|Year : 2019 | Volume
| Issue : 5 | Page : 52-58
Drug-induced fibrosing syndromes: A scoping review
Sakir Ahmed1, Prasanta Padhan1, Partisha Gupta2
1 Department of Clinical Immunology and Rheumatology, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, Odisha, India
2 Department of Internal Medicine, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, Odisha, India
|Date of Web Publication||2-Dec-2019|
Dr. Sakir Ahmed
Department of Clinical Immunology and Rheumatology, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar - 751 024, Odisha
Source of Support: None, Conflict of Interest: None
There are numerous case reports implicating drugs in the pathogenesis of scleroderma-like fibrotic syndromes. A MEDLINE and SCOPUS search was made in an attempt to review these drugs. The entire spectrum of sclerodermatous disorders ranging from localized morphea, fasciitis, and linear scleroderma to the classical diffuse systemic sclerosis with typical autoantibody formation have been reported in association with drugs. Some drugs such as bleomycin and pentazocine have been established to cause fibrosis and are used to create animal models of systemic sclerosis. There are controversies regarding the role of others such as beta-blockers. Certain chemotherapeutic agents and ergot derivatives can also lead to fibrosing disorders. The new checkpoint inhibitors have been shown to develop systemic sclerosis like disease among other “immune related adverse effects.” The mechanisms leading to fibrosis are poorly understood in case of most drugs due to paucity of data. This limits therapeutic strategies. However, many of these syndromes regress if the causative drug is withdrawn early. Thus, it is imperative for clinicians to have knowledge about these syndromes and identify them early.
Keywords: Adverse effects, drug reaction, fibrosis, scleroderma, scleroderma mimic
|How to cite this article:|
Ahmed S, Padhan P, Gupta P. Drug-induced fibrosing syndromes: A scoping review. Indian J Rheumatol 2019;14, Suppl S1:52-8
| Introduction|| |
Systemic sclerosis is the prototype idiopathic fibrotic disease. However, there are instances when environmental causes have been implicated in its pathogenesis, as in case of the Erasmus syndrome. Similarly, drug-induced scleroderma-like syndromes have been widely reported in literature. The majority of this data are in the form of case reports or case series. The recognition of such syndromes has helped forward our incremental understanding of systemic sclerosis and of fibrosis. Therapies to prevent, retard, stop, or even reverse fibrosis are the need of the hour. Thus understanding the etiopathogenesis of underlying fibrosis can help in strategizing targeted therapies.
The problem with fibrosis is that the etiology is often not clear. Thus, drug-induced fibrosing syndromes provide a unique situation where the etiology of fibrosis can be attributed to one major factor. These syndromes are rare and unpredictable. This again limits their utility to understand pathogenesis of fibrosis. However, the ingenuity of science has harnessed such drugs to prepare animal models of systemic sclerosis. Such models are indispensable both for exploring pathological pathways, and for drug testing in pre-clinical trials.
Another implication of knowing drug-induced fibrosing syndromes is that some of them can be reversed by stopping the offending drug early.,, Thus, clinicians, especially ones dealing with fibrotic disorders including rheumatologists, dermatologists, pulmonologists, gastroenterologists, and nephrologists should be acquainted with these syndromes.
With this background, we attempted to enumerate the drugs reported to cause fibrosing syndromes, assess the strength of the evidence, and identify the hypothetical mechanisms leading to fibrosis.
| Search Strategy|| |
The bibliographic databases - SCOPUS and MEDLINE were searched using the words “fibrosis” and “drug induced” as per the recommendations for a biomedical review. The search results were restricted to articles in English only. Those dealing with animal models or fibrosis in animals were excluded. The resultant 1739 hits were individually screened by two authors, and with the consensus of all three authors, 42 articles were finalized [Figure 1]. Based on these articles, the manuscript was prepared including the personal opinion of the authors. Wherever necessary, further searches were carried out for the associations of individual drugs with, or their possible mechanisms leading to, fibrosis.
| Histological Changes|| |
Various changes have been reported in the early stages of drug-induced fibrosis that include lymphocytic infiltration in connective tissue, plasma cell infiltrate, with or without perivascular inflammation, areas of necrosis, and laying down of collagen.
| Mechanisms of Drug-Induced Fibrosis|| |
The real mechanisms are still unknown since the reported cases of drug induced fibrosis are far and few. However, one commonly suggested hypothesis has been ischemia. Since drugs like ergot derivatives cause vasoconstriction and beta-blockers lead to decreased cardiac output, ischemia was initially postulated to lead to fibrosis. The most extensively studied has been bleomycin-induced fibrosis. Mostly, plasmacytoid dendritic cells, Th1- and Th17-helper T-cells have been implicated in bleomycin-induced fibrosis., Although the exact point of initiation is still not known, inciting drugs lead to endothelial dysfunction, activation of macrophages, and ultimately conversion of fibroblasts into myofibroblasts. These may be influenced by genetic factors such as polymorphisms in the bleomycin hydroxylase gene that can increase the availability of bleomycin in the circulation. Other mechanisms such as endothelial mesenchymal transition, inflammasome activation, M2 macrophage polarization, and NETosis may also play role similar to systemic sclerosis. This finally culminates in the activation of fibroblasts and deposition of extracellular matrix including collagen. However, studies are needed to establish these hypotheses.
