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Observation |

Nephrogenic Systemic Fibrosis:  Late Skin Manifestations FREE

Nannie Bangsgaard, MD; Peter Marckmann, MD, DMSc; Kristian Rossen, MD; Lone Skov, MD, DMSc
[+] Author Affiliations

Author Affiliations: Departments of Dermatology (Drs Bangsgaard and Skov) and Pathology (Dr Rossen), University Hospital of Copenhagen Gentofte, Hellerup, and Department of Nephrology, University Hospital of Copenhagen Herlev, Herlev (Dr Marckmann), Denmark. Dr Marckmann is now with the Department of Nephrology, Odense University Hospital, Odense, Denmark.


Arch Dermatol. 2009;145(2):183-187. doi:10.1001/archdermatol.2008.551.
Text Size: A A A
Published online

ABSTRACT

Background  Nephrogenic systemic fibrosis (NSF) is a serious disease that occurs in patients with severe renal disease and is believed to be caused by gadolinium-containing contrast agents. A detailed description of the late skin manifestations of NSF is important to help dermatologists and nephrologists recognize the disease.

Observations  We studied 17 patients with NSF late in the disease. All patients showed epidermal atrophy and hairlessness of the affected regions, primarily the lower legs. Affected areas were symmetrically distributed and hyperpigmented in most cases. Eleven patients showed confluent dermal plaques with thickening and hardening. In contrast, 3 patients presented with wrinkled, redundant skin as seen in cutis laxa. Patients with NSF had significantly poorer scores than control patients on the Daily Life Quality Index (mean [SD], 11. 4 [7.4] vs 1.5 [2. 3]; P < .001).

Conclusions  This descriptive case series of patients with NSF gives a detailed clinical picture of the skin manifestations late in the disease. It demonstrates that the clinical picture in the late stage has a varied presentation and that NSF has a significant effect on the quality of life.

Figures in this Article

Nephrogenic systemic fibrosis (NSF) is a relatively newly described, rare, and serious disease that has been reported only in patients with severe renal disease. The first cases were identified in 1997, but the disease was not described until 2000. Since then, the number of cases has gradually increased.1,2 The findings were first described as a dermatologic disease, but evidence has emerged that other organs may be involved, and NSF is now generally believed to be a systemic disease with skin changes as the most prominent symptom.3,4

Early in 2006, a relationship between exposure to gadolinium-based contrast agents and NSF was suggested.5 Soon thereafter, several centers reported gadolinium exposure in patients with NSF.69 In addition, free gadolinium was detected in tissues affected by NSF, supporting the possible pathogenetic role of gadolinium in this disease.1012

Many NSF cases described to date have been in the early phase of the disease.1,3,7 In our opinion, the skin manifestations in the late stages of NSF are different from those seen early in the disease and have a varied presentation.13,14 A detailed description of the skin manifestations of NSF late in the disease is important to help dermatologists and nephrologists recognize the disease and thereby avoid diagnostic delay. This study was performed to describe the clinical skin changes seen in patients with NSF years after onset of their symptoms and to evaluate the profile of serum procollagen III peptide (PIIIP) at this stage of the disease. The study further aimed to evaluate the impact of the disease on patients' quality of life.

METHODS

The Department of Nephrology at Herlev Hospital in Denmark has a large cohort of clinical and histologically verified cases of gadodiamide-related NSF. The cohort, now totaling 28 patients, has been described in recent reports.6,1316 At the initiation of this study in May 2007, there were 25 patients. Seven patients died and 1 emigrated before the study started. All 17 remaining patients were included. Ten age- and sex-matched patients without NSF who were receiving regular hemodialysis therapy were included as controls.

The study was conducted during October and November 2007 in accordance with the Declaration of Helsinki. Prior approval was obtained from the national Research Ethics Committee, and all patients gave written informed consent before participating.

A single investigator (N.B.) carried out a detailed cutaneous examination of all 17 patients with NSF. Quality of life was assessed by means of the Daily Life Quality Index (DLQI) questionnaire. The DLQI contains 10 questions, each with a score of 1 to 3. The maximum possible score of 30 indicates the worst quality of life. The DLQI has been validated in healthy populations and those with dermatologic conditions for repeatability, internal consistency, and sensitivity to change.1719

Blood samples for analysis of PIIIP were collected. The PIIIP level was determined by standard methods with a normal range of 1.7 to 4.2 μg/L.

