patient with a history of multiple DMARDs-resistancy showed a marked favorable response to this drug. The present study indicates that minocycline may be an effective DMARD with highly safe performance for patients with active and refractory RA. This is the first demonstration of the benefit of minocycline in the Japanese patients.

Topics: Aged; Anti-Bacterial Agents; Antirheumatic Agents; Arthritis, Rheumatoid; Female; Humans; Male; Middle Aged; Minocycline; Treatment Outcome

To compare 3 sets of criteria for meaningful improvement in a rheumatoid arthritis (RA) clinical trial, and to evaluate the implications of these criteria sets for RA trial design.. Data were obtained from the Minocycline in Rheumatoid Arthritis (MIRA) trial (primary outcome measures: 50% improvement in joint tenderness and 50% improvement in joint swelling, based on joint scores). These MIRA data were evaluated against 1) the Paulus criteria (20% improvement in 4 of 6 measures: joint tenderness scores, joint swelling scores, physician's and patient's global assessments, erythrocyte sedimentation rate [ESR], and morning stiffness); and 2) the American College of Rheumatology (ACR) criteria (20% improvement in joint tenderness and joint swelling counts, and in 3 of 5 other measures: physician's and patient's global assessments, ESR, modified Health Assessment Questionnaire, and patient's pain assessment). The ACR criteria were modified using 3 of 4 remaining measures, since baseline pain assessment data were not available.. Percentages of minocycline-treated patients versus placebo-treated patients showing meaningful improvement were as follows: by MIRA criteria, for joint tenderness, 56% versus 41% (P = 0.021), and for joint swelling, 54% versus 39% (P = 0.023); by Paulus criteria, 41% versus 28% (P = 0.040); and by ACR criteria, 44% versus 26% (P = 0.004). Both the modified ACR criteria and the Paulus criteria demonstrated a reduced placebo response rate. Compared with the MIRA criteria, the ACR criteria increased, and the Paulus criteria decreased, absolute between-group differences in improvement; however, both criteria sets increased relative percentages of patients showing improvement in the minocycline group versus the placebo group. Study design considerations indicated that application of the ACR criteria would reduce the required sample size.. Different placebo response rates and treatment group differences were found using the 3 RA improvement criteria sets. These findings support the use of the ACR criteria for defining improvement in RA clinical trials.

Topics: Adult; Aged; Arthritis, Rheumatoid; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Minocycline; Placebos; Treatment Outcome

To determine if minocycline is an effective therapy for seropositive rheumatoid arthritis (RA) when used within the first year of disease.. The Rheumatoid Arthritis Investigational Network enrolled 46 patients with RA of <1 year duration into a 6-month study of minocycline (100 mg twice daily) versus placebo. All patients were rheumatoid factor positive. The primary end point of the study was successful completion of 6 months of treatment with no drug toxicity while maintaining 50% improvement in composite symptoms of arthritis.. Eighteen of the 46 patients who were enrolled met 50% improvement criteria at 3 months, and maintained at least a 50% improvement for 6 months with no significant drug toxicity. Among them were 15 of the 23 patients (65%) treated with minocycline and 3 of 23 patients (13%) treated with placebo (P < 0.001).. In patients with early seropositive RA, therapy with minocycline is superior to placebo.

Topics: Adult; Aged; Arthritis, Rheumatoid; Double-Blind Method; Female; Humans; Male; Middle Aged; Minocycline; Placebos; Time Factors

To assess radiographically determined disease progression in patients in the Minocycline in Rheumatoid Arthritis (MIRA) Trial.. A double blind, randomized, multicenter, 48 week trial of oral minocycline (200 mg/day) or placebo in 6 clinical centers in the United States. Patients include 219 adults with active RA previously receiving limited treatment with disease modifying drugs. Posteroanterior films of the hands from baseline and final visits, blinded for sequence, were read for erosions and joint space narrowing by trained observers. Outcomes included rate of disease progression (change/month) and percentage of patients with progression from baseline, newly involved joints, and newly erosive disease.. Using intent-to-treat analyses, progression rates for erosions (0.11 +/- 0.42 minocycline, 0.17 +/- 0.41 placebo; p = 0.47) and joint space narrowing (0.16 +/- 0.55 minocycline and 0.23 +/- 0.71 placebo; p = 0.14) were similar. (Power 43% to detect a 50% difference.) Newly erosive joints occurred more frequently in the placebo group (44 vs 32%; p = 0.08), not a statistically significant difference.. Radiographic measurement of disease progression using 4 measures failed to show a significant difference between minocycline and placebo treatment, although for all methods there was a trend toward treatment benefit, consistent with reported clinical results. A one year trial duration, high measurement variability, and slow rate of radiographic progression in this cohort may explain the low power to detect a treatment effect. The measurement that denoted "newly involved" joints was most sensitive in detecting change. In future trials longer term assessment (minimum 2 years) of radiographic changes and further comparison of measures of disease progression are warranted.

Topics: Adult; Aged; Anti-Bacterial Agents; Arthritis, Rheumatoid; Arthroscopy; Female; Humans; Male; Middle Aged; Minocycline; Placebos; Radiography; Treatment Outcome

The objective of this study was to analyze the anti-inflammatory effect of minocycline in rheumatoid arthritis. Serum samples of 65 RA patients who completed a 26-week randomized double-blind trial of minocycline (100 mg twice a day) versus placebo were studied. In this trial some clinical parameters and in particular the acute phase response decreased significantly in the minocycline-treated group. Serum levels of albumin and interleukin-6 (IL-6) were compared with CRP levels in order to study the acute phase response. Furthermore, rheumatoid factor (RF) and total immunoglobulin isotypes as well as serum levels of soluble interleukin-2 receptor (sIL2-2R) were determined in order to study immunological parameters of the disease. Immunoglobulins and cytokines were measured by ELISA. Serum levels of albumin remained stable, whereas serum CRP levels decreased both in the minocycline- and in the placebo-treated group. Serum levels of IL-6 decreased in the minocycline-treated group only and this decrease was positively correlated with the decrease in CRP levels. Minocycline significantly decreased serum IgM-RF, IgA-RF, total IgM and total IgA levels. In addition the ratio of IgM-RF/total IgM decreased in the minocycline-treated group. No such changes were observed in the placebo-treated group. The anti-inflammatory effect of minocycline in RA patients may be due to the reduction in the synthesis of IL-6 and rheumatoid factor.

Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Double-Blind Method; Female; Humans; Immunoglobulin A; Immunoglobulin M; Interleukin-6; Male; Middle Aged; Minocycline; Rheumatoid Factor; Serum Albumin

Topics: Arthritis, Rheumatoid; Double-Blind Method; Humans; Minocycline; Placebos; Treatment Outcome

To assess the relationships between serum concentrations of minocycline and clinical efficacy and toxicity during the treatment of patients with rheumatoid arthritis (RA) with minocycline.. Forty patients with active RA were administered minocycline (maximal oral dose 100 mg twice a day) for 26 weeks. At 3 time points during the treatment, serum samples were collected for measurement of minocycline activity using a microbiological assay. An analysis of variance was performed to estimate an extrapolated concentration at time = 0 (C0) for each patient separately and this value of C0 was regarded to be proportional to the average serum concentration in each patient. The relation between C0 and clinical response and between C0 and the occurrence of adverse effects was evaluated.. Minocycline was detected in 96 serum samples from 37 patients. Eighty-two percent of the variance in serum concentrations was accounted for by a model incorporating patient, dose, and time effects. A weak correlation between C0 and clinical response, as expressed by a Ritchie articular index and number of swollen joints, was demonstrated. No correlation was seen between C0 and toxicity, including gastrointestinal or vestibular adverse effects.. Results suggest a relationship between the serum concentrations of minocycline and the clinical response, including Ritchie articular index and number of swollen joints, in the treatment of patients with RA. No relationship was seen between the serum concentrations of minocycline and its toxicity.

Topics: Adult; Aged; Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Minocycline; Osmolar Concentration; Prospective Studies; Treatment Outcome

To assess the safety and efficacy of minocycline in the treatment of rheumatoid arthritis.. A double-blind, randomized, multicenter, 48-week trial of oral minocycline (200 mg/d) or placebo.. 6 clinical centers in the United States.. 219 adults with active rheumatoid arthritis who had previous limited treatment with disease-modifying drugs.. As the primary outcomes, 60 diarthrodial joints were examined for tenderness, and 58 joints were examined for swelling (hips excluded). Grip strength, evaluator's global assessment, morning stiffness, Modified Health Assessment Questionnaire, patient's global assessment, hematocrit, erythrocyte sedimentation rate, platelet count, and IgM rheumatoid factor levels were also assessed; radiographs of both hands and wrists were taken.. 109 and 110 patients were randomly assigned to receive minocycline and placebo, respectively. At entry, demographic, clinical, and laboratory measurements were similar in both groups. Most patients had mild to moderate disease activity and some evidence of destructive disease. At the week 48 visit, 79% of the minocycline group and 78% of the placebo group continued to receive the study medication. At 48 weeks, more patients in the minocycline group than in the placebo group showed improvement in joint swelling (54% and 39%) and joint tenderness (56% and 41%) (P < 0.023 for both comparisons). The minocycline group also showed greater improvement in hematocrit, erythrocyte sedimentation rate, platelet count, and IgM rheumatoid factor levels (all P values < 0.001), and more patients receiving minocycline had laboratory values within normal ranges at 48 weeks. For the remaining outcomes, P values ranged from 0.04 to 0.76, all greater than the critical value of 0.005 (Bonferroni adjustment for multiple comparisons). The frequency of reported side effects was similar in both groups, and no serious toxicity occurred.. Minocycline was safe and effective for patients with mild to moderate rheumatoid arthritis. Its mechanisms of action remain to be determined.

Topics: Administration, Oral; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Minocycline; Patient Compliance; Patient Dropouts; Prednisone; Treatment Outcome

Topics: Arthritis, Rheumatoid; Double-Blind Method; Humans; Minocycline; Placebos

To determine the efficacy of minocycline in the treatment of rheumatoid arthritis (RA).. Minocycline (maximal oral daily dose 200 mg) or placebo was administered in a 26-week, randomized, double-blind study to 80 patients with active RA, who were treated or had previously been treated with at least one disease-modifying antirheumatic drug.. There were 15 premature discontinuations: 6 (5 taking minocycline) because of adverse effects, 8 (all taking placebo) because of lack of efficacy, and 1 (taking placebo) because of intercurrent illness. There was a statistically significant improvement in the minocycline group over the placebo group. There was a pronounced improvement in laboratory parameters of disease activity; however, improvement in clinical parameters was less impressive. The observed adverse effects attributable to minocycline were mainly gastrointestinal symptoms and dizziness.. The results of the present study suggest that minocycline is beneficial and relatively safe in RA patients.

Topics: Adult; Aged; Analysis of Variance; Arthritis, Rheumatoid; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Minocycline; Prospective Studies; Treatment Outcome

In a 48-week open trial, 18 patients with active rheumatoid arthritis (RA), resistant to second line agents, received 200 mg minocycline daily. Twelve patients completed 48 weeks of therapy. Statistically significant improvement was noted in almost all variables of disease activity. Three patients discontinued therapy because of lack of improvement, 2 patients because of side effects and one patient was lost to followup. Cytofluorographic analysis revealed a significant decrease in expression of a T cell activation antigen (gp 26). Our data suggest that minocycline could be a useful therapeutic agent in RA.

Topics: Adult; Aged; Antigens, Differentiation, T-Lymphocyte; Arthritis, Rheumatoid; Female; Gene Expression; Humans; Male; Middle Aged; Minocycline; Tetracycline Resistance; Time Factors; Tumor Necrosis Factor Receptor Superfamily, Member 7