In case of opioids, some links have been found between opioids and fibrosis. Hypertrophic scars have high levels of all the three opioid receptors (mu-, delta- and kappa-) as compared to normal skin. The opioid antagonist naltrexone has been shown to reverse hepatic fibrosis in a mouse model. Thus, understanding the pathogenesis of drug-induced fibrosis will help in identifying newer targets to combat fibrosis.
| Drugs Associated With Fibrosis|| |
The various drugs associated with fibrosis are enumerated in [table 1]. Details of the most commonly associated drugs are discussed below:
The significance of bleomycin lies in that it is the most commonly used animal model of systemic sclerosis. There are many variations of this model, but discussion of these is beyond the scope of this manuscript.
Bleomycin has a bithiazole structure that helps it to intercalate between DNA strands and has a pyrimidine and imidazole ring that binds iron. This iron helps in the formation of free oxygen species that leads to DNA and lipid peroxidation. Commonly, bleomycin is used for germ-line tumors and Hodgkin lymphoma and is linked to drug-induced pulmonary fibrosis.
Taxanes are mitotic inhibitors derived from the Pacific yew tree. They act by inhibiting microtubule assembly required for cell division. Paclitaxel was the initial taxane used as a chemotherapeutic drug, and there are rare reports of fibrosis induced by it. Although most are reports of pulmonary fibrosis, even widespread systemic sclerosis like phenotype with myositis has also been reported.
Since paclitaxel is difficult to obtain, a semisynthetic derivative docetaxel is more widely used now for prostate, breast, and ovarian malignancies. The interstitial pneumonitis caused by docetaxel can be reversible after withdrawal of the drug. However, the fibrosis is not limited to the lung, and docetaxel has been associated with lacrimal gland and nasal mucosa fibrosis too. Like paclitaxel, it has also been associated with diffuse systemic sclerosis like phenotype.
Other chemotherapeutic agents
Various agents have been implicated in fibrosis, but these reports need to be interpreted with caution since these drugs are used in malignancies, and malignancies themselves can be associated with systemic sclerosis or interstitial lung disease (dermatomyositis) phenotypes. Thus, there might be a false association made with drugs if the fibrosing symptoms are discovered after administration of chemotherapy. Another potential confounder is radiation that can also lead to fibrosis.
Some drugs reported in association with fibrosis are gemcitabine, doxorubicin, and pemetrexed. Gemcitabine has been linked to hepatic fibrosis (5 cases) and skin fibrosis especially when used along with docetaxel (14 cases).
Doxorubicin is known to cause cardiac fibrosis  and even renal fibrosis that is transforming growth factor-β mediated. It has been reported to be associated with bladder contracture after intravesicular instillation. However, this needs to be interpreted with caution as there are a number of drugs that have been implicated to cause bladder contracture after intravesicular administration. The evidence for pemetrexed is less with limited case reports of lung fibrosis, renal fibrosis,,, and one of scleroderma limited to the legs.
Fibrosis of the serosal membranes (pleural, peritoneum, and pericardial) and of the lung caused by ergotamine had been recognized long ago. The most common manifestation is retroperitoneal fibrosis, and it can lead to fibrosis of the myocardium and cardiac valves. With the availability of safer drugs to control postpartum hemorrhage and migraine headache, the use of ergot derivatives for these indications has drastically reduced. However, some dopaminergic ergot derivatives are still being used for neurological conditions. Of these, pergolide has been implicated in serosal fibrosis  and cardiac valve fibrosis. Similarly, there are also reports of bromocriptine leading to similar complications, albeit less frequently. Other drugs implicated are nicergoline, dihydroergocristine, and dihydroergotamine.
Of all the opioids, pentazocine has been the most commonly implicated in the genesis of skin fibrosis. In drug abusers, the presence of adulterants such as quinine, lactose, lidocaine, caffeine, inositol, dextrose, sucrose, procaine, starch, magnesium silicate (talc), and mannitol can further potentiate the fibrotic process. Rarely, it also involves the muscles. The involvement of muscles distal to injection site proves that it is not just a local reaction. Moreover, extensive fibrosis due to pentazocine use has been considered a scleroderma mimic that does not have Raynaud phenomenon, sclerodactyly, or typical autoantibodies found in systemic sclerosis. Similar associations have been reported with methadone.
Propranolol, metoprolol, atenolol, and other beta-blockers have been implicated in the pathogenesis of retroperitoneal fibrosis., There are in vitro experiments to support this concept. Most of the case reports of retroperitoneal fibrosis are from 1970 to 2000, where beta-blockers were commonly used as antihypertensive agents. It has been suggested that hypertension might have been an early manifestation of retroperitoneal fibrosis, and other features manifested after beta-blockers were started as antihypertensives. Beta-blockers have been shown to have antifibrotic effects in heart failure. This cannot be overlooked before attributing fibrosis to beta-blockers.