The PIIIP levels and DLQI data were analyzed with descriptive statistic measures (mean and SD). Independent-sample t tests were used to compare values for patients with NSF and controls. Tests for normal distribution were done with a probability plot. Equal variance was not assumed. P < .01 was considered statistically significant. Data are given as mean (SD) unless otherwise indicated.

RESULTS

The study comprised 17 patients with NSF, 7 women and 10 men between the ages of 35 and 70 years. Baseline characteristics are outlined in the Table. The average interval between the onset of symptoms and clinical examination was 42 months (range, 20-98 months).

Table Graphic Jump LocationTable. Clinical Characteristics of 17 Patients With Long-Lasting Nephrogenic Systemic Fibrosis According to Dermatologic Examination in October and November 2007
OBJECTIVE SKIN FINDINGS

Skin findings, as observed at the clinical examination, are summarized in the Table. One patient had no current skin abnormalities. In the remaining patients, the skin findings were distributed symmetrically on the extremities. In all patients the lower legs were involved. The clinical findings were confined to the lower legs in 6 patients and to the lower legs and thighs in 3 patients; in the remaining 7 patients, arms or fingers were also affected.

The superficial skin changes were similar in all patients, but different ends of a spectrum of severity were represented. All 16 currently affected patients showed some degree of epidermal atrophy and loss of hair in the affected areas. Ten of them showed associated hyperpigmentation. Four patients exhibited hyperkeratosis with scaling. Seven patients showed the cobblestone appearance of peau d’orange.

The clinical deep skin changes were more inconsistent. Eleven patients presented with areas of confluent dermal plaques of thickening and hardening, 3 of them with a sharp demarcation to unaffected skin. The remaining 5 patients showed no or only minor dermal hardening. Three of them presented with areas characteristic of cutis laxa, with the skin appearing inelastic and redundant and hanging in loose, pendulous folds. There was a wide range of severity in these patients. Patient 16 presented with widespread bilateral, symmetrically distributed, sharply demarcated areas involving the lower legs and thighs. At the opposite end of the spectrum, patient 14 presented with only small but sharply demarcated affected areas distally on the arms and legs with slight atrophy and loss of hair. Patient 1 had a mixed clinical presentation of both deep hardening and wrinkled, redundant skin. Examples of the 2 different dermal manifestations, hardening and wrinkled redundant skin, are shown in Figure 1.

Place holder to copy figure label and caption
Figure 1.

Late skin manifestations of nephrogenic systemic fibrosis. A, Patient 9, with dermal fibrosis and hardening. B, Patient 16, with slack skin appearance.

Graphic Jump Location
DLQI SCORES

Fifteen patients and 10 controls completed the DLQI questionnaire. The 2 patients who did not complete the questionnaire where very ill and hospitalized.

Scores are summarized in Figure 2. The DLQI mean score was 11. 4 (7.4), ie, markedly impaired with scores similar to those with severe dermatologic disease.20 The high scores were mainly due to restrictions in activity, with most problems reported in questions 3 (house activities), 5 (social/leisure activities), and 6 (sports). In contrast, the scores for controls were significant lower, with a mean of 1.5 (2.3) (P < . 001).

Place holder to copy figure label and caption
Figure 2.

Daily Life Quality Index (DLQI) scores in patients with nephrogenic systemic fibrosis (NSF) and controls. Horizontal lines indicate means. Patient numbers given with the data points correspond to patient numbers in the Table.

Graphic Jump Location
PIIIP LEVELS AND HISTOLOGIC FINDINGS

The patients with NSF had a mean PIIIP level of 12.9 (6.6) μg/L, statistically significantly higher than the mean value for controls of 7.6 (2.6) μg/L(P = .01). Three patients (patients 8, 9, and 15) had a PIIIP level higher than 20 μg/L. These 3 patients were severely affected by the disease, with contractures and reports of weakness and pain; patients 9 and 15 were confined to wheelchairs.