The coronavirus disease (COVID-19) is a pandemic disease that threatens worldwide public health, and rheumatoid arthritis (RA) is the most common autoimmune disease. COVID-19 and RA are each strong risk factors for the other, but their molecular mechanisms are unclear. This study aims to investigate the biomarkers between COVID-19 and RA from the mechanism of pyroptosis and find effective disease-targeting drugs.. We obtained the common gene shared by COVID-19, RA (GSE55235), and pyroptosis using bioinformatics analysis and then did the principal component analysis(PCA). The Co-genes were evaluated by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and ClueGO for functional enrichment, the protein-protein interaction (PPI) network was built by STRING, and the k-means machine learning algorithm was employed for cluster analysis. Modular analysis utilizing Cytoscape to identify hub genes, functional enrichment analysis with Metascape and GeneMANIA, and NetworkAnalyst for gene-drug prediction. Network pharmacology analysis was performed to identify target drug-related genes intersecting with COVID-19, RA, and pyroptosis to acquire Co-hub genes and construct transcription factor (TF)-hub genes and miRNA-hub genes networks by NetworkAnalyst. The Co-hub genes were validated using GSE55457 and GSE93272 to acquire the Key gene, and their efficacy was assessed using receiver operating curves (ROC); SPEED2 was then used to determine the upstream pathway. Immune cell infiltration was analyzed using CIBERSORT and validated by the HPA database. Molecular docking, molecular dynamics simulation, and molecular mechanics-generalized born surface area (MM-GBSA) were used to explore and validate drug-gene relationships through computer-aided drug design.. COVID-19, RA, and pyroptosis-related genes were enriched in pyroptosis and pro-inflammatory pathways(the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome complex, death-inducing signaling complex, regulation of interleukin production), natural immune pathways (Network map of SARS-CoV-2 signaling pathway, activation of NLRP3 inflammasome by SARS-CoV-2) and COVID-19-and RA-related cytokine storm pathways (IL, nuclear factor-kappa B (NF-κB), TNF signaling pathway and regulation of cytokine-mediated signaling). Of these, CASP1 is the most involved pathway and is closely related to minocycline. YY1, hsa-mir-429, and hsa-mir-34a-5p play an important role in the expression of CASP1. Monocytes are high-caspase-1-expressing sentinel cells. Minocycline can generate a highly stable state for biochemical activity by docking closely with the active region of caspase-1.. Caspase-1 is a common biomarker for COVID-19, RA, and pyroptosis, and it may be an important mediator of the excessive inflammatory response induced by SARS-CoV-2 in RA patients through pyroptosis. Minocycline may counteract cytokine storm inflammation in patients with COVID-19 combined with RA by inhibiting caspase-1 expression.

Topics: Arthritis, Rheumatoid; Caspase 1; COVID-19; Cytokine Release Syndrome; Cytokines; Humans; Inflammasomes; Minocycline; Molecular Docking Simulation; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; SARS-CoV-2

Rheumatoid arthritis is an autoimmune disease that leads to cartilage destruction, synovial joint inflammation, and bacterial joint/bone infections. In the present work, methotrexate and minocycline-loaded nanoparticles (MMNPs) were developed with an aim to provide relief from inflammation and disease progression/joints stiffness and to control the bacterial infections associated with rheumatoid arthritis. MMNPs were developed and optimized by solvent evaporation along with high-pressure homogenization technique using poly(lactic-co-glycolic acid) (50:50%) copolymer. FTIR spectrometric results showed the compatibility nature of methotrexate, minocycline, and poly(lactic-co-glycolic acid). The MMNPs showed particle size ranging from 125.03 ± 9.82 to 251.5 ± 6.23 nm with charge of around - 6.90 ± 0.8 to - 34.8 ± 4.3 mV. The in vitro release studies showed a sustained release pattern with 75.11% of methotrexate (MTX) release and 49.11% of minocycline hydrochloride (MNC) release at 10 h. The developed MMNPs were found to be stable at refrigerated condition and non-hemolytic nature (< 22.0%). MMNPs showed superior cytotoxicity for studied concentrations (0.1 to 1000 μM) compared with free MTX at both 24 and 48 h treatment period in a dose/time-dependent manner in inflammatory RAW 264.7 cells. Anti-bacterial studies indicate that the efficacy of the developed MMNPs to control infections was compared with pure MNC. In vivo anti-arthritis showed effective arthritis reduction potential of the developed MMNPs upon intravenous administration. This proof of concept implies that MTX with MNC combined nanoparticles may be effective to treat RA associated with severe infections. Graphical abstract.

Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Methotrexate; Minocycline; Nanoparticles

Topics: Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Hyperpigmentation; Male; Minocycline

Topics: Arthritis, Infectious; Arthritis, Rheumatoid; Denosumab; Drug Therapy, Combination; Female; Humans; Hyperpigmentation; Kidney Failure, Chronic; Melanosis; Middle Aged; Minocycline; Prednisone

To compare the risk of incident hypertension between initiators of tumor necrosis factor (TNF)-α inhibitors and initiators of nonbiologic disease modifying antirheumatic drugs (hereafter referred to as nonbiologics) in rheumatoid arthritis patients taking methotrexate monotherapy.. We conducted a cohort study using insurance claims data (2001-2012) from the US. We identified initiators of use of either TNF-α inhibitors or nonbiologics. Subsequent exposure to these agents was measured monthly in a time-varying manner. The outcome of interest was incident hypertension, defined by a diagnosis and a prescription for an antihypertensive drug. Marginal structural models estimated hazard ratios (HRs) adjusted for both baseline and time-varying confounders. To validate the primary analysis, we designed a verification analysis to evaluate a known association between leflunomide (a nonbiologic disease modifying agent) and hypertension.. We identified 4,822 initiations of TNF-α inhibitor use and 2,400 of nonbiologic use. Crude incidence rates of hypertension per 1,000 person-years of follow-up were 36 (95% CI [confidence interval]: 32, 41) for the TNF-α inhibitor group and 42 (95% CI: 34, 51) for the nonbiologics group. The crude HR of TNF-α inhibitors versus nonbiologics for the risk of incident hypertension was 0.85 (95% CI: 0.67, 1.1). After adjusting for both baseline and time-varying covariates using marginal structural models, the HR was 0.95 (95% CI: 0.74, 1.2). In the verification analysis, the adjusted HR of incident hypertension was 2.3 (95% CI: 1.7, 3.0) in leflunomide initiators compared with methotrexate initiators.. Treatment with TNF-α inhibitors was not associated with a reduced risk of incident hypertension compared with nonbiologics in rheumatoid arthritis patients.See Video Abstract at http://links.lww.com/EDE/B36.