Vitamins and food supplements
Though cutaneous reaction with Vitamin K1 (phytomenadione) is rare, it has earned the eponym Texier's disease., Both morphea like lesions and fasciitis have been reported in association with phytomenadione., Vitamin B12 injections have been implicated to cause injection site fibrosis. Although there have been reports of scleroderma like illness after administration of multiple or a combined vitamin, our interpretation of these papers is that they are isolated and the data presented are limited and not convincing. Although food supplements are technically not drugs, it is imperative to mention the eosinophilia-myalgia syndrome. It had broken out as an epidemic in 1989 with more than 1500 cases reported. After the Food and Drug Administration of the United States banned L-tryptophan, the incidence declined drastically. Later, it was shown that it was not L-tryptophan itself but possibly two contaminants that precipitated this syndrome.
Checkpoint inhibitors have drastically changed the face of cancer immunotherapy. Although it has unprecedented success, many of the cases that respond develop rheumatic diseases secondarily. The appearance of a rheumatic syndrome is taken as a good prognostic marker that signals the effectiveness of the drug in an individual. Systemic sclerosis like diseases have been reported among the other rheumatic conditions.,
Interferon injections have been implicated to cause scleroderma like illness in patients with multiple sclerosis. It has also been implicated in the formation of localized scleroderma (morphea)., In a genetically predisposed individual, interferon can trigger fibroblast activation. Other cytokines are used therapeutically in human disease. However, in mouse models, injection of interleukin-2 has demonstrated liver and renal fibrosis. Another mimic of scleroderma can be sclerodermatous graft versus host disease with the presence of antinuclear antibodies. Although not a drug-induced fibrosis, it is possibly due to the chronic cytokine stimulation and presents a way to better understand and target systemic fibrosing disorders.
Fibrosing disorders caused by organic solvents like polyvinyl chloride are beyond the scope of this review.
Other drugs implicated
Among isolated case reports, capecitabine, hydroxyurea, and ustekinumab  have been associated with scleroderma. In a clinical trial of a cathepsin K inhibitor, Balicatib, one female developed generalized morphea that resolved after withdrawal of the drug.
D-penicillamine has also been reported to cause fibrosis and even emergence of autoantibodies found in systemic sclerosis.
| Suspecting Drug-Induced Fibrosis|| |
Although the literature provides little information about when to suspect drug-induced fibrosis, expert opinions suggest that the absence of typical features like Raynaud phenomenon or antinuclear antibodies should alert us to the fact that there might be some other precipitating factor for the fibrosis. Again, this is not a definitive rule since even drug-induced fibrosis has been shown to have Raynaud phenomenon and autoantibodies. Thus, the strongest pointer may be a temporal association with the administration of the drug.
| Therapeutic Options|| |
The evidence for therapeutics is very much limited. A good number of cases have reversal of fibrotic manifestations once the offending drug is withdrawn. For the other, a plethora of treatment has been tried from phototherapy to kinase inhibitors. Only in case of graft versus host disease, there are reports of successful therapy of fibrotic manifestations using mTOR (mechanistic Target of Rapamycin) inhibition.
| Other Implications|| |
As discussed in the introduction, drug-induced fibrosis may present unique caveats that can help us unravel the pathogenesis of fibrosis. The most has been learnt from the Bleomycin murine model that also acts as the most common mouse model to test therapeutics before human trials. Unfortunately, many other drugs implicated have been rare events, making it difficult to use them as models for pathogenesis. This may be overcome by having a monitoring and reporting system in place so that tissue samples from such cases can be obtained early. These manifestations are rare, and this implies that there are other factors that determine their precipitation. This can be genetic predisposition, epigenetic changes, influence of concomitant drugs, and disease processes. Although uncommon, physicians should be able to recognize them in clinical practice.
Limitations of the study
Although we attempted to include all drugs associated with fibrosis, it is difficult to cover all case reports individually. There is a thin line in a drug directly causing fibrosis and leading to fibrosis secondary to organ damage. There may be several other drugs leading to hypersensitivity pneumonitis or interstitial nephritis that lead to fibrosis in the lungs and in the kidneys, respectively. Similarly, a lot of drug causing liver damage can lead to hepatic fibrosis. However, to keep the topic manageable and coherent, we had to limit the manuscript to drugs causing systemic fibrosis or scleroderma (including localized scleroderma) features.
Another limitation of this review is that we could not report on the prevalence of such syndromes because a majority are far-flung case reports or series. It is very difficult to find a denominator of how many patients were treated, of which a proportion might have developed such syndromes. Nevertheless, it can easily be understood that the incidence is much less than the incidence of “idiopathic” systemic sclerosis.
| Conclusion|| |
Drug-induced fibrotic syndromes are relatively rare conditions, and thus, spurious associations may be reported. They can present with the entire spectrum of disease from localized morphea to classical features of systemic sclerosis including vasculopathy and autoantibodies. With the advent of checkpoint inhibitors in cancer therapy, newer drugs may manifest with sclerodermatous manifestations. Thus, the clinician should be aware of the drugs that have strong associations with fibrosis, as well as be alert to identify any new drug with similar manifestations.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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