In all patients the diagnosis of NSF had previously been histologically confirmed according to criteria defined by Cowper et al.21 In 5 patients we were able to analyze biopsy specimens collected during early and late stages of the disease. In all 5 patients fibrosis was present in the late biopsy specimen. In 2 patients the fibrosis was worse than in the early stage, and in 3 patients the fibrosis was less prominent than in the early stage. In patient 3, who seemed clinically unaffected, fibrosis was present in the subcutis. In patients 1, 11, and 16, who clinically presented with loose skin, the histologic finding was a marked reduction of elastic fibers at all levels of the skin combined with different degrees of fibrosis. The loss of elastic fibers for all 3 patients was more prominent in the biopsy specimens collected late in the disease, supporting the clinical course seen in these patients.

COMMENT

This descriptive case series gives a detailed clinical picture of the late skin manifestations in patients with NSF. The skin manifestations seen at the onset of symptoms and in the early stage of the disease have been described, with edema, erythema, and warmth being present in addition to the fibrosis in the affected area.1,3,7 The skin changes described in our patients late in the disease are different, with a clinically stationary picture of symmetrically distributed areas of various degrees of epidermal atrophy and hair loss. In most cases these findings were combined with confluent dermal plaques of thickening and hardening, but in a few patients they were noted along with wrinkled, redundant skin, as seen in cutis laxa.

It is important to recognize that NSF in the late stage of the disease can present without the typically described hardening of fibrosis but with the appearance of wrinkled, redundant skin. This late manifestation has previously been described in a 26-year-old white man with end-stage renal disease, who initially presented with the characteristic changes of thickening. Findings in a skin biopsy specimen were representative of NSF. During the following 2 years, the skin manifestations changed to wrinkled, redundant skin, and a skin biopsy specimen disclosed the thickening of collagen together with elastolysis in the dermis.22 This clinical and histologic manifestation was present in 3 of our patients. None of these patients had contractures. It is worth noting that these patients also had a reduced quality of life and reported pain, weakness, and restricted activity related to the affected areas.

The skin changes described for the patients with NSF, including thickened, hardened skin with hyperpigmentation and occasional flexion contractures, are characteristic of other fibrosing disorders. Our cases, however, demonstrated the clinical and histologic features that distinguish NSF from other similar fibrosing disorders, such as scleromyxedema and morphea/scleroderma. Our patients with NSF showed an acral distribution of the lesions and involvement of lower rather than upper limbs. Morphea/scleroderma usually begins on the trunk and subsequently spreads to involve the limbs. In classic scleromyxedema the head and neck are usually also involved.23 These areas were not affected in any of our patients.

We have seen extremely high levels of PIIIP in a few patients with NSF early in the disease. Under normal circumstances the collagen level remains constant except during active fibrosis. Among the different procollagens found in humans, PIIIP is one of the most abundant. Serum PIIIP level has been established to reflect the degree of tissue fibrosis in various fibrotic diseases and is used routinely to evaluate liver fibrosis in patients with psoriasis treated with methotrexate.2426 Elevated PIIIP levels have been reported in patients with renal failure; values have been moderate and without correlation to renal function.27,28 Accordingly, the range of PIIIP in our controls was higher than that seen in a normal population. The PIIIP range in our patients in the late stage of disease was significantly higher than that for controls. There appears to be a correlation between PIIIP level and severity of disease, with severe cases being associated with higher concentrations. This was not statistically evaluated. It may be that PIIIP is an indicative marker for still-active disease in patients with NSF.

The results of the DLQI questionnaire showed significantly impaired quality of life. Scores were similar to those with severe dermatologic diseases, such as psoriasis, indicating a considerable effect on patients' lives.20 Compared with controls, patients with NSF scored significantly higher on the DLQI. If data from the 2 severely affected hospitalized patients had been available, we expect the difference would have been even higher. The high scores are mainly due to restrictions in activity, with most problems reported in questions 3 (house activities), 5 (social/leisure activities), and 6 (sports).

In conclusion, this descriptive case series has demonstrated the cutaneous manifestations in NSF late in the disease to be different from those seen early in the disease and to have a varied presentation. In addition, the study has proved NSF to have a significant effect on the quality of life.

ARTICLE INFORMATION

Correspondence: Nannie Bangsgaard, MD, Department of Dermatology, University Hospital of Copenhagen Gentofte, Niels Andersens Vej 65, DK-2900 Hellerup, Denmark (Nanban01@geh.regionh.dk).

Accepted for Publication: May 16, 2008.

