Imatinib mesylate treatment of nephrogenic systemic fibrosis

Authors

  • Jonathan Kay,

    Corresponding author
    1. Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts
    • Rheumatology Unit, Massachusetts General Hospital, 55 Fruit Street, Yawkey 2-174, Boston, MA 02114
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    • Dr. Kay received grant support from Novartis to conduct a study of imatinib mesylate for the treatment of nephrogenic systemic fibrosis.

  • Whitney A. High

    1. University of Colorado Health Sciences Center, Denver
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    • Dr. High has received honoraria (less than $10,000) from Alpha Medical, Inc., an independent CME company, for speaking on the general topic of gadolinium in nephrogenic systemic fibrosis.


Abstract

Objective

To examine the effectiveness of imatinib mesylate in the treatment of nephrogenic systemic fibrosis (NSF).

Methods

Two patients with stage 5 chronic kidney disease and NSF were treated with oral imatinib mesylate at a dosage of 400 mg/day. Skin thickening and tethering were assessed using the modified Rodnan skin thickness score (MRSS), and knee joint flexion contractures were measured with a goniometer.

Results

Each patient displayed progressive reduction of skin thickening and tethering, with a steady decrease in the MRSS, following the initiation of imatinib mesylate treatment. The patient who had knee joint contractures achieved increased knee extension with passive range-of-motion exercises once his skin thickening and tethering had begun to decrease. Within weeks of stopping imatinib mesylate, the skin changes recurred in each patient. Recurrent skin thickening and tethering again improved in the patient who resumed taking imatinib mesylate for longer than 2 weeks. Skin biopsies performed both before and after initial dosing of that patient revealed less fibrosis and less staining for type I procollagen after imatinib mesylate treatment, but essentially unchanged tissue gadolinium content.

Conclusion

Imatinib mesylate treatment decreases fibrosis and results in the relatively rapid and steady improvement of skin changes and knee joint contractures in patients with stage 5 chronic kidney disease and NSF, despite the persistence of gadolinium in the tissues. Because skin changes recurred after discontinuation of imatinib mesylate, the duration for which treatment may be required is undetermined.

Nephrogenic systemic fibrosis (NSF) is an extremely disabling and often painful condition affecting up to 13% of individuals with chronic kidney disease (1). Patients with NSF develop progressive skin hardening, tethering, and hyperpigmentation, predominantly affecting the extremities (2). Flexion contractures of the fingers, elbows, and knees develop in advanced NSF and may severely impair physical function (3). Extracutaneous fibrosis involving muscle and viscera also occurs in NSF (4).

The development of NSF is strongly associated with prior exposure to gadolinium-containing contrast media during magnetic resonance imaging (MRI) in patients with stage 5 chronic kidney disease (1, 5). Gadolinium, which is not present in the skin of healthy individuals, has been detected by electron microscopy in affected skin (6) and has been quantified by mass spectrometry (7), strongly suggesting a causal relationship.

Spontaneous improvement has been reported only in 2 individuals with NSF in whom acute renal failure resolved (8). Mildly decreased skin thickening has been reported in 7 patients treated with extracorporeal photopheresis, 3 of whom exhibited improvement in ambulation (9), and “slight reversal” of skin changes was observed in another patient treated with pentoxifylline (5). Other therapeutic modalities, such as topical and oral steroids, immunosuppressive drugs, and plasmapheresis, have generally failed to improve the skin changes of NSF (3).

Transforming growth factor β1 (TGFβ1) messenger RNA (mRNA) is increased in the skin, fascia, and striated muscle affected by NSF (4). TGFβ stimulates extracellular matrix (ECM) protein synthesis both through a Smad-dependent signaling pathway and through a Smad-independent signaling pathway that involves the tyrosine kinase c-Abl (10). Imatinib mesyllate (Gleevec; Novartis, East Hanover, NJ) is a 2-phenylaminopyrimidine compound that selectively inhibits signaling mediated by c-Abl, c-Kit, and the platelet-derived growth factor receptor (PDGFR) (11), as well as Smad-independent signaling by the TGFβ receptor (TGFβR) (10). It has been approved by the Food and Drug Administration for the treatment of chronic myelogenous leukemia associated with the Philadelphia chromosome transformation, myelodysplastic/myeloproliferative diseases associated with PDGFR gene rearrangements, aggressive systemic mastocytosis, hypereosinophilic syndrome, dermatofibrosarcoma protuberans, and gastrointestinal stromal tumors (GISTs). By inhibiting the c-Abl kinase and tyrosine kinase activity of PDGFRs, imatinib mesylate decreases type I collagen and fibronectin synthesis by dermal fibroblasts and reduces ECM synthesis and accumulation in bleomycin-induced experimental dermal fibrosis (12).

