Secondary amyloidosis complicating psoriasis

Journal of the American Academy of Dermatology Volume 32, Number 3

Wittenberg,Oursler, and Peters

skin from immunccompromisedrenal transplant patients. Arch Dermatol 1993;129:1585-8. 50. Demetrick DJ, Inoue M, Lester WM, et al. Human papillomavirus type 16 associatedwith oral squamouscarcinoma in a cardiac transplant recipient. Cancer 1990; 66:1726-31. 51. Sontheimer RD, BergstresserPR, Gammas P, et al. Perturbation of epidermal Langerhans cells in immunosup

pressedhuman renal allograft recipients.Transplantation 1984;37:168-74. 52. McGregor JM, Reddi G, MacDonald D, et al. HLA-Al 1 in renal allograft recipientswith skin cancer.J Invest Dermatol 1991;98:261-2. 53. CzarneckiD, Watkins F, Leahy S, et al. Skin cancersand HLA frequenciesin renal transplant recipients.Dermatology 1992;185:9-11.

Secondary amyloidosis complicating psoriasis Gregory P. Wittenberg,

MD, Judith R. Oursler, MD, and Margot

S. Peters, MD

Rochester, Minnesota Background: Amyloidosis is a heterogeneous group of disorders characterized by extracellular deposition of fibrillar protein. Secondary amyloidosis occurs in patients with chronic infectious or inflammatory processes. Only 18 cases of secondary amyloidosis complicating

psoriasis have been reported. Objective: We characterized secondary amyloidosis complicating psoriasis. Methods: We reviewed all cases of coexisting psoriasis and amyloidosis seen at the Mayo Clinic from 1950 to 1992. The clinical characteristics were summarized, and the literature was reviewed. Results: There were 28 casesof coexistent disease, and in five of these psoriasis was the only inflammatory condition preceding the development of secondary amyloidosis. Histopathologic confirmation with Congo red staining was available in four cases, and immunohistochemical confirmation of the characteristic amyloid A subtype was performed in two.

Conhsiont Follow-up of four patients supports the view that amyloidosis associated with psoriasis is an aggressive disease that may be fatal. (J AM ACAD DERMATOL 1995;32:465-8.) Amyloidosis is defined as the extracellular deposition of amyloid, a protein composed of fine, nonbranching fibrils that aggregate into P-pleated sheets. Amyloidosis has been divided into subtypes on the basis of biochemical and clinical characteristics. Some clinical subtypes include primary amyloidosis, heredofamilial amyloidosis, local amyloidosis, senile amyloidosis, and amyloidosis associated with long-term hemodialysis. The two most common biochemical subtypes are amyloid A (AA), found in secondary and some familial forms of the disorder, and amyloid L, found in primary and multiple myeloma-associated amyloidosis. ’ From the Department dation. Accepted Reprint Mayo Copyright

of Dermatology,

for publication

Nov.

Mayo

Clinic

Foun-

7, 1994.

requests: M. S. Peters, MD, Department Clinic, 200 First St. SW, Rochester, MN @ 1995 by the American

0190-9622/95 $3.00+0

and Mayo

Academy

16/l/61867

of Dermatology, 55905.

of Dermatology,

Inc.

Secondary amyloidosis is commonly associated with a variety of chronic inflammatory disorders such as rheumatoid arthritis, ankylosing spondylitis, and osteomyelitis. It has been only rarely reported to be associated with psoriasis. AA can be isolated from secondary amyloid. This is a unique, insoluble protein with a molecular weight of approximately 8.5 kd. It is made up of 76 amino acid residues arranged in a single chain. The putative precursor to AA is an antigenically related protein, serum AA (SAA). This is a normal soluble serum component that behaves as an acute-phase reactant. SAA associates with the high-density lipoprotein-3 subclass of serum lipoproteins and is therefore sometimes referred to as apo-SAA. It is synthesized and released by hepatocytes under the control of interleukin a. The precise regulation of the conversion of SAA to the insoluble AA protein of amyloidosis is not understood. However, the induction of AA amyloidosis is thought to be a multifactorial process influenced by 465

Journal of the American Academy of Dermatology March 1995

466 Wittenberg,Oursler, and Peters

Fig. 1. Glomerulus, showing positive immunohistochemical

staining for AA protein.

(X260.)

Table I. Clinical characteristicsof patientswith psoriasis-relatedamyloidosis

Age(~4at Patient

No.

