Tetracycline and its later derivatives have disease-modifying anti-rheumatic drug (DMARD) effects in addition to their bacteriostatic antimicrobial actions, including effects on matrix metalloproteinases (MMPs), nitric oxide, phospholipase A2, inflammatory cytokines, immune-modulatory and anti-oxidant effect, as well as effects on angiogenesis, apoptosis, MAP kinases, TGF beta and poly (ADP-ribose) polymerase-1. The use of tetracyclines and their effectiveness to help manage the complications of scleroderma, such as skin sclerosis, calcinosis cutis, and pulmonary fibrosis are outlined in the following studies.
Minocycline for Refractory Calcinosis in Systemic Sclerosis: A Single-Centre Observational Cohort Study
This study abstract was presented at the annual (2019) American College of Rheumatology, which had been conducted by various authors at the UCL Medical School, Royal Free Campus, London, United Kingdom, and the UCL Division of Medicine, Centre for Rheumatology and Connective Tissue Diseases, London, UK, London, United Kingdom. In the largest case series of its kind to date, 78 systemic sclerosis (SSc) patients with refractory calcinosis were treated with minocycline to assess possible benefit and any adverse events. Daily doses ranged from 50-200mg over the course of 6-12 weeks in repeated rounds. During the treatment timeframe, the patient cohort tolerated minocycline well and 50% of patients responded positively. The authors speculated that favorable response may be due to autoantibody subtype and that their findings support further study.
Vasodilation is not the only approach to the management of cutaneous ulceration in systemic sclerosis Rheumatology (Oxford). 2017 Sep 1;56(9):1559. doi: 10.1093/rheumatology/kex175.
(Please note that some of the images included in this paper depicting calcified digital ulcerations in an advanced case of diffuse scleroderma may be disturbing to some readers).
In a paper, published in the British Society of Rheumatology Oxford Academic Journal in September, 2017, by the Royal National Hospital for Rheumatic Diseases, Royal United Hospitals NHS Foundation Trust Department of Pharmacy and Pharmacology, University of Bath, UK, the author, John D. Pauling discusses the value of using minocycline as a treatment for digital ulceration (DU) due to calcinosis-related systemic sclerosis (SSc). In this article, Pauling describes the case of a 49-year old woman with a 9-year history of diffuse cutaneous SSc, who in spite of treatment with commonly-used medications in attempts to control DU, she continued to suffer with new lesions occurring. In contrast, within 4 months of minocycline use, she experienced rapid improvement of all existing DU and no new lesions occurred. As a result of these noteworthy results, Pauling expresses the need to assess the etiological drivers of SSc-DU when considering treatment options and that minocycline is often overlooked as a useful therapeutic for SSc. He also remarks that despite experiencing cosmetic blue-gray skin hyperpigmentation, the patient chose to continue treatment.
Diagnostic and Treatment Strategies of Dermatologists for Treating Morphea in Hungary. Acta Dermatovenerol Croat. 2018 Apr;26(1):21-24.
Researchers in the Dermatology Department of Semmelweis University in Budapest, Hungary, developed a questionnaire that was sent to Hungarian dermatologists to determine the diagnostic and treatment strategies employed for morphea patients. Four-fifths of 101 respondents replied that they tested for Lyme disease (a tick-borne infection that has been strongly correlated with morphea in the scientific literature), and although topical steroid preparations were used for skin lesions, most doctors preferred antibiotic therapy (either doxycycline or penicillin) for systemic treatment (presumably for the triggering infection). As only a small percentage (6.9%) of doctors in Hungary responded that they use the immune-suppressant, methotrexate, these study authors expressed the need for universal diagnostic and treatment guidelines for morphea, referring to the guidelines employed in western nations that recommend the use of systemic steroids and methotrexate.
[Treatment of subcutaneous calcinosis in systemic disorders]. Rev Med Interne. 2014 Jul;35(7):444-52. doi: 10.1016/j.revmed.2014.04.018. Epub 2014 May 28.
Article abstract in La Revue de Medédine Interne outlining treatments that include the systemic use of minocycline for calcinosis cutis, a common metabolic disturbance of calcium and/or phosphate metabolism in connective tissue diseases, such as limited scleroderma and dermatomyositis.
Calcinosis cutis in autoimmune connective tissue diseases. Dermatol Ther. 2012 Mar-Apr;25(2):195-206. doi: 10.1111/j.1529-8019.2012.01492.x.