We describe here 2 patients with NSF who responded to imatinib mesylate treatment with improvement in skin tethering and knee joint contractures.

PATIENTS AND METHODS

Skin involvement was assessed using the modified Rodnan skin thickness score (MRSS) (13).

The same examiner evaluated each patient at each visit. Flexion contracture of the knee joint was assessed by measuring maximal passive extension with a goniometer and rounding the value to the nearest multiple of 5°. The center of the goniometer was placed at the lateral femoral condyle, with the proximal arm positioned along the longitudinal axis of the femur and the distal arm aligned with the long axis of the tibia. Although flexion contractures appeared symmetric in both patients, the knee with the greater flexion contracture at baseline was assessed for change at subsequent visits.

Paraffin-embedded skin biopsy specimens were processed by the clinical pathology laboratories at the hospitals where the biopsies had been performed. Immunohistochemical staining of these specimens was performed using the following antibodies: monoclonal anti-CD34 (clone QBEnd/10; Ventana Medical Systems, Tucson, AZ), monoclonal anti-CD68 (clone KP1; Ventana Medical Systems), monoclonal anti–type I procollagen (clone M58; Chemicon, Temecula, CA), and polyclonal anti–factor XIIIa (Calbiochem, San Diego, CA). The institutional review boards at the authors' hospitals approved the assessment of skin biopsy specimens for gadolinium content.

Patient 1.

The patient, a 75-year-old white man, underwent a right nephrectomy at age 53 to treat renal cell carcinoma. His renal function gradually declined, and hemodialysis was initiated at age 74. In July 2005, 2 months after beginning hemodialysis, he underwent MR angiography (MRA) of both legs with gadodiamide. In August 2006, he developed posterior neck pain, prompting MRI of his cervical spine, again with gadodiamide. Staphylococcus aureus discitis of the C3–C4 intervertebral disc was diagnosed, and he was treated with external immobilization of his cervical spine and 12 weeks of intravenous vancomycin and oral rifampin. To monitor his progress during antibiotic therapy, he underwent 2 subsequent MRIs using gadodiamide.

Within 1 month, he began to experience stiffening of his hands and feet. By September 2006, the skin on his hands and legs was dyspigmented and firmer than skin elsewhere. During the ensuing 3 months, his skin changes progressed and early contractures of the fingers, elbows, and knees were noted, progressing such that he could not walk and was confined to a wheelchair or bed. Findings of a biopsy of skin from his left lower leg, performed in October 2006, were consistent with NSF and demonstrated fibrosis, mucin deposition, and infiltration of CD34+, type I procollagen–positive, CD68+, and factor XIIIa–positive cells. Measurement of gadolinium in this same tissue demonstrated 130 parts per million (μg/gm dry weight) of gadolinium (7).

Because of the severity of his skin involvement, his physical disability, and the lack of a consistently effective treatment for NSF, he was offered a 4-month course of imatinib mesylate. After providing informed consent, he began treatment with 400 mg/day oral imatinib mesylate in November 2006.

Patient 2.

The patient, a 65-year-old white man with type 2 diabetes mellitus, hypertension, and atrial fibrillation requiring warfarin anticoagulation, developed chronic kidney disease at age 59, and peritoneal dialysis was initiated at age 62. In February 2005, he underwent MRA of his aorta with gadopentetate dimeglumine. One year later, he began to experience stiffness, tightness, and thickening of the skin of his lower legs and fingers. In October 2006, biopsy of skin on his right lower leg demonstrated dermal fibrosis and septal widening, mucin deposition, and infiltration of CD34+, type I procollagen–positive, CD68+, and factor XIIIa–positive cells, consistent with NSF. Measurement of gadolinium in this tissue demonstrated 28 ppm (μg/gm dry weight) of gadolinium (7).

This patient also was offered treatment with imatinib mesylate. After providing informed consent, he began taking 400 mg/day oral imatinib mesylate in December 2006. Shortly thereafter, his peritoneal dialysis catheter stopped functioning and he began hemodialysis.

