Successful Treatment of Renal Amyloidosis Due to Familial Cold Autoinflammatory Syndrome Using an Interleukin 1 Receptor Antagonist

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Title:Successful treatment of renal amyloidosis due to familial cold autoinflammatory syndrome usingan interleukin 1 receptor antagonist

Author:Thornton, B DHoffman, H MBhat, ADon, Burl R MD, University of California, Davis

Publication Date:03-01-2007

Publication Info:Postprints, UC Davis

Permalink:http://escholarship.org/uc/item/9mt371q2

Additional Info:The published version of this article is available at: http://www.elsevier.com/wps/product/cws_home/623276

Keywords:amyloidosis, anakinra, familial cold autoinflammatory syndrome, interleukin 1

Abstract:Familial cold autoinflammatory syndrome (FCAS) is an autosomal dominant disordercharacterized by episodic fever, arthralgias, conjunctivitis, and rash triggered by cold exposure.FCAS is rarely associated with progressive renal insufficiency caused by renal amyloidosis.The genetic defect in patients with this disorder is caused by a mutation in the gene encodingthe protein cryopyrin, leading to uninhibited activation of systemic inflammation through specificcellular signaling with increased production of a number of key cytokines, including interleukin1. We describe the successful treatment of a patient with renal amyloidosis caused by FCAS byusing a novel interleukin 1-receptor antagonist. Use of specific anticytokine therapy may be a newparadigm in the treatment of patients with renal amyloidosis caused by systemic inflammatorydiseases.

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Successful Treatment of Renal Amyloidosis due to FamilialCold Autoinflammatory Syndrome Using an Interleukin 1

Receptor Antagonist

Brian D. Thornton, MD, Hal M. Hoffman, MD, Adarsh Bhat, MD, and Burl R. Don, MD

Familial cold autoinflammatory syndrome (FCAS) is an autosomal dominant disorder characterizedby episodic fever, arthralgias, conjunctivitis, and rash triggered by cold exposure. FCAS rarely wasassociated with progressive renal insufficiency caused by renal amyloidosis. The genetic defect inpatients with this disorder is caused by a mutation in the gene encoding the protein cryopyrin, leading touninhibited activation of systemic inflammation through specific cellular signaling with increasedproduction of a number of key cytokines, including interleukin 1. We describe the successful treatment ofa patient with renal amyloidosis caused by FCAS by using a novel interleukin 1–receptor antagonist.Use of specific anticytokine therapy may be a new paradigm in the treatment of patients with renalamyloidosis caused by systemic inflammatory diseases.Am J Kidney Dis xx:xxx. © 2007 by the National Kidney Foundation, Inc.

INDEX WORDS: Amyloidosis; anakinra; familial cold autoinflammatory syndrome; interleukin 1.

Familial Cold Autoinflammatory Syndrome(FCAS) is an autosomal dominant inflam-

matory disease categorized by recurrent intermit-tent episodes of rash, fever, arthralgia, and con-junctivitis after generalized exposure to cold.Attacks usually occur 1 to 3 hours after coldexposure and last less than 24 hours. The causeof FCAS is a defect in a protein termed cryopyrinthat results from a mutation in the CIAS1 gene(also known as NALP3/PYPAF1) localized onchromosome 1q44.1 Defective cryopyrin causesenhanced expression of a number of key cyto-kines, including interleukin 1 (IL-1), leading tosystemic inflammation. Muckle-Wells syndromeand chronic infantile neurological cutaneous ar-ticular syndrome are 2 inflammatory conditionsalso resulting from mutations in CIAS1. Al-though occurring in up to a third of patients withMuckle-Wells syndrome, only a small percent-age of patients with FCAS develop progressivechronic kidney disease secondary to AA renalamyloidosis. The main therapy for patients withFCAS has been supportive care with nonsteroi-dal anti-inflammatory drugs or corticosteroidsfor local symptomatic relief, but previously, therewas no definitive treatment for the disease. Re-cently, several patients with CIAS1 genetic muta-tions were treated with anakinra (Kineret; Am-gen USA), an IL-1 receptor antagonist resultingin significant clinical attenuation and preventionof inflammatory episodes.2-4 Characteristic up-regulation of inflammatory markers also was

prevented in patients treated with anakinra.3 Wepresent a patient with FCAS complicated byrenal amyloidosis and progressive renal insuffi-ciency treated with anakinra who had a markeddecrease in proteinuria and attenuation of progres-sive renal failure.

