A 52 year old female with CKD

and “vasculitis”: a case report

and literature review of mixed

cryoglobulinemia

Case

• Presents to establish care

• Vasculitis - undetermined type

• - generalized malaise, arthralgias, rash,

• - proteinuria and impaired kidney function with pregnancy 20y ago (2nd pregnancy; 1st pregnancy uncomplicated)

• - caused HTN (urgency)

• - biopsy in Hungary many y ago inconclusive

• Years later developed HCV, but she identified no risk factors other than blood transfusions (in Eastern Europe) as a child

• Was advised by hepatologist (Dr. Bedford) to wait for HCV treatment until new drugs become available

Case

• - liver biopsy 5/2013 "pretty good" - no significant damage (verbal report per patient)

• -BMBX 5/2013 "abnormal protein"

• For a period of 12 mo, she took 12-14 per day of NSAID pills; continues to use these sometimes for pain

• HTN x whole life

• Hired by UCLA few mo ago, but a few weeks ago developed severe HTN

• Started on amlodipine recently, then developed weight gain and fluid retention (puffy eyes, puffy stomach, swollen ankles)

• BP at PMD was 130/70 2d ago

• Home BP: 120-140/70-80

Case

• Past Medical History

• • H/O vasculitis

• • Hypertension

• • Hepatitis C virus infection

• • MGUS (monoclonal gammopathy of unknown significance)

• • Low back pain

• • Chronic kidney disease (CKD), stage III (moderate)

• Former smoker, 20 pack years

Case

• Current outpatient prescriptions:

• amlodipine (NORVASC) 5 mg tablet daily

• bisoprolol (ZEBETA) 5 mg by mouth daily

• fluoxetine 10 mg tablet by mouth daily

• hydrochlorothiazide 25 mg by mouth daily

• Lisinopril tablet 20 mg by mouth daily

Exam • BP: 159/90; Pulse: 93; Temp: 99.2 °F (37.3 °C); SpO2: 99%

• General: No apparent distress, well-appearing

• Eyes: Anicteric, pupils equally round and reactive to light

• Mouth/Oral: Oropharynx clear without lesions, good dentition

• Neck: supple, trachea midline, no thyromegaly

• Heme: no bleeding or bruising; no lymphadenopathy in neck, axilla, or groin

• Chest: Normal work of breathing, clear to auscultation

• Coronary: regular, dual heart sounds with no added sounds, Jugular venous pressure normal

• Abdomen: Normoactive, soft, nontender, nondistended, no masses or hepatosplenomegaly

• Extremities: no clubbing, cyanosis; trace edema; 2+ posterior tibial pulses

• Skin: warm and dry, no rash; darkened appearance to skin on legs reminiscent of a prior vasculitic rash; no stigmata of liver dz

• Neuro: alert, moving all extremities, normal gait, no tremor

Lab testing from 7/25/2013 at St

Johns

• Cr 1.9, K 4.7, tCO2 19, Na 139, Ca 9.0,

Hb 12.4

• ANA neg, ANCA neg, ESR 5, cryocrit

negative

• ALT 43, AST 47

Intial Plan

• Avoid NSAIDS

• Change HCTZ to lasix for the edema

• Check CKD labs in 1 week (to enable checking K for lasix also)

• Cont other meds

• Obtain records of renal US; bone marrow biopsy; note from hematologist re. Type of paraprotein; and liver biopsy if possible; and hepatology note regarding activity of HCV.

Intial “CKD Lab” testing

• WBC 5.1, Hb 11.4, PLT 400, MCV 86

• Na 137, K 4.9, Cl 107, tCO2 20, BUN 47,

Cr 1.6 (eGFR 34)

• UA: 1+ blood, 30 RBC, 23 WBC, 2+ leuk

est, 2+ protein, prot/cr ratio 0.87; ACR

590; iCa 1.06, phos 5.0, vitD 14, PTH 67

Case continues:

• 2 weeks later telephone call: increased polyarthralgia, skin rash; I advised her to followup with me and called in a medrol pack in the mean time

• 2 weeks after that: to ER for hypertensive urgency BP about 220-230/120-110 on multiple readings; given clonidine, norvasc, and an antibiotic for asymptomatic pyuria

Next clinic appointment 6 weeks

after initial presentation • 1 week after HTN urgency she presents for clinic followup. Reports

that she didn’t followup with me sooner because she was avoiding doing to doctors due to concerns about losing her new job with UCLA. She plans to quit her job and considers transitioning to her husband’s Kaiser insurance. She did not remember to get any outside records.

• Exam showed: – Face- mildly swollen;

– Abdomen: Normoactive, soft, nontender, nondistended, no masses or hepatosplenomegaly

– Extremities: no edema

– MSK: no synovitis. Chronic large 2nd MCP joint. L elbow swelling where recent IV was placed.

– Skin: warm and dry; a few red areas; brown discoloration of the BLE

2nd set of labs – took about 2

weeks to come back • ER: Cr 1.4, BUN 48; UA: 1+ blood, 133 RBC, 310 WBC, 3+ protein

• My office 1 week after ER: – Na 133, K 4.8, Cl 104, tCO2 22, BUN 46, Cr 1.6, Gluc 89, Ca 7.9, M

1.4, P 4.9, ESR 46, vitD 14

– UA: 49 RBC, 6 WBC, 2+