Author Contributions: Drs Bangsgaard, Marckmann, and Skov had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Bangsgaard, Marckmann, and Skov. Acquisition of data: Bangsgaard and Skov. Analysis and interpretation of data: All authors. Drafting of the manuscript: Bangsgaard and Skov. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Bangsgaard. Administrative, technical, and material support: Bangsgaard and Skov. Study supervision: Marckmann and Skov.

Financial Disclosure: None reported.

Additional Contributions: We are indebted to clinical photographers Fie Sløk and Helene Ryttersgaard.

REFERENCES

Cowper  SERobin  HSSteinberg  SMSu  LDGupta  SLeBroit  PE Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet 2000;356 (9234) 1000- 1001
PubMed
Marckmann  P Nephrogenic systemic fibrosis: epidemiology update. Curr Opin Nephrol Hypertens 2008;17 (3) 315- 319
PubMed
Mendoza  FAArtlett  CMSandorfi  NLatinis  KPiera-Velazquez  SJimenez  SA Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature. Semin Arthritis Rheum 2006;35 (4) 238- 249
PubMed
Ting  WWStone  MSMadison  KCKurtz  K Nephrogenic fibrosing dermopathy with systemic involvement. Arch Dermatol 2003;139 (7) 903- 906
PubMed
Grobner  T Gadolinium: a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2006;21 (4) 1104- 1108
PubMed
Marckmann  PSkov  LRossen  K  et al.  Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 2006;17 (9) 2359- 2362
PubMed
Khurana  ARunge  VMNarayana  MGreene  JFNickel  AE Nephrogenic systemic fibrosis: a review of 6 cases temporally related to gadodiamide injection (Omniscan). Invest Radiol 2007;42 (2) 139- 145
PubMed
Moreno-Romero  JASegura  SMascaró  JM  Jr  et al.  Nephrogenic systemic fibrosis: a case series suggesting gadolinium as a possible aetiological factor. Br J Dermatol 2007;157 (4) 783- 787
PubMed
Lauenstein  TCSalman  KMorreira  R  et al.  Nephrogenic systemic fibrosis: center case review. J Magn Reson Imaging 2007;26 (5) 1198- 1203
PubMed
High  WAAyers  RAChandler  JZito  GCowper  SE Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol 2007;56 (1) 21- 26
PubMed
Thakral  CAlhariri  JAbraham  JL Long-term retention of gadolinium in tissues from nephrogenic systemic fibrosis patient after multiple gadolinium-enhanced MRI scans: case report and implications. Contrast Media Mol Imaging 2007;2 (4) 199- 205
PubMed
Abraham  JLThakral  CSkov  LRossen  KMarckmann  P Dermal inorganic gadolinium concentrations: evidence for in vivo transmetallation and long-term persistence in nephrogenic systemic fibrosis. Br J Dermatol 2008;158 (2) 273- 280
PubMed
Marckmann  PSkov  LRossen  KThomsen  HS Clinical manifestation of gadodiamide-related nephrogenic systemic fibrosis. Clin Nephrol 2008;69 (3) 161- 168
PubMed
Khurram  MSkov  LRossen  KThomsen  HSMarckmann  P Nephrogenic systemic fibrosis: a serious iatrogenic disease of renal failure patients. Scand J Urol Nephrol 2007;41 (6) 565- 566
PubMed
Marckmann  PSkov  LRossen  KHeaf  JGThomsen  HS Case-control study of gadodiamide-related nephrogenic systemic fibrosis. Nephrol Dial Transplant 2007;22 (11) 3174- 3178
PubMed