CASE REPORT

A 61-year-old white woman with FCAS was referred tothe Nephrology Service in June 2002 at the University ofCalifornia Davis Medical Center for evaluation of protein-uria. Pertinent past medical history included an episode ofpoststreptococcal glomerulonephritis at age 14 years, hyper-tension with left ventricular hypertrophy, long-term nonste-roidal anti-inflammatory use of oxaprozin (Daypro; ParPharmaceutical USA), anemia, migraine headaches, andhypothyroidism. Since birth, she had experienced typicalFCAS symptoms of fever, rash, malaise, conjunctivitis, andarthralgias after cold exposure. FCAS diagnosis was con-firmed by genetic testing performed at the University of

From the Division of Nephrology, University of CaliforniaDavis Medical Center; and Division of Rheumatology, Allergyand Immunology and Department of Pediatrics, University ofCalifornia at San Diego School of Medicine, La Jolla, CA.

Received June 6, 2006; accepted in revised form October20, 2006.

Support: None. Potential conflicts of interest: None.Address reprint requests to Burl R. Don, MD, University

of California Davis Medical Center, 4150 V St, Ste 3500,Sacramento, CA 95817. E-mail: [email protected]

© 2007 by the National Kidney Foundation, Inc.0272-6386/07/xx0x-0001$32.00/0doi:10.1053/j.ajkd.2006.10.026

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California, San Diego, showing an L353P mutation. Numer-ous family members were afflicted with the same condition(Fig 1), some of whom developed stage 5 chronic kidneydisease.

One month before referral to the nephrology service, thenonsteroidal anti-inflammatory drug was discontinued. Shepreviously was maintained on 25 mg of the angiotensinreceptor blocker losartan (Cozaar; Merck & Co USA) forhypertension. Initial physical examination was significantfor hypertension, with blood pressure of 162/82 mm Hg, 1�

bilateral lower-extremity pitting edema, and an induratedpapular rash on both arms. Urinalysis was notable fordipstick proteinuria with protein of 300 mg/dL with blandurinary sediment on microscopic examination. Subsequentserological testing included hepatitis B surface antigen,hepatitis C antibody, antinuclear antibody, antineutrophilcytoplasmic autoantibody, human immunodeficiency vi-rus, complement level, cryoglobulins, and both serum andurine protein electrophoresis. All test results were unre-markable, except for urine electrophoresis, which showedan abnormal band in the beta region quantified at 7 mg/dL.Follow-up immunofixation testing was negative for a mono-clonal protein.

The patient initially was treated with colchicine based onits anti-inflammatory effects in patients with familial Medi-terranean fever. Losartan dose was titrated to 100 mg/d, andthe patient was started on paroxetine (Paxil; GalaxoSmithK-line Inc USA) because another family member noted adecrease in symptomatic inflammatory episodes while admin-istered this medication. Initially, the patient did not consentto a renal biopsy. Treatment with colchicine did not alter herproteinuria and was tolerated poorly because of worseningof her migraine headaches. Paroxetine did not decrease thefrequency of her symptoms. Three months after the initialconsultation, the patient underwent renal biopsy because of

worsening proteinuria and an increase in creatinine levelfrom 0.9 mg/dL (80 �mol/L) to 1.2 mg/dL (106 �mol/L).Renal biopsy was definitive for a diagnosis of amyloidosis(Fig 2). Steroid therapy was offered to the patient, but declinedbecause of the side-effect profile. During the next 9 months, thepatient’s proteinuria worsened to protein of almost 6 g/d, andserum creatinine level increased to 1.3 mg/dL (115 �mol/L).