To determine whether a higher dose of imatinib mesylate might yield further improvement in his skin changes, his daily dose was increased from 400 mg to 600 mg at the end of January 2007. Because of a hospitalization in February 2007 for evaluation and treatment of chronic gastrointestinal bleeding, he stopped taking imatinib mesylate for 2 weeks. One week later, he resumed taking 600 mg/day oral imatinib mesylate, but he again stopped taking it after 6 days, when he underwent elective surgical repair of an abdominal hernia. He once again resumed taking 400 mg/day oral imatinib mesylate in May 2007. However, because of difficulty controlling his international normalized ratio (INR), he discontinued imatinib mesylate 2 weeks later. Since discontinuation of imatinib mesylate, his warfarin anticoagulation has been managed more easily.

RESULTS

Following the initiation of oral imatinib mesylate, each patient displayed progressive reduction of skin thickening and tethering, with a steady decrease in the MRSS (Figures 1A and B). While receiving 400 mg/day oral imatinib mesylate for 15 weeks, patient 1 had a decrease in his MRSS from 42 to 16 (Figure 1A). Over the subsequent 9 weeks, during which he took no imatinib mesylate, his MRSS increased to 33. While taking 400 mg/day oral imatinib mesylate, patient 2 also exhibited a reduction in his MRSS from 12 to 2 (Figure 1B). Within 5 weeks of stopping imatinib mesylate, his skin changes recurred and extended to involve his abdomen, resulting in an MRSS of 15.

Figure 1.

A and B, Changes in the modified Rodnan skin thickness score (MRSS) over time in patient 1 (A) and patient 2 (B) with imatinib mesylate treatment. C and D, Changes in knee joint flexion contractures over time in patient 1 (C) and patient 2 (D) with imatinib mesylate treatment. The daily dose of imatinib mesylate is indicated on the solid bar above each graph.

Because of worsening skin changes that developed with treatment discontinuation, patient 1 requested that imatinib mesylate be restarted. Within 5 weeks of resuming 400 mg/day oral imatinib mesylate, his MRSS decreased from 33 to 10 and remained in that range with continued treatment (Figure 1A). Patient 2 elected not to restart imatinib mesylate, except for a brief 2-week period, and he experienced persistence of and slight progression of his skin thickening and tethering during the subsequent 20 weeks (Figure 1B).

As his MRSS decreased, and with physical therapy using passive range-of-motion exercises, patient 1 experienced a reduction of his knee joint flexion contractures from 25° at week 6 to 10° at week 15, and he was able to walk ∼20 feet with the assistance of a walker (Figure 1C). This improvement persisted during the first 5 weeks after he stopped taking imatinib mesylate. However, after he had not taken imatinib mesylate for 9 weeks, he again developed 25° flexion contractures of both knees. Because of medical issues unrelated to his NSF, he did not receive regular physical therapy after reinitiating imatinib mesylate, yet he remains able to walk with the assistance of a walker. Patient 2 had no knee joint flexion contractures when he began taking imatinib mesylate (Figure 1D). However, when his skin changes began to progress after he discontinued imatinib mesylate, knee joint flexion contractures developed and gradually progressed over time.

Other than fluid retention, which was successfully corrected by dialysis treatment, neither patient experienced any adverse effect related to imatinib mesylate. Patient 1 developed gastrointestinal upset that resolved when corticosteroid replacement with 7.5 mg/day oral prednisone was begun to treat adrenal insufficiency, 17 weeks after the reinitiation of imatinib mesylate. Neither patient developed congestive heart failure (CHF).

Skin biopsy specimens obtained from patient 1 before and after initial dosing with imatinib mesylate were compared. Both specimens were obtained from the same anatomic area, with the second specimen obtained immediately adjacent to the resolved scar from the prior procedure, but the first procedure was an excisional biopsy and the second was a punch biopsy. Despite the 2 biopsies having been performed using different techniques, when tissue sections of the same thickness (3.5 μm), stained at the same institution in a sequential manner on the same day, were compared side-by-side using the same microscope and under identical lighting, the specimen obtained after 15 weeks of imatinib mesylate therapy revealed less fibrosis (Figures 2A and B) and less staining for type I procollagen (Figures 2C and D), which correlates with the formation of new collagen (14). Furthermore, in the specimen obtained after imatinib mesylate treatment, fewer type I procollagen–positive cells were present in the upper dermis (Figure 2D). The second biopsy specimen contained 124 ppm (μg/gm dry weight) of gadolinium, essentially unchanged from the amount of gadolinium in the pretreatment biopsy specimen (7).