Rydahl  CThomsen  HSMarckmann  P High prevalence of nephrogenic systemic fibrosis in chronic renal failure patients exposed to gadodiamide, a gadolinium-containing magnetic resonance contrast agent. Invest Radiol 2008;43 (2) 141- 144
PubMed
Mazzotti  EPicardi  ASampogna  FSera  FPasquini  PAbeni  DIDI Multipurpose Psoriasis Research on Vital Experimental Experiences Study Group, Sensitivity of the Dermatology Life Quality Index to clinical change in patients with psoriasis. Br J Dermatol 2003;149 (2) 318- 322
PubMed
Finlay  AYKhan  GK Dermatology Life Quality Index (DLQI): a simple practical measure for routine clinical use. Clin Exp Dermatol 1994;19 (3) 210- 216
PubMed
Shikiar  RBresnahan  BWStone  SPThompson  CKoo  JRevicki  DA Validity and reliability of patient reported outcomes used in psoriasis: results from two randomized clinical trials. Health Qual Life Outcomes2003153
PubMed doi:10.1186/1477-7525-1-53
Katugampola  RPHongbo  YFinlay  AY Clinical management decisions are related to the impact of psoriasis on patient-rated quality of life. Br J Dermatol 2005;152 (6) 1256- 1262
PubMed
Cowper  SESu  LDBhawan  JRobin  HSLeBoit  PE Nephrogenic fibrosing dermopathy. Am J Dermatopathol 2001;23 (5) 383- 393
PubMed
Glaich  ASMartinelli  PTMarkus  RFHsu  S Generalized elastolysis following nephrogenic fibrosing dermopathy. J Am Acad Dermatol 2005;53 (1) 174- 176
PubMed
Cokonis Georgakis  CDFalasca  GGeorgakis  AHeymann  WR Scleromyxedema. Clin Dermatol 2006;24 (6) 493- 497
PubMed
Frei  AZimmerman  AWeigand  K The N-terminal propeptide of collagen III in serum reflects activity and degree of fibrosis in patients with chronic liver disease. Hepatology 1984;4 (5) 830- 834
PubMed
Guseva  NGAnikina  NVMyllyla  R  et al.  Markers of collagen and basement membrane metabolism in sera of patients with progressive systemic sclerosis. Ann Rheum Dis 1991;50 (7) 481- 486
PubMed
Boffa  MJSmith  AChalmers  RJ  et al.  Serum type III procollagen aminopeptide for assessing liver damage in methotrexate-treated psoriatic patients. Br J Dermatol 1996;135 (4) 538- 544
PubMed
Soylemezoglu  OWild  GDalley  AJ  et al.  Urinary and serum type III collagen: markers of renal fibrosis Nephrol Dial Transplant 1997;12 (9) 1883- 1889
PubMed
Honkanen  EFröseth  BGrönhagen-Riska  C Serum hyaluronic acid and procollagen III amino terminal propeptide in chronic renal failure. Am J Nephrol 1991;11 (3) 201- 206
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Late skin manifestations of nephrogenic systemic fibrosis. A, Patient 9, with dermal fibrosis and hardening. B, Patient 16, with slack skin appearance.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Daily Life Quality Index (DLQI) scores in patients with nephrogenic systemic fibrosis (NSF) and controls. Horizontal lines indicate means. Patient numbers given with the data points correspond to patient numbers in the Table.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Clinical Characteristics of 17 Patients With Long-Lasting Nephrogenic Systemic Fibrosis According to Dermatologic Examination in October and November 2007