Topics: Adalimumab; Adult; Antibodies, Monoclonal; Antirheumatic Agents; Arthritis, Rheumatoid; Azathioprine; Certolizumab Pegol; Cohort Studies; Cyclophosphamide; Etanercept; Female; Humans; Hydroxychloroquine; Hypertension; Incidence; Infliximab; Male; Methotrexate; Middle Aged; Minocycline; Penicillamine; Proportional Hazards Models; Retrospective Studies; Risk Factors; Sulfasalazine; Tumor Necrosis Factor-alpha

Topics: Antibodies, Monoclonal; Arthritis, Rheumatoid; Azathioprine; Biological Products; Clarithromycin; Drug Substitution; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Infliximab; Middle Aged; Minocycline; Mycobacterium chelonae; Mycobacterium Infections, Nontuberculous; Prednisone; Skin Diseases, Bacterial; Tigecycline; Tumor Necrosis Factor-alpha

Topics: Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Eruptions; Female; Humans; Hyperpigmentation; Leg Dermatoses; Minocycline

Topics: Aged; Anti-Bacterial Agents; Arthritis, Rheumatoid; Humans; Hyperpigmentation; Male; Minocycline; Risk Factors; Skin

The autophagic vacuolar myopathies (AVM) are a group of inherited myopathies defined by the presence of autophagic vacuoles in pathological muscle specimens. AVM can be categorized into three groups: acid maltase deficiency, myopathies characterized by autophagic vacuoles with unique sarcolemmal features, and rimmed vacuolar myopathies (RVM). While the pathogeneses of these conditions are still being elucidated, some drugs (e.g., chloroquine, its analog, hydroxychloroquine, and colchicine) can also cause AVM. Minocycline is a disease-modifying anti-rheumatic drug that may be used in the treatment of rheumatoid arthritis (RA). Here, we describe the first case of minocycline-associated AVM with rimmed vacuole formation.. A 75-year-old woman suffering from RA has been continuously treated with minocycline (200 mg/day) for the past 7 years. During this time, she developed a myopathy that predominantly affected her lower limbs. Histological studies of biopsied muscle revealed scattered atrophic myofibers with rimmed vacuoles that contained pigment granules. Histochemical staining revealed that the pigment comprised both iron and melanin, which is consistent with type II minocycline-induced cutaneous pigmentation. Under electron microscopy, autophagic vacuoles were consistently observed in association with numerous collections of pigment granules.. This is the first report of minocycline-induced pigmentation in skeletal muscle. The strong association between autophagic vacuoles and the accumulation of minocycline-induced pigments suggest that long-term minocycline treatment induced pigment accumulation, leading to elevation of autophagic activity and RVM. It might also be possible that minocycline directly activated autophagy, as the observed pigments are known to form complexes containing minocycline and/or its metabolites. As long-term minocycline treatment is expected to be used more widely in the future, we must draw attention to this adverse effect.

Topics: Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Female; Humans; Lysosomal Storage Diseases; Minocycline; Muscular Diseases

Minocycline is a tetracycline family antibiotic that has anti-inflammatory and immunomodulatory properties. These properties have shown promise in the treatment of conditions such as rheumatoid arthritis, Huntington disease, and multiple sclerosis. As lymphocyte activation is involved in the pathogenesis of many of these diseases, T cells are postulated to be a primary target in minocycline therapy. Previous studies have demonstrated attenuation of CD4(+) T cell activation by minocycline, but a specific mechanism has not been elucidated. In this study, we investigated the effect of minocycline on the activity of three key transcription factors regulating CD4(+) T cell activation: NF-κB, AP-1 (activator protein 1), and NFAT (nuclear factor of activated T) cells. Our data demonstrate that minocycline selectively impairs NFAT-mediated transcriptional activation, a result of increased phosphorylation and reduced nuclear translocation of the isoform NFAT1. Minocycline increased the activity of the NFAT kinase GSK3 and decreased intracellular Ca(2+) flux, both of which facilitate NFAT1 phosphorylation. These findings provide a novel mechanism for minocycline induced suppression of CD4(+) T cell activation and may better inform the application of minocycline as an immunomodulatory agent.

Topics: Active Transport, Cell Nucleus; Anti-Bacterial Agents; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Calcium Signaling; CD4-Positive T-Lymphocytes; Cell Nucleus; Cells, Cultured; Enzyme Activation; Enzyme Activators; Glycogen Synthase Kinase 3; Humans; Huntington Disease; Lymphocyte Activation; Minocycline; Multiple Sclerosis; NF-kappa B; NFATC Transcription Factors; Phosphorylation; Protein Isoforms; Transcription Factor AP-1

Topics: Adult; Animals; Anti-Bacterial Agents; Antibodies, Monoclonal; Arthritis, Psoriatic; Arthritis, Rheumatoid; Bacterial Typing Techniques; Clarithromycin; Ethambutol; Female; Fingers; Fishes; Hand Dermatoses; Humans; Immunocompromised Host; Immunosuppressive Agents; Infliximab; Methotrexate; Middle Aged; Minocycline; Mycobacterium Infections, Nontuberculous; Mycobacterium marinum; Rifabutin; Skin Diseases, Bacterial; Tumor Necrosis Factor-alpha

Minocycline and doxycycline are safe and moderately effective disease-modifying anti-rheumatic drugs (DMARDs) in the treatment of early, DMARD-naïve rheumatoid arthritis (RA), although little is known about their use outside clinical trials. We characterize the use of minocycline and doxycycline in community-dwelling RA patients by examining associated prescribing patterns, patient-level determinants of use, and side-effect profiles.. We studied 15,716 patients with RA observed between 1998 and 2009 while participating in a long-term US observational study.. Minocycline or doxycycline was prescribed by 18% of rheumatologists (interquartile range one to two patients per physician) to 9% of RA patients. Significant differences between minocycline-treated and doxycycline-treated patients and nontreated patients included age (58.4 years vs. 59.8 years), RA duration (14.8 years vs. 13.7 years), Caucasian race (93.7% vs. 89.7%), lifetime DMARDs and biologics (3.3 vs. 2.5), prednisone use (40.1% vs. 35.3%), and Medical Outcomes Study 36-Item Short Form Survey physical component summary score (35.0 vs. 36.4). In multivariable Cox regression, patients initiating minocycline or doxycycline had increased disease activity, more comorbidities, and a greater number of prior nonbiologic DMARDs. Side effects were reported by 17.8% of minocycline users and 11.8% of doxycycline users. Skin complaints accounted for 54% of minocycline patient-reported side effects. The most commonly effected organ systems for doxycycline were gastrointestinal (35.4%) and skin (33.7%). Approximately 75% of side effects were of mild or moderate severity.. Rheumatologists have not embraced minocycline or doxycycline as primary treatment options for RA and reserve their use primarily in patients with long-standing, refractory disease. These drugs are generally well tolerated, with skin complaints, nausea, and dizziness being the most common patient-reported side effects.

