Open-Label Study of Clarithromycin in Patients with Undifferentiated Connective Tissue Disease

doi:10.1016/j.semarthrit.2006.04.005

Seminars in Arthritis and Rheumatism

Volume 36, Issue 2, October 2006, Pages 82-87

https://doi.org/10.1016/j.semarthrit.2006.04.005 Get rights and content

Objective

The macrolide family of antibiotics (erythromycin, clarithromycin, and others), have both antimicrobial and immunomodulatory effects. This study explored the effect of clarithromycin on the clinical course of patients with undifferentiated connective tissue disease (UCTD) in a 12-week open-label study.

Methods

The diagnosis of UCTD was based on symptoms/signs of connective tissue disease, and the presence of 1 or more positive autoimmune disease tests, but with insufficient criteria to make a definitive diagnosis. Screening and monthly follow-up visits over 12 weeks included the following: history and physical examination; concurrent medications; the 68/66 tender/swollen joint count; visual analog scores 0 to 100 mm for patient and physician global assessment of disease activity, and patient pain; antinuclear antibody panel, rheumatoid factor, erythrocyte sedimentation rate, C-reactive protein, and blood chemistry.

Results

Seven patients with rheumatic disease were treated with clarithromycin; 6 of 7 had symptomatic relief. Two subjects treated empirically before the decision to perform an open-label study responded favorably. Four of 5 patients who completed the prospective open-label study had mean maximal improvements from baseline of 78, 75, and 79% in patient pain, patient global, and investigator global assessments, respectively. Pain relief occurred as early as 1 week. Drug withdrawal with rechallenge in 2 patients resulted in flare followed by recapture of symptomatic relief.

Conclusions

Clarithromycin, a macrolide antibiotic, led to clinical improvement in patients with UCTD. Efficacy and safety data support further investigation of macrolide antibiotic use as a primary or adjunctive treatment in various connective tissue diseases.

Section snippets

Methods

The open-label treatment protocol was approved by the University Hospitals of Cleveland IRB. A diagnosis of UCTD was based on symptoms/signs of connective tissue disease, and the presence of 1 or more positive autoimmune disease tests, but with insufficient clinical and laboratory criteria to make a definitive diagnosis (4, 5). Screening and follow-up visits included history and physical examination including tender (up to 68) and swollen (up to 66) joint counts. Efficacy assessments were made

Case reports

Two patients were serendipitously noted to have improvement in their connective tissue disease symptoms in response to clarithromycin being administered for an unrelated infection, as follows.

A 70-year-old white woman had complaints of diffuse polyarthralgia and dry eyes. In the past year she had laryngitis, bronchitis, blepharitis, and a seventh nerve (Bell’s) palsy. Physical examination revealed no joint swelling, tenderness, or limitation. At symptom onset she had a positive ANA 1:320

Patient 1

At presentation, this 59-year-old white man had a history of recurrent low-grade fevers, generalized muscle and joint pain, fatigue, and intermittent swelling of the hands, knees, ankles, and wrists. Laboratory studies consisted of the following: ANA titer 1:40; slightly elevated complement levels CH50, 304 units (normal 97 to 297); C4, 47 ng/dL (normal 15 to 45 ng/dL); and a slightly elevated angiotensin-converting enzyme level of 112 U/L (normal 14 to 110 U/L) A gallium scan performed in May

Discussion

The macrolide family of antibiotics have a broad spectrum of antibacterial activity as well as a number of nonantimicrobial effects (1, 2). The potential immunoregulatory effects of the macrolide derivatives were observed in patients with asthma (7) and panbronchiolitis (1). Macrolide antibiotics modify the function of inflammatory cells including neutrophils, macrophages, and lymphocytes (7, 8, 9, 10, 11). Inhibitory effects of macrolides on release of pro-inflammatory cytokines, antioxidant

Acknowledgment

The dedicated efforts of Michele Sawicki, Arthritis Translational Research Program Assistant, in manuscript preparation and processing are deeply appreciated.