References

Cowper  SERobin  HSSteinberg  SMSu  LDGupta  SLeBroit  PE Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet 2000;356 (9234) 1000- 1001
PubMed
Marckmann  P Nephrogenic systemic fibrosis: epidemiology update. Curr Opin Nephrol Hypertens 2008;17 (3) 315- 319
PubMed
Mendoza  FAArtlett  CMSandorfi  NLatinis  KPiera-Velazquez  SJimenez  SA Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature. Semin Arthritis Rheum 2006;35 (4) 238- 249
PubMed
Ting  WWStone  MSMadison  KCKurtz  K Nephrogenic fibrosing dermopathy with systemic involvement. Arch Dermatol 2003;139 (7) 903- 906
PubMed
Grobner  T Gadolinium: a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2006;21 (4) 1104- 1108
PubMed
Marckmann  PSkov  LRossen  K  et al.  Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 2006;17 (9) 2359- 2362
PubMed
Khurana  ARunge  VMNarayana  MGreene  JFNickel  AE Nephrogenic systemic fibrosis: a review of 6 cases temporally related to gadodiamide injection (Omniscan). Invest Radiol 2007;42 (2) 139- 145
PubMed
Moreno-Romero  JASegura  SMascaró  JM  Jr  et al.  Nephrogenic systemic fibrosis: a case series suggesting gadolinium as a possible aetiological factor. Br J Dermatol 2007;157 (4) 783- 787
PubMed
Lauenstein  TCSalman  KMorreira  R  et al.  Nephrogenic systemic fibrosis: center case review. J Magn Reson Imaging 2007;26 (5) 1198- 1203
PubMed
High  WAAyers  RAChandler  JZito  GCowper  SE Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol 2007;56 (1) 21- 26
PubMed
Thakral  CAlhariri  JAbraham  JL Long-term retention of gadolinium in tissues from nephrogenic systemic fibrosis patient after multiple gadolinium-enhanced MRI scans: case report and implications. Contrast Media Mol Imaging 2007;2 (4) 199- 205
PubMed
Abraham  JLThakral  CSkov  LRossen  KMarckmann  P Dermal inorganic gadolinium concentrations: evidence for in vivo transmetallation and long-term persistence in nephrogenic systemic fibrosis. Br J Dermatol 2008;158 (2) 273- 280
PubMed
Marckmann  PSkov  LRossen  KThomsen  HS Clinical manifestation of gadodiamide-related nephrogenic systemic fibrosis. Clin Nephrol 2008;69 (3) 161- 168
PubMed
Khurram  MSkov  LRossen  KThomsen  HSMarckmann  P Nephrogenic systemic fibrosis: a serious iatrogenic disease of renal failure patients. Scand J Urol Nephrol 2007;41 (6) 565- 566
PubMed
Marckmann  PSkov  LRossen  KHeaf  JGThomsen  HS Case-control study of gadodiamide-related nephrogenic systemic fibrosis. Nephrol Dial Transplant 2007;22 (11) 3174- 3178
PubMed
Rydahl  CThomsen  HSMarckmann  P High prevalence of nephrogenic systemic fibrosis in chronic renal failure patients exposed to gadodiamide, a gadolinium-containing magnetic resonance contrast agent. Invest Radiol 2008;43 (2) 141- 144
PubMed
Mazzotti  EPicardi  ASampogna  FSera  FPasquini  PAbeni  DIDI Multipurpose Psoriasis Research on Vital Experimental Experiences Study Group, Sensitivity of the Dermatology Life Quality Index to clinical change in patients with psoriasis. Br J Dermatol 2003;149 (2) 318- 322
PubMed
Finlay  AYKhan  GK Dermatology Life Quality Index (DLQI): a simple practical measure for routine clinical use. Clin Exp Dermatol 1994;19 (3) 210- 216
PubMed
Shikiar  RBresnahan  BWStone  SPThompson  CKoo  JRevicki  DA Validity and reliability of patient reported outcomes used in psoriasis: results from two randomized clinical trials. Health Qual Life Outcomes2003153
PubMed doi:10.1186/1477-7525-1-53
Katugampola  RPHongbo  YFinlay  AY Clinical management decisions are related to the impact of psoriasis on patient-rated quality of life. Br J Dermatol 2005;152 (6) 1256- 1262
PubMed
Cowper  SESu  LDBhawan  JRobin  HSLeBoit  PE Nephrogenic fibrosing dermopathy. Am J Dermatopathol 2001;23 (5) 383- 393
PubMed
Glaich  ASMartinelli  PTMarkus  RFHsu  S Generalized elastolysis following nephrogenic fibrosing dermopathy. J Am Acad Dermatol 2005;53 (1) 174- 176
PubMed
Cokonis Georgakis  CDFalasca  GGeorgakis  AHeymann  WR Scleromyxedema. Clin Dermatol 2006;24 (6) 493- 497
PubMed
Frei  AZimmerman  AWeigand  K The N-terminal propeptide of collagen III in serum reflects activity and degree of fibrosis in patients with chronic liver disease. Hepatology 1984;4 (5) 830- 834
PubMed
Guseva  NGAnikina  NVMyllyla  R  et al.  Markers of collagen and basement membrane metabolism in sera of patients with progressive systemic sclerosis. Ann Rheum Dis 1991;50 (7) 481- 486
PubMed
Boffa  MJSmith  AChalmers  RJ  et al.  Serum type III procollagen aminopeptide for assessing liver damage in methotrexate-treated psoriatic patients. Br J Dermatol 1996;135 (4) 538- 544
PubMed
Soylemezoglu  OWild  GDalley  AJ  et al.  Urinary and serum type III collagen: markers of renal fibrosis Nephrol Dial Transplant 1997;12 (9) 1883- 1889
PubMed
Honkanen  EFröseth  BGrönhagen-Riska  C Serum hyaluronic acid and procollagen III amino terminal propeptide in chronic renal failure. Am J Nephrol 1991;11 (3) 201- 206
PubMed

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