Topics: Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Community Health Services; Doxycycline; Female; Humans; Male; Medication Adherence; Middle Aged; Minocycline; Patient Satisfaction; Practice Patterns, Physicians'; Treatment Outcome

Vitamin D research is discussed in light of the hypothesis that the lower average levels of vitamin D frequently observed in autoimmune disease are not a sign of deficiency. Instead, it is proposed that the lower levels result from chronic infection with intracellular bacteria that dysregulate vitamin D metabolism by causing vitamin D receptor (VDR) dysfunction within phagocytes. The VDR dysfunction causes a decline in innate immune function that causes susceptibility to additional infections that contribute to disease progression. Evidence has been accumulating that indicates that a number of autoimmune diseases can be reversed by gradually restoring VDR function with the VDR agonist olmesartan and subinhibitory dosages of certain bacteriostatic antibiotics. Diseases showing favorable responses to treatment so far include systemic lupus erythematosis, rheumatoid arthritis, scleroderma, sarcoidosis, Sjogren's syndrome, autoimmune thyroid disease, psoriasis, ankylosing spondylitis, Reiter's syndrome, type I and II diabetes mellitus, and uveitis. Disease reversal using this approach requires limitation of vitamin D in order to avoid contributing to dysfunction of nuclear receptors and subsequent negative consequences for immune and endocrine function. Immunopathological reactions accompanying bacterial cell death require a gradual elimination of pathogens over several years. Practical and theoretical implications are discussed, along with the compatibility of this model with current research.

Topics: Animals; Anti-Bacterial Agents; Arthritis, Reactive; Arthritis, Rheumatoid; Autoimmune Diseases; Bacterial Infections; Calcifediol; Calcitriol; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Imidazoles; Minocycline; Psoriasis; Receptors, Calcitriol; Sarcoidosis; Scleroderma, Systemic; Sjogren's Syndrome; Spondylitis, Ankylosing; Tetrazoles; Thyroid Diseases; Uveitis

Protein Arginine Deiminase 4 (PAD4) has emerged as a leading target for the development of a Rheumatoid Arthritis (RA) pharmaceutical. Herein, we describe the development of a novel screen for PAD4 inhibitors that is based on a PAD4-targeted Activity-Based Protein Profiling reagent, denoted Rhodamine-conjugated F-Amidine (RFA). This screen was validated by screening 10 Disease Modifying Anti-Rheumatic Drugs (DMARDs) and identified streptomycin, minocycline, and chlortetracycline as micromolar inhibitors of PAD4 activity.

Topics: Arthritis, Rheumatoid; Chlortetracycline; Combinatorial Chemistry Techniques; Enzyme Inhibitors; Fluorescent Dyes; Hydrolases; Minocycline; Models, Biological; Molecular Structure; Protein-Arginine Deiminase Type 4; Protein-Arginine Deiminases; Streptomycin; Tetracycline

Mycobacterium mucogenicum is a recently characterized organism that rarely may cause human infections. This rapidly growing mycobacterium is commonly identified in tap water. Both immunosuppressed and immunocompetent patients may develop infections from Mycobacterium mucogenicum. Some patients have experienced lethal disease, including sepsis. Infections occurring in the skin and soft tissues have been described only after a preceding injury. We present the first case of infection with Mycobacterium mucogenicum occurring in a patient on the TNF-alpha antagonist etanercept and without any prior soft tissue injury.

Topics: Anti-Bacterial Agents; Arthritis, Rheumatoid; Clarithromycin; Etanercept; Female; Humans; Immunoglobulin G; Immunosuppressive Agents; Middle Aged; Minocycline; Mycobacterium Infections; Opportunistic Infections; Receptors, Tumor Necrosis Factor; Skin Diseases, Bacterial; Tumor Necrosis Factor-alpha

Minocycline is recognized as an effective, well-tolerated therapy in rheumatoid arthritis (RA), although its use has been associated with the development of cutaneous hyperpigmentation.. To assess the clinical determinants and frequency of minocycline-induced hyperpigmentation in patients with RA.. A retrospective medical record review of all patients with RA seen in 2 academic rheumatology practices was performed to identify subjects who had received at least 1 month of continuous minocycline therapy. Patient demographics, disease characteristics, medication use, and medication side effects were abstracted from the medical record. Using Cox proportional hazards regression and restricting the analysis to the initial minocycline course, we examined the association of patient factors and concomitant medications with the development of hyperpigmentation.. Of 121 patients with at least 1 minocycline course of 30 days or more, 44 (36%) developed documented hyperpigmentation, including 33 during the initial course over a median duration of 9.1 month (range 2.2-77.8 months). Hyperpigmentation was most commonly seen on the upper and lower extremities and the head/neck region. Minocycline-induced hyperpigmentation led to the discontinuation of treatment in 3 patients, with 12 additional patients receiving a dose reduction. Increasing age was the only clinical determinant significantly associated with hyperpigmentation (HR = 1.04; 95% CI 1.00-1.07, P = 0.04). There were no significant associations of sex, weight, concomitant prednisone, or aspirin use with the development of hyperpigmentation.. Minocycline-induced hyperpigmentation is a common complication seen with minocycline use in the treatment of RA, and seems to increase with age.

Topics: Adult; Age Factors; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Female; Hospitals, University; Hospitals, Veterans; Humans; Hyperpigmentation; Male; Middle Aged; Minocycline; Nebraska; Prevalence; Proportional Hazards Models; Retrospective Studies; Risk Factors

Minocycline is particularly useful in patients with rheumatoid arthritis (RA) with previous major sepsis, where anti-tumor necrosis factor is relatively contraindicated. Pigmentation is a documented side effect, but predisposing factors in an RA population have not been established. We investigated minocycline induced pigmentation in a population with RA to determine whether skin type and eye color influence predisposition to this side effect.. Patients with RA attending a rheumatology unit who had received minocycline were contacted by telephone and some were also interviewed in the clinic. Those receiving therapy for more than 3 months were assessed. Hair color, eye color, tendency to burn in the sun, and dose and duration of therapy were documented. The frequency, type, and distribution of pigmentation were established.. Of 37 patients identified, 10 were excluded because the duration of therapy was less than 3 months. Of the remaining 27 patients, 85% were female, with median age 64 years (range 44-88) and median disease duration 23.5 years (range 4-51). Eleven patients (41%) developed pigmentation after a median of 12 months. Four of the 11 stopped their minocycline due to pigmentation. Hair color, eye color, and tendency to burn in the sun did not predict patients who developed pigmentation.. Pigmentation is a common side effect in patients receiving minocycline therapy for more than 3 months. Most patients do not stop therapy due to pigmentation. Those who stop are more likely to be female, less than 70 years of age, and have facial pigmentation.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Arthritis, Rheumatoid; Drug Eruptions; Female; Humans; Male; Middle Aged; Minocycline; Pigmentation Disorders; Skin

Topics: Adult; Aged; Aged, 80 and over; Antirheumatic Agents; Arthritis, Rheumatoid; Female; Hospitals, District; Hospitals, General; Humans; Male; Middle Aged; Minocycline; Retrospective Studies