DX/SeX

1

60/M

2 3 4

69/M 68/M 62/M

5

74/F

CRF, Chronic *Duration of TFollow-up 3 *Follow-up 5

LhUXti0Il*

(yr)

10

30 2 10

6

Arthltis

Yes

Yes Yes

Pustules

No

No No

No

No

Yes

Yes

renal failure; Dx, diagnosis. psoriasis before diagnosis of amyloidosis. yeras after diagnosis of amyloidosis showed years after diagnosis of amyloidosis showed

some progression some progression

the type of inflammatory stimulation, the nature of the SAA isotope,and the geneticbackgroundof the patient.2 Eighteencasesof secondaryamyloidosisrelated to psoriasis havebeen described.3-15 We report five new casesof secondaryamyloidosisassociatedwith psoriasisand comparethem with thosecasespreviously described. METHODS All casesof coexistent amyloidosis and psoriasis seen at the Mayo Clinic from 1950 to 1992 were reviewed. Of the 28 cases found, those associated with myeloma or with other possible causes of secondary amyloidosis such as chronic inflammatory disease were excluded. Of the nine cases that remained, four were excluded: two because amyloid was localized only to the carpal tunnel region, one because amyloidosis presented as localized disease

Outcome

CRFt CRF; no follow-up Died 9 mo after Dx; CRF Died 3 yr after Dx; cause unspecified CRF$

Site of amyloid

Kidney Kidney, rectum Kidney, rectum Kidney Kidney, fat pad

of chronic renal failure, but the patient was not dialysis of CRF, but patient was not dialysis dependent.

dependent.

limited only to a vocal cord tumor, and one because amyloid was found only in the bladder. Of the remaining five cases,four were diagnosed as amyloidosis documented by biopsy and in the fifth case the diagnosis was suspected clinically. The clinical and laboratory features of these five cases were compared. Immunohistochemical staining techniques were used to determine the biochemical type of amyloid in the cases in which biopsy specimens were available (2 of 5). A battery of amyloid stains was used on paraffin-embedded tissue, with antibodies against albumin, K free light chain, X free light chain, and AA (Dako, Carpinteria, Calif.), serum amyloid P (Calbiochem, La Jolla, Calif.), and prealbumin and ,&uicroglobulin (Boehringer-Mannheim, Indianapolis, Ind.). Serum protein electrophoresis, urine protein electrophoresis, and bone marrow biopsy results were used to confirm the secondary nature of the amyloid when tissue was not available for immunohistochemical study.

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467

Table II. Casereportsof psoriasis-associated amyloidosis Study (reference No.)

3 4 (3 patients)

Age (yr) at diagnosis .9.X

34/M

Duration* (yr)

0.5

Arthritis

Pnstnles

Yes

No

NA/NA NA/NA NA/NA 63/F 37t/M

NA NA NA 50 6

NA NA NA Yes Yes

NA NA NA No Yes

10 11

54t/M 29”r/M 44/F NA/M NA/NA NA/NA 50/M 35/M

2 NA 26 NA NA NA 14 17

No Yes No Yes Yes Yes Yes Yes

Yes No Yes NA NA NA No No

12

64/F

16

Yes

Yes

13 14

59/M 32/M

39 25

No Yes

No No

15

23/F

11

YeS

No

5 6 (2 patients) 7 8 9 (3 patients)

Outcome

Died;CRF 8 mo after Dx of amyloidosis NA NA NA NA Died,ARF andCRF 8 mo after Dx of proteinuria Died;diarrhea Died;CRF NA NA NA NA NA Stableat 6 mo after Dx of amyloidosis Died;nephroticsyndrome6 mo afterDx of amyloidosis Died;CRF Stable20 mo afterDx of amyloidosis Improvedwith etretinateand PUVA

Acute renal failure; CRF, chronic renal failure; Dx, diagnosis; NA, not available. *Duration of psoriasis before diagnosis of amyloidosis. tAmyloidosis diagnosed at autopsy.

ARF,

&ESULTS

Five patients were believed to have secondary amyloidosisrelated to psoriasis(Table I). Histopathologic confirmation by localization of Congo red in renal or rectal tissue was availablein four casesand by immunohistochemicalstainingin two; in one, secondaryamyloidosiscausedby psoriasis wassuspectedclinically. In patients2 and 5 staining for AA waspositive,confirming the presenceof secondary amyloidosis(Fig. 1). Tissue from patient 2 also was positive for amyloid P. In both patients stains for albumin, K free light chain, X free light chain, prealbumin,and ,&-microglobulin werenegative. Serum protein electrophoresis,urine protein electrophoresis,andbonemarrow biopsyconfirmed the secondarynature of the amyloidosisin patients 1, 3, and 4. The clinical characteristicsof the five patientsare summarizedin Table I. The averageageat diagnosis of amyloidosiswas 66.6 years (range,60 to 74 years).Four of the patientsweremen. The average duration of psoriasisbeforethe diagnosisof amyloi-

dosiswas 11.6years(range,2 to 30 years).Four of five patientshad associatedpsoriatic arthropathy, and three had significant deformities.Only one of the five patientshad had pustular psoriasis.Extent of psoriaticinvolvementtendedto be severe;in three of the five it wasdescribedaseither“generalized”or involvingmore than 80%of the bodysurfaceareaat somepoint during the courseof the disorder. The distribution of the amyloid was often extensive,but most oftenit involvedthe kidneysandgastrointestinaltract. Follow-upwasavailablein four of the five patients.Two died within 3 yearsof the diagnosisof amyloidosis.One of thesedeathswas directly related to the amyloidosis.Follow-up was availablefor 3 and 5 yearsin the remainingpatients. Each had someprogressionof chronicrenal insufficiency,but neither becamedialysis dependent. DISCUSSION The first caseof secondaryamyloidosisassociated with psoriasiswasdescribedby Moise et a1.3in 1965. Only 18casesof psoriasiswith concomitantamyloi-