Figure 2.

Comparison of skin biopsy specimens from patient 1 before (A and C) and after (B and D) 15 weeks of treatment with imatinib mesylate. Sections are shown at similar magnification and under equivalent lighting and demonstrate different tinctorial staining qualities indicative of less fibrosis after treatment (hematoxylin and eosin stained) (A and B) and less overall staining for type I procollagen and fewer type I procollagen–positive fibrocytes, particularly in the upper dermis, after treatment (type I procollagen immunohistochemical stained) (C and D). The horizontal gray line in each panel identifies the level of the eccrine ducts, structures that occur at a relatively uniform depth in a given region of the body. (Original magnification × 12.5.)

DISCUSSION

Treatment with imatinib mesylate resulted in relatively rapid and steady improvement in skin thickening and tethering in 2 patients with stage 5 chronic kidney disease and NSF. The patient who had knee joint flexion contractures achieved reduction of his flexion contractures with passive range-of-motion exercises once his skin thickening and tethering had begun to decrease. Skin gadolinium content did not decrease significantly with imatinib mesylate treatment; however, upon histologic examination of skin, decreased fibrosis and type I procollagen staining correlated with the observed clinical improvement. In each patient, after discontinuation of imatinib mesylate, skin changes progressed within 1 to 2 months and knee joint flexion contractures also worsened or developed de novo. Strikingly, recurrent skin thickening and tethering improved in the patient who resumed taking imatinib mesylate for longer than 2 weeks. The recurrence of skin thickening and tethering after discontinuation of imatinib mesylate and the response to retreatment suggest a direct relationship between the administration of imatinib mesylate and improvement in NSF skin changes.

Imatinib mesylate is metabolized primarily in the liver and is excreted in bile. Dosing need not be adjusted in stage 5 chronic kidney disease (15). When used to treat chronic myelogenous leukemia and GISTs, side effects of imatinib mesylate are typically mild to moderate in severity and generally resolve after the initial 2 months of treatment. The most common side effects include fluid retention, nausea, and muscle cramps (16). Several patients treated with imatinib mesylate for hematologic malignancy have developed new-onset CHF, but the incidence of CHF among patients treated with imatinib mesylate in clinical trials was not increased above that in the general population (17, 18). Because imatinib mesylate weakly inhibits the cytochrome P450 2C9 and 3A4 isoenzymes that are involved in the metabolism of warfarin, coadministration of imatinib mesylate and warfarin has resulted in alteration of the INR (19).

Among its several mechanisms of action, imatinib mesylate blocks signal transduction through both the TGFβR and the PDGF-BB receptor. Both TGFβ and PDGF are known to mediate fibrosis. TGFβ mRNA levels are increased in the skin, fascia, and striated muscle of patients with NSF (4), but studies have not yet been conducted to examine PDGF expression in tissues from patients with NSF. Gadolinium deposited in the skin of patients with NSF might serve as a persistent stimulus for fibrosis, perhaps by inducing the production of TGFβ or other profibrotic cytokines. Our observations in these 2 patients with NSF suggest that imatinib mesylate, perhaps by inhibiting signal transduction through the TGFβR or PDGF-BB receptor, down-regulates fibrosis in NSF. Since the skin changes of NSF improved over weeks during treatment with imatinib mesylate, it would appear that the fibrosis and skin remodeling are dynamic in nature and capable of modulation. Upon discontinuation of imatinib mesylate, skin fibrosis appears to resume, with persistence of gadolinium in tissue in these cases. Because the half-life of skin collagen is extremely long (20), the reduction in the MRSS and the decrease in fibrosis observed over 15 weeks suggest that imatinib mesylate may also increase the production of proteases that degrade collagen, such as matrix metalloproteinases, and decrease the production of their inhibitors (21).

This is the first report of clinical and histologic improvement in patients with a fibrosing disorder treated with imatinib mesylate. Further study of imatinib mesylate in a larger group of patients with NSF is warranted to confirm and extend these observations. If additional patients respond similarly, imatinib mesylate may be an effective long-term treatment for NSF and other fibrosing disorders that currently are without effective treatment.

AUTHOR CONTRIBUTIONS

Dr. Kay had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Kay.

Acquisition of data. Kay, High.

Analysis and interpretation of data. Kay, High.

Manuscript preparation. Kay, High.

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