Alkaptonuria, a rare autosomal-recessive disorder caused by mutations in the HGD gene and a deficiency of homogentisate 1,2-dioxygenase, is characterized by accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue resulting in joint disease. Certain medications have been reported to cause cutaneous hyperpigmentation resembling that of alkaptonuria. We present 5 such cases. Eighty-eight patients with a possible diagnosis of alkaptonuria were examined at the National Institutes of Health Clinical Center between June 2000 and March 2004. The diagnosis of alkaptonuria was confirmed or ruled out by measurement of HGA in the urine. Five patients with findings consistent with ochronosis, including pigmentary changes of the ear and mild degenerative disease of the spine and large joints, were diagnosed clinically as having alkaptonuria, but the diagnosis was withdrawn based on normal urine HGA levels. All 5 patients were women who had taken minocycline for dermatologic or rheumatologic disorders for extended periods. Minocycline-induced hyperpigmentation should be considered in the differential diagnosis of ochronosis. This could be of increased significance now that minocycline and other tetracyclines have been proposed as therapeutic options for rheumatoid arthritis, bringing a new population of patients with ochronosis and arthritis to medical attention with the potential, but incorrect, diagnosis of alkaptonuria.

Topics: Abscess; Acne Vulgaris; Adult; Aged; Alkaptonuria; Arthralgia; Arthritis, Rheumatoid; Diagnosis, Differential; Facial Dermatoses; Female; Humans; Hyperpigmentation; Middle Aged; Minocycline; Radiography

Minocycline is an oral antibiotic widely used for the long-term treatment of acne and rheumatoid arthritis. A few patients develop antineutrophil cytoplasmic antibodies (ANCAs) during minocycline therapy. In this report, the authors describe a case of severe pauci-immune crescentic and necrotizing glomerulonephritis associated with positive cytoplasmic ANCA (C-ANCA) titers and proteinase 3 (PR3) levels after minocycline therapy. Discontinuation of minocycline and initiation of immunosuppressive treatment resulted in improvement of renal function and decline in C-ANCA titers and PR3 levels. A high degree of suspicion, testing for ANCA titers, prompt discontinuation of the drug, and initiation of immunosuppressive treatment are crucial to the diagnosis and treatment of drug-induced ANCA-associated glomerulonephritis.

Topics: Adult; Animals; Antibodies, Antineutrophil Cytoplasmic; Arthralgia; Arthritis, Rheumatoid; Autoimmune Diseases; Bites and Stings; Diagnostic Errors; Female; Glomerulonephritis; Humans; Immunosuppressive Agents; Minocycline; Myeloblastin; Serine Endopeptidases; Ticks

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Arthritis, Rheumatoid; Female; Humans; Leg; Minocycline; Skin Pigmentation

Topics: Anti-Bacterial Agents; Antirheumatic Agents; Arteritis; Arthritis, Rheumatoid; Diagnosis, Differential; Etanercept; Fatal Outcome; Humans; Immunoglobulin G; Male; Middle Aged; Minocycline; Receptors, Tumor Necrosis Factor; Sepsis

Minocycline is one of the major drugs for acne and is effective in rheumatoid arthritis (RA). We describe the first case of drug induced lupus secondary to the use of minocycline in a patient with RA. The dificulties of making this diagnosis as well as the implications for its pathogenesis are discussed.

Topics: Adrenal Cortex Hormones; Aged; Anti-Bacterial Agents; Arthritis, Rheumatoid; Diagnosis, Differential; Diagnostic Errors; Humans; Lupus Erythematosus, Systemic; Male; Minocycline; Treatment Outcome

Topics: Adult; Aged; Anti-Bacterial Agents; Arthritis, Rheumatoid; Female; Humans; Middle Aged; Minocycline; Skin Pigmentation

We discribe a rare case of rheumatoid arthritis (RA) complicated with bronchiolitis obliterans that was successfully treated with minocycline. Sixty four-year old woman with a four-years history of RA was admitted to the hospital because of dyspnea on exertion and polyarthritis. Pulmonary function test revealed marked decrease in V25 (0.10 l/s: 6.9%) and MMFR (12.6%). High resolution CT of the lung showed scattered centri-lobular micronodules in both lung fields, mucoid impaction, and hyperinflation. These findings indicated the presence of bronchiolitis obliterans. After 3 months of the treatment with minocycline, the patient showed a significant improvement of both arthritis and pulmonary function. Chest CT findings also improved after 1 year. The present case suggests that minocycline is effective for the treatment of bronchiolitis obliterans seen in patients with RA.

Topics: Anti-Bacterial Agents; Arthritis, Rheumatoid; Bronchiolitis Obliterans; Female; Humans; Middle Aged; Minocycline

Topics: Anti-Bacterial Agents; Arthritis, Rheumatoid; Humans; Minocycline; Treatment Outcome

To determine the comparability of a text to a mannequin format for the assessment of joint counts (JC) among patients with rheumatoid arthritis (RA) participating in a randomized clinical trial (RCT).. A subgroup of patients participating in the MIRA (Minocycline in RA) RCT completed self-administered JC and joint scores (JS), which were compared to those of a trained assessor.. JC and JS data were consistently higher for the patient than for the assessor. Higher correlations were obtained for JC than for JS.. Our data suggest JC can be used in the context of clinical trials or in the clinical setting, but are not interchangeable with trained assessor JC.

Topics: Anti-Bacterial Agents; Arthritis, Rheumatoid; Female; Humans; Male; Manikins; Middle Aged; Minocycline; Pain; Randomized Controlled Trials as Topic; Self-Examination

Topics: Anti-Bacterial Agents; Arthritis, Rheumatoid; Humans; Minocycline; Scleritis

Topics: Anti-Bacterial Agents; Arthritis, Rheumatoid; Autoimmune Diseases; Humans; Minocycline

To describe a case of tooth discoloration in an adult after minocycline treatment for arthritis.. A 68-year-old white women presented with blue-black staining of her lower anterior teeth after 4 months of minocycline therapy for arthritis. Her other medications are not known to cause discoloration of teeth. While the patient continued taking minocycline, her dentist was not able to remove the discoloration. Within 1 month after discontinuation of the minocycline, the dentist was able to remove the discoloration entirely.. Minocycline, a synthetic derivative of tetracycline, has been shown to cause abnormal pigmentation of the skin, thyroid gland, nails, bone, sclera, and conjunctiva in adults. It also has been shown to cause tooth discoloration in a few patients. This case is unusual in that the tooth discoloration disappeared after discontinuing minocycline therapy.. This complication of minocycline is more commonly thought of in the pediatric population. However, clinicians need to be aware of this adverse drug reaction, as this agent may be used increasingly in the treatment of adults with arthritis.