468

Wittenberg,

Oursler, and Peters

dosishad beenreported.3-‘5The clinical featuresof thesecasesaresummarizedin Table II. Twelve patients had psoriatic arthritis, and four had pustular psoriasis.6$‘7’ 2 The increasedinflammation associated with psoriatic arthropathyor pustular disease presumablyexplainsthe increasedincidenceof secondaryamyloidosisin thesesettings,becausechronic inflammatory diseaseis thought to be pathogenic. This study describesthe largestseriesof patients with psoriasisandassociatedamyloidosisto date.Of our five patients,four had psoriaticarthritis andone had pustularpsoriasisandconcomitantpsoriaticarthropathy.In all casesthe diagnosisof psoriasisprecededthat of amyloidosisby 2 to 30 years (mean, 11.6years) in our patientsand from 2 to 50 years (mean, 18.8years)in thosein the literature (information availablein 11of 18 cases). More than 50%of the 18patientsin the literature had significantrenalamyloidosis,andsevenshowed gastrointestinaldysfunction(information available in 12 of 18 cases).3-15 All our patients had renal amyloidosis,but the extent of gastrointestinalinvolvementwasnot documented,becauseno patients hadgastrointestinalsymptoms.From thesedata it is clearthat renal andgastrointestinalimpairment can be severein patients with psoriasisand associated amyloidosis.Kidney and liver function should be monitored,especiallyin patientswith severepsoriasis and arthropathy.An ideal opportunity for such screeningis in the courseof methotrexatetherapy, when evidenceof amyloidosiscan be sought with specialstainsduring routine liver biopsies. The follow-up data found in the literature are summarized in Table II. Of the nine patients for whom follow-upinformation wasprovided,six died, and five of thesedeathswerecausedby amyloid-inducedkidney failure. Of the deathscausedby amyloid-inducedkidney failure, two occurredwithin 8 months of the diagnosisof amyloidosisand one af-

Journal of the American Academy of Dermatology March 1995

ter an unspecifiedinterval;two patientshad amyloidosisdiagnosedat autopsy.Only one patient was thoughtto haveimproved,and shehad beentreated with etretinateand PUVA.” This courseis similar to that seenin our patients,amongwhom two of the five patients died and the remaining three had chronic renal insufficiency. REFERENCES

1. Husby G, SlettenK. Chemical and clinicalclassificationof amyloidosis1985. Stand J Immunol 1986;23:253-65. 2. KisilevskyR. From arthritis to Alzheimer’sdisease:current conceptsof the pathogen&s of amyloidosis.Can J Physiol Pharmacol 1987;65:1805-15. 3. Moise R, Asch L, Imbs JL. Rhumatisme psoriasiqueet amylose.Strasbourg Med 1965;16:245-53. 4. Reed WB, Wright V. Psoriaticarthritis. In: Hill AGS, ed. Modern trends in rheumatology. London: Butterworth, 1966:375-83. 5. FergusonA, Downie WW. Gastrointestinalamyloidosisin psoriatic arthritis. Ann Rheum Dis 1968;27:245-8. 6. Berger PA. Amyloidosis-a complication of pustular psoriasis.Br Med J 1969;2:351-3. 7. Brownstein MH, Helwig EB. Systemicamyloidosiscomplicating dermatoses.Arch Dermatol 1970;102:1-7. 8. Mackie RM, Burton J. Pustular psoriasisin association with renal amyloidosis.Br J Dermatol 1974;90:567-71. 9. Lambert JR, Ansell BM, StephensonE, et al. Psoriaticarthritis in childhood. Clin Rheum Dis 1976;2:339-52. 10. Qureshi MSA, Sandle GI, Kelly JK, et al. Amyloidosis complicating psoriatic arthritis. Br Med J 1977;2:302. 11. Willoughby CP, Bennett MK, BanerjiA, et al. Gastrointestinal amyloidosiscomplicatingpsoriaticarthropathy. Postgrad Med J 1981;57:663-7. 12. David M, Abraham D, Weinberger A, et al. Generalized pustular psoriasis,psoriatic arthritis, and nephrotic syndrome associatedwith systemicamyloidosis.Dermatologica 1982;165:168-71. 13. Amir-Ansari B, JoekesAM, ParkinsonMC. Amyloidosis complicating psoriasis.Postgrad Med J 1982;58:364-6. 14. Sharma SC, Mortimer G, Kennedy S, et al. Secondary amyloidosisaffecting the skin in arthropathic psoriasis.Br J Dermatol 1983;108:205-10. 15. Ekenstam E, MichaelssonG, Hallgren R. Responseof secondary amyloidosisin psoriasisto treatment with etretinate and ultraviolet light. Br Med J 1986;293:733-4.