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Cited by (9)

Usefulness of macrolides as anti-inflammatories in respiratory diseases
2010, Archivos de Bronconeumologia
Los macrólidos son antibióticos que además de su acción antibacteriana pueden presentar un cierto efecto antiinflamatorio por disminución de la actividad de las células inmunitarias y alteración de las células bacterianas.
Ya en los años 80 se observó un aumento de la supervivencia en pacientes afectados de panbronquiolitis difusa después de tratarse con eritromicina. En la actualidad, el uso de macrólidos en diferentes enfermedades de carácter inflamatorio crónico ha aumentado significativamente. En la fibrosis quística, el asma, las bronquiectasias, entre otras, se han observado mejoras clínicas asociadas a la administración de macrólidos.
Sin embargo, y a pesar del aparente beneficio clínico que parecen aportar, los resultados publicados hasta la fecha son controvertidos y no permiten obtener resultados concluyentes. Esto hace necesario realizar futuros ensayos clínicos para confirmar o rebatir el uso a largo plazo de estos fármacos, que no están exentos de efectos adversos, principalmente la aparición de especies bacterianas resistentes.
The macrolides are antibiotics that, besides their anti-bacterial action, have an anti-inflammatory effect, by decreasing the activity of the immune cells and bacteria cell changes.
An increase the survival of patients suffering from diffuse panbronchiolitis was already seen in the 1980s, after being treated with erythromycin. Currently, the use of macrolides in various chronic inflammatory diseases has increased significantly. Clinical improvements associated to the administration of macrolides have been observed in diseases such as, cystic fibrosis, asthma, and bronchiectasis.
However, despite the apparent clinical benefit they seem to provide, the published results up until now are controversial and conclusive results are unable to be obtained. This means that further clinical trials are necessary to confirm or refute the long-term use of these drugs, which are not free of adverse effects, mainly the appearance of resistant bacteria.
Macrolide antibiotics as immunomodulatory medications: Proposed mechanisms of action
2008, Pharmacology and Therapeutics
Macrolide antibiotics administered in sub-antimicrobial doses improve pulmonary function and decrease exacerbation frequency for persons with diffuse panbronchiolitis or cystic fibrosis. Data also suggest a beneficial effect of macrolide antibiotics in the treatment of steroid dependent asthma. Many potential immunomodulatory effects of macrolide antibiotics have been reported including the ability to down-regulate prolonged inflammation, decreasing airway mucus secretion, inhibiting bacterial biofilm, decreasing the production of reactive oxygen species, inhibiting neutrophil activation and mobilization, accelerating neutrophil apoptosis, and blocking the activation of nuclear transcription factors. Macrolides initially decrease, then increase, and have finally a sustained suppression of cytokine secretions from normal human bronchial epithelial cells through inhibition and activation of extracellular signal-regulated kinases (ERK) and then reversibly retard cell proliferation probably through ERK. Consistent with this, macrolide antibiotics possibly reduce mucin production as well as neutrophil migration by interfering with ERK signal transduction.
Mixed Connective Tissue Disease, Overlap Connective Tissue Disease and Undifferentiated Connective Tissue Disease
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Antibiotic therapy in autoimmune disorders
2014, Clinical Practice
Clarithromycin in rheumatoid arthritis: The addition to methotrexate and low-dose methylprednisolone induces a significant additive value - A 24-month single-blind pilot study
2013, Rheumatology International
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: Sources of Support: University Hospitals of Cleveland Research Institute.

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Open-Label Study of Clarithromycin in Patients with Undifferentiated Connective Tissue Disease

Objective

Methods

Results

Conclusions

Section snippets

Methods

Case reports

Patient 1

Discussion

Acknowledgment

Am J Med

Ann Allergy Asthma Immunol

Respir Med

Am J Med

Am J Med

Am J Med

Am J Med

Long-term low-dose administration of erythromycin to patients with diffuse panbronchiolitis

Respiration

Clarithromycin in rheumatoid arthritis patients not responsive to disease-modifying anti-rheumatic drugs: an open, uncontrolled pilot study

Clin Exp Rheumatol

Incomplete lupus erythematosus

Arch Intern Med