Article abstract in Dermatology and Therapy describing the use of minocycline and various other treatments for calcinosis cutis, commonly suffered in connective tissue diseases, such as systemic scleroderma and dermatomyositis.
Calcinosis in rheumatic diseases. Semin Arthritis Rheum. 2005 Jun;34(6):805-12.
A MEDLINE search of articles between 1972-2004, published in Seminars in Arthritis and Rheumatism, mentioning minocycline among currently available treatments, but also describing deficiencies in an organized approach to calcinosis treatment due to a lack of a generally accepted classification, systemic studies and clinical therapeutic trials .
Treatment of cutaneous calcinosis in limited systemic sclerosis with minocycline. Ann Rheum Dis. 2003 Mar;62(3):267-9.
Study evaluating the safety of long-term use of low dose minocycline in a small group of limited cutaneous systemic sclerosis (lcSSc) patients, published in the Annals of Rheumatic Diseases. Authors concluded that minocycline was safe for long-term use and surmised that its effectiveness for calcinosis control among nearly all the study participants was likely due to inhibition of matrix metalloproteinases , anti-inflammatory effects, calcium binding properties and that its antibacterial actions may also be involved.
Tetracyclines and pulmonary inflammation. Endocr Metab Immune Disord Drug Targets. 2007 Dec;7(4):232-6.
A review of recent research relating to tetracycline and its derivatives (chlortetracycline, oxytetracycline, minocycline, doxycycline, methacycline and lymecycline) to help to control pulmonary inflammation.
The role of long-term doxycycline in patients of idiopathic pulmonary fibrosis: The results of an open prospective trial. Lung India. 2009 Jul-Sep; 26(3): 81–85.
Researchers ran a small, open prospective trial of 7 patients with idiopathic pulmonary fibrosis (IPF) to evaluate the safety of doxycycline for long term use in this group of patients. Study authors conclude that their findings merit a clinical trial of doxycycline for the management of IPF patients, stating that tetracycline is “... widely used and (a) relatively safe drug (that) can add a new dimension to the therapeutic regimen.”
An alternative therapy for idiopathic pulmonary fibrosis by doxycycline through matrix metalloproteinase inhibition. Lung India. 2011 Jul;28(3):174-9. doi: 10.4103/0970-2113.83972.
An 24-week, open prospective study of idiopathic pulmonary fibrosis (IPF) patients in which study authors found that doxycycline demonstrated significant benefit due to its anti-matrix metalloproteinase (anti-MMP) activities. Measureable improvement was noted in the 6 min walk test (6MWT), St. Georges respiratory questionnaire (SGRQ), forced vital capacity (FVC), and general quality of life.
Minocycline in scleroderma. Acta Dermatovenerologica Croatica, 2000, Jan; 8. 145-149.
Croatian researchers conducted a small, open minocycline trial in 6 patients with early diffuse scleroderma, mirroring the Harvard research conducted earlier by Drs. David E. Trentham, Christine H. Le, and Alejandro Morales, etal, that was published in The Lancet in 1998. The Croatian study authors remark that although its mechanism of action in systemic scleroderma (SSc) is unknown and that it should be regarded as a long-term therapy during which time dose titration may be necessary, they conclude that minocycline “deserve(s) a large-scale study in SSc.”
Tetracyclines: nonantibiotic properties and their clinical implications. J Am Acad Dermatol. 2006 Feb;54(2):258-65.
The numerous non-antibiotic properties of tetracyclines are discussed in this commentary, as well as their potential clinical applications in skin and other diseases, including autoimmune diseases, such as sacrcoidosis, rheumatoid arthritis, and scleroderma.
Treatment of scleroderma. Arch Dermatol. 2002 Jan;138(1):99-105.
Researchers at Mount Sinai School of Medicine in New York discuss the array of available treatments for the various forms of scleroderma, including the use of minocycline for systemic scleroderma.
Minocycline does not alter collagen type I metabolism of dermal fibroblasts in culture. Archives of Dermatological Research; May 2002, Volume 294, Issue 3, pp 103–108.
In attempting to unravel why minocycline has been successful in treating skin fibrosis in systemic scleroderma (SSc), German researchers focused on the potential of its anti-fibrotic actions. Their findings were that minocycline had no direct anti-fibrotic in-vitro effects on human skin fibroblasts and, therefore, concluded that there must be other mechanisms involved with the observed clinical effects of this antibiotic for the treatment of SSc.