Topics: Aged; Arthritis, Rheumatoid; Female; Humans; Minocycline; Tooth Discoloration

Minocycline-induced cutaneous pigmentation is an adverse effect that may be more common than is generally realized. It is usually reported in patients undergoing chronic minocycline therapy for acne vulgaris.. The case of a 69-year-old woman taking minocycline for rheumatoid arthritis is presented, and its differential diagnosis discussed in order to characterize the clinical features of minocycline-induced cutaneous pigmentation.. Patients undergoing minocycline therapy for rheumatoid arthritis may develop bluish-grey pigmentation over the legs and forearms. Cutaneous pigmentation is a well recognized adverse effect of minocycline therapy that is usually reported in young patients on chronic therapy for acne vulgaris. However, the antiinflammatory properties of minocycline have also made it useful in the management of various inflammatory conditions such as rheumatoid arthritis.1 We report the case of a 69-year-old woman who developed progressive cutaneous pigmentation, affecting mainly the legs, approximately 3 months after beginning minocycline therapy for rheumatoid arthritis.

Topics: Aged; Anti-Bacterial Agents; Arthritis, Rheumatoid; Diagnosis, Differential; Drug Eruptions; Extremities; Female; Humans; Minocycline; Pigmentation Disorders

Topics: Anti-Bacterial Agents; Arthritis, Rheumatoid; Female; Humans; Middle Aged; Minocycline; Vasculitis, Leukocytoclastic, Cutaneous

Topics: Anti-Bacterial Agents; Arthritis, Rheumatoid; Humans; Metalloendopeptidases; Minocycline

Topics: Anti-Bacterial Agents; Arthritis, Rheumatoid; Humans; Minocycline; Randomized Controlled Trials as Topic; Scleritis; Uveitis

The purpose of the present study was to evaluate the toxicity and tolerability of methotrexate (MTX)/gold (G; group 1) combination therapy as compared to other MTX combinations [MTX with hydroxychloroquine (HCQ; group 2), MTX with sulphasalazine (SASP; group 3) and MTX with minocycline (MNC; group 4)]. The hospital records of 127 consecutive rheumatoid arthritis (RA) patients who were treated with these combinations during a period of 24 months were retrospectively reviewed. The toxicity and tolerability of the MTX/G combination was compared to the other dual MTX combinations and also to MTX alone using data previously reported by us on 126 RA patients treated with single MTX therapy. The mean exposure time to treatment was 16 months in group 1 and 13 months in the other dual MTX combinations. During the period of follow-up, the combination was stopped in 22 out of 42 patients in group 1 (52%) in comparison with 54 patients out of 86 patients (63%) in the other dual regimen groups. The discontinuation rate was highest in group 4 (due to side effects and lack of compliance) and this was statistically significant in comparison with group 1. The proportion of adverse events was lowest in group 1 (14%) and highest in groups 3 and 4 (25%). Side effects were reversible and comparable with those of MTX alone (23%). No fatal or life-threatening side effects were recorded during any of these MTX combination therapies. We concluded that the combinations of MTX with G, HCQ, SASP and MNC in RA were relatively well tolerated. No increase in toxicity compared with MTX alone was observed. The lowest rate of side effects was noted in group 1, while group 4 presented the highest discontinuation rate.

Topics: Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Female; Gold; Humans; Hydroxychloroquine; Male; Middle Aged; Minocycline; Retrospective Studies; Sulfasalazine; Treatment Outcome

To examine the effect of alleles encoding the "shared"/"rheumatoid" epitope on rheumatoid arthritis (RA) disease severity in patients who participated in the minocycline in RA (MIRA) trial.. Of 205 patients with a week-48 visit, blood was available for typing of HLA-DRB1 and HLA-DQB1 in 174 (85%) and successfully completed in 169 (82%). Baseline erosions were used to assess disease severity and new erosions at the last visit served as a proxy for progression.. At baseline, there was no association between the presence of erosive disease or rheumatoid factor status and the dose of rheumatoid epitope (homozygous, heterozygous, none) or the specific alleles identified. At the final visit, a gradient was observed for the 3 allelic subgroups (and their gene doses) in the occurrence of new erosions among the Caucasian placebo-treated, but not the minocycline-treated, patients. A treatment group/HLA-DR4 epitope interaction was demonstrated in multivariate analyses. Approximately two-thirds of African-American patients did not have the rheumatoid epitope.. HLA-DRB1 oligotyping may be useful in predicting the progression of disease in some Caucasian patients. Our study corroborates the infrequency of the epitope among African-American patients with RA.

Topics: Alleles; Anti-Bacterial Agents; Arthritis, Rheumatoid; Black People; Cohort Studies; Epitopes; Haplotypes; HLA-DR Antigens; Humans; Minocycline; Multicenter Studies as Topic; Multivariate Analysis; Rheumatoid Factor; Severity of Illness Index; White People

The direct and indirect inhibitory potential of D-penicillamine toward human neutrophil and synovial fluid gelatinase B, a marker enzyme for disease severity in RA, was investigated. Gelatinase and plasminogen activator activities were assessed by SDS-polyacrylamide gel electrophoresis zymography. D-penicillamine significantly inhibits purified and synovial fluid gelatinase B in vitro at concentrations attainable in vivo and also blocks in vitro plasminogen activation. Protease inhibition may be a mechanism of action for D-penicillamine as DMARD.

Topics: Anti-Bacterial Agents; Antirheumatic Agents; Arthritis, Rheumatoid; Biomarkers; Collagenases; Deferiprone; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Endopeptidases; Humans; Matrix Metalloproteinase 9; Minocycline; Penicillamine; Pyridones; Severity of Illness Index; Synovial Fluid

Tetracyclines have recently been shown to have "chondroprotective" effects in inflammatory arthritides in animal models. Since nitric oxide (NO) is spontaneously released from human cartilage affected by osteoarthritis (OA) or rheumatoid arthritis in quantities sufficient to cause cartilage damage, we evaluated the effect of tetracyclines on the expression and function of human OA-affected nitric oxide synthase (OA-NOS) and rodent inducible NOS (iNOS). Among the tetracycline group of compounds, doxycycline > minocycline blocked and reversed both spontaneous and interleukin 1 beta-induced OA-NOS activity in ex vivo conditions. Similarly, minocycline > or = doxycycline inhibited both lipopolysaccharide- and interferon-gamma-stimulated iNOS in RAW 264.7 cells in vitro, as assessed by nitrite accumulation. Although both these enzyme isoforms could be inhibited by doxycycline and minocycline, their susceptibility to each of these drugs was distinct. Unlike acetylating agents or competitive inhibitors of L-arginine that directly inhibit the specific activity of NOS, doxycycline or minocycline has no significant effect on the specific activity of iNOS in cell-free extracts. The mechanism of action of these drugs on murine iNOS expression was found to be, at least in part, at the level of RNA expression and translation of the enzyme, which would account for the decreased iNOS protein and activity of the enzyme. Tetracyclines had no significant effect on the levels of mRNA for beta-actin and glyceraldehyde-3-phosphate dehydrogenase nor on levels of protein of beta-actin and cyclooxygenase 2 expression. These studies indicate that a novel mechanism of action of tetracyclines is to inhibit the expression of NOS. Since the overproduction of NO has been implicated in the pathogenesis of arthritis, as well as other inflammatory diseases, these observations suggest that tetracyclines should be evaluated as potential therapeutic modulators of NO for various pathological conditions.

Topics: Animals; Arthritis, Rheumatoid; Cartilage; Cell Line; DNA Primers; Doxycycline; Enzyme Induction; Humans; Interferon-gamma; Kinetics; Lipopolysaccharides; Macrophages; Mice; Minocycline; Nitric Oxide Synthase; Organ Culture Techniques; Osteoarthritis; Polymerase Chain Reaction; Tetracyclines

Topics: Anti-Bacterial Agents; Arthritis, Rheumatoid; Clinical Trials as Topic; Humans; Minocycline; Treatment Outcome

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Humans; Minocycline

Topics: Arthritis, Rheumatoid; Humans; Minocycline

Topics: Arthritis, Rheumatoid; Humans; Minocycline

Topics: Arthritis, Rheumatoid; Humans; Minocycline

Topics: Arthritis, Rheumatoid; Humans; Minocycline

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Bacterial Infections; Double-Blind Method; Drug Combinations; Humans; Methotrexate; Minocycline; Organogold Compounds; Placebos; Randomized Controlled Trials as Topic

Minocycline may prove to be a valuable agent in adjunctive treatment of RA. The use of minocycline is attractive because of its relatively benign adverse effect profile in common dosages, although vestibular toxicity has occurred frequently when doses of 400 mg/d have been used. Adverse effects that do occur usually subside after discontinuation of the drug. Currently, the studies available offer no definitive conclusion concerning the use of tetracyclines for this purpose. These trials do show promise, however, and suggest that larger, controlled, double-blind studies with prolonged use of minocycline in patients are needed for confirmation of its efficacy in RA.

Topics: Administration, Oral; Arthritis, Rheumatoid; Clinical Trials as Topic; Humans; Minocycline

Topics: Arthritis, Rheumatoid; Humans; Minocycline

Topics: Anti-Bacterial Agents; Arthritis, Rheumatoid; Humans; Infections; Minocycline

Ten patients with active definite or classical rheumatoid arthritis (RA) were treated with oral minocycline (maximal daily dose 400 mg) during 16 weeks in an open study. Seven patients reported side effects (in most cases vestibular) leading to premature discontinuation in one. Half of the efficacy variables improved significantly after 4 weeks of therapy. At the end of the study all variables were significantly changed compared with their pretreatment values. We conclude that minocycline may be beneficial in RA. This effect needs to be confirmed in controlled studies.

Topics: Administration, Oral; Adult; Aged; Arthritis, Rheumatoid; Drug Evaluation; Female; Humans; Male; Middle Aged; Minocycline; Tetracyclines

To determine if tetracyclines can inhibit human synovial collagenase from rheumatoid tissue, paired synovial tissue (or synovial fluid) was collected from 7 patients before and after oral administration of minocycline (100 mg BID) for 10 days. With each patient serving as his own control, the postminocycline collagenase activities fell an average of 67% from pretreatment values. Qualitative SDS-PAGE revealed decreased loss of alpha collagen components and reduced formation of alpha A digestion fragments. Addition of minocycline or a chemically modified tetracycline to synovial culture media in vitro profoundly inhibited collagenase activity. Further study of this action of tetracyclines could serve as a probe of the role of collagenase in rheumatoid arthritis and lead to development of agents capable of modifying the tissue destructive actions of collagenase.

Topics: Arthritis, Rheumatoid; Edetic Acid; Humans; In Vitro Techniques; Microbial Collagenase; Minocycline; Synovial Fluid; Synovial Membrane; Tetracyclines

Tetracyclines (including the semi-synthetic analogues, minocycline and doxycycline) are considered useful adjuncts in periodontal therapy because they suppress Gram-negative periodontopathogens. Recently, these antibiotics were found to inhibit mammalian collagenase activity, a property which may also be of therapeutic value. It has been suggested that the anti-collagenase properties of the tetracyclines are independent of their antibiotic efficacy. To advance this hypothesis further, we chemically converted tetracycline hydrochloride to its non-antimicrobial analogue, de-dimethylaminotetracycline. This chemically-modified tetracycline (CMT), although no longer an effective antibiotic, was found to inhibit the in vitro activity of collagenase from partially purified extracts of human rheumatoid synovial tissue and rachitic rat epiphysis. In a preliminary in vivo study, pathologically-excessive collagenase in skin and gingiva was induced by rendering adult male rats diabetic, and the oral administration of CMT to these rats significantly reduced the excessive collagenase activity in both tissues. Moreover, CMT administration did not affect the severe hyperglycemia in these rats but did prevent, at least in part, the diabetes-induced loss of body weight, skin weight, and skin collagen mass; these effects suggest a lack of toxicity in this animal model. A proposed clinical advantage of CMT over conventional tetracyclines, in the treatment of diseases characterized by excessive collagenolytic activity, is the lack of development of antibiotic-resistant micro-organisms during prolonged use. However, the consideration of clinical trials to support this hypothesis must await further laboratory and extensive toxicity tests.

Topics: Animals; Arthritis, Rheumatoid; Cartilage, Articular; Diabetes Mellitus, Experimental; Humans; Male; Metronidazole; Microbial Collagenase; Minocycline; Rats; Rats, Inbred Strains; Rickets; Skin; Streptozocin; Tetracycline; Tetracyclines