In March 2003, after submitting a request to the Univer-sity of California Davis Medical Center Institutional ReviewBoard, approval was granted for compassionate use of therecombinant human IL-1 receptor antagonist anakinra forthe patient based on preliminary data for its use in patientswith Muckle-Wells syndrome.2 In June 2003, treatment withanakinra was started at a dose of 100 mg/d subcutaneously,but was decreased to 100 mg every other day because of thedevelopment of leukopenia (white blood cell count, 3.1 �103/�L [3.1 � 109/L]). During the next 12 months, protein-uria decreased to protein less than 1 g/d, serum creatininelevel remained stable at 1.2 mg/dL (106 �mol/L; Fig 3), andwhite blood cell count has remained within the normalrange. Her lifelong symptoms of FCAS improved signifi-cantly within days of starting therapy and resolved com-pletely with continued therapy.

DISCUSSION

FCAS originally was described in 1940,5 and,until recently, a molecular understanding of themechanism of disease was lacking. This disorderis exceptional enough that it was not until 2001that a sizeable population was studied systemati-cally to define disease phenotype and generateproposed diagnostic criteria (Table 1).6 A studyof 6 families consisting of 45 subjects showed

Figure 1. Family pedigreeshows FCAS-affected familymembers and those receivinganakinra therapy. The patientdescribed in this case report isnoted.

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key phenotypic characteristics, including age ofonset within the first 6 months of life and recur-rent fevers, chills, arthralgias, conjunctivitis, andrash. Although more commonly seen in patientswith Muckle-Wells syndrome, amyloidosis wasdescribed in a few families with FCAS.

Typical laboratory features associated with FCASinclude leukocytosis7 and elevated erythrocyte sedi-mentation rate. As with other inflammatory condi-tions, levels of acute-phase reactants, includingC-reactive protein and haptoglobin, may be in-creased.8 Patients with FCAS also show a largeincrease in serum IL-6 levels after cold challenge.3

Skin biopsy shows a dense polymorphonuclearleukocytic infiltrate without evidence of histaminerelease.9 Historically, there have been few effectivetreatments for patients with FCAS, although ana-bolic steroids, corticosteroids, and colchicine, havebeen used with limited success.7,10,11

Hoffman et al1 identified the CIAS1 gene onchromosome 1q44 as the gene responsible for bothFCAS and Muckle-Wells syndrome. More than 40CIAS1 mutations were reported in patients withFCAS, Muckle-Wells syndrome, and chronic infan-tile neurological cutaneous articular syndrome. Cen-tral to each of these disorders is uninhibited activa-

Figure 2. Photomicrograph of the patient’s renal biopsy viewed under immunofluorescence microscopy stained withCongo red. Positive immunofluorescence is noted in 2 glomeruli and arterioles, consistent with the presence of amyloiddeposits. (Original magnification �400.)

Figure 3. Spot urine pro-tein-creatinine ratios beforeand after treatment with anak-inra. Note the marked decreasein proteinuria associated withanakinra therapy.

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tion of the inflammatory cascade through specificcellular signaling (Fig 4). CIAS1 encodes a proteintermed cryopyrin. Cryopyrin interacts with an-other protein termed apoptosis-associated speck-like with a caspase recruitment domain proteinthrough PYRIN-PYRIN interactions in a com-plex known as the inflammasome. The PYRINdomain is a protein motif identified in proteinsinvolved in apoptotic and inflammatory path-ways.11,12 Activation of the inflammasome by anumber of infectious and noninfectious triggersleads to the cleavage of procaspase to activatedcaspase 1 and the eventual cleavage of pro–IL-IB,

allowing for the release of active IL-1B.13 IL-1Bthen is available to bind to the IL-1 receptor andfurther mediate inflammatory cytokine produc-tion.14 In vitro evidence suggests that the inflamma-some activates nuclear factor-�B directly, leadingto the production of a number of proinflammatorycytokines, including IL-6 and IL-8. Additional invitro evidence suggests that mutations in cryopyrincause a constitutively active or hyperresponsiveinflammasome, resulting in increased cytokine re-lease and systemic inflammatory symptoms.

The CIAS1 mutation L353P was identified inapproximately 90% of reported North Americanpatients with FCAS and is caused by a commonancestor. The family described in this report hasthe same mutation, but is not related to the otherfamilies. Whereas several members of the familydescribed in this report developed renal disease,presumably caused by amyloidosis, this compli-cation was not described in other L353P fami-lies. In addition, only 1 sister of a set of identicaltwins in this family developed amyloidosis, reaf-firming the complex cause of amyloidosis.

Table 1. Proposed Diagnostic Criteria for FCAS

1. Recurrent intermittent episodes of fever and rash thatprimarily follow natural, experimental, or both types ofgeneralized cold exposures

2. Autosomal dominant pattern of disease inheritance3. Age of onset �6 mo4. Duration of most attacks �24 h5. Presences of conjunctivitis associated with attacks6. Absence of deafness, periorbital edema,

lymphadenopathy, and serositis

Figure 4. Mutated cryopyrin (denoted by red X) interacts with ASC through PYRIN-PYRIN domain interactions free ofregulatory control as a result of the mutation. This results in amplified activation of downstream mediators (red arrows)through the normal signaling cascade (black arrows) through procaspase 1 and pro–IL-1�. Anakinra effectively competeswith IL-1� for the IL-1 receptor, thereby blocking release of the inflammatory cytokines that lead to typical FCAS symptoms.Abbreviations: PYD, PYRIN domain; ASC, apoptosis associated speck like protein with a caspase recruitment domain;NF-�B, nuclear factor-�B; IL-1Ra, IL-1 receptor antagonist. (Adapted from Lancet, volume number 364, Prevention ofcold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist,Hoffman HM, Rosengren S, Boyle DL, et al, pp 1779-1785, copyright 2004, with permission from The Lancet.)

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Anakinra is a recombinant IL-1 receptor antago-nist protein currently approved for use in patientswith rheumatoid arthritis for whom treatment hasfailed with 1 or more other disease-modifying anti-rheumatic drugs. Preliminary results for anakinrause in patients with rheumatoid arthritis are en-couraging; however, its efficacy in patients withdiseases caused by mutations in CIAS1 is aston-ishing. In almost every case reported, there isnear resolution of disease symptoms within 24 to48 hours of the initial injection.2,3 Although rare,the hereditary periodic fever syndromes providea unique opportunity to study inflammatory path-ways. This case report exemplifies the significantrole for chronic inflammation in the developmentof AA amyloidosis and shows a unique disease-specific therapy previously not available. Thispatient has now received anakinra for 3 years,and to our knowledge, this is the longest treat-ment duration known. More importantly, thispatient has gained a quality of life she neverthought possible. Performing a repeated renalbiopsy had been considered to assess histologicalchange after anakinra therapy, but given the risksof renal biopsy and her clinical improvement, itwas considered not to be clinically indicated.Follow-up echocardiogram confirmed persistentleft ventricular hypertrophy without evidence ofcardiac amyloidosis. The successful treatment ofrenal amyloidosis through blockade of IL-1 showsthat specific anticytokine treatment may providedirected therapies for other conditions associatedwith chronic systemic inflammation.

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3. Hoffman HM, Rosengren S, Boyle DL, et al: Preven-tion of cold-associated acute inflammation in familial coldautoinflammatory syndrome by interleukin-1 receptor antag-onist. Lancet 364:1779-1785, 2004

4. Hawkins PN, Lachmann HJ, Aganna E, McDermottMF: Spectrum of clinical features in Muckle-Wells syn-drome and response to anakinra. Arthritis Rheum 50:607-612, 2004

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6. Hoffman HM, Wanderer AA, Broide DH: Familialcold autoinflammatory syndrome: Phenotype and genotypeof an autosomal dominant periodic fever. J Allergy ClinImmunol 108:615-620, 2001

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9. Tindall JP, Beeker SK, Rosse WF: Familial cold urti-caria. A generalized reaction involving leukocytosis. ArchIntern Med 124:129-134, 1969

10. Ormerod AD, Smart L, Reid TM, Milford-Ward A:Familial cold urticaria. Investigation of a family and re-sponse to stanozolol. Arch Dermatol 129:343-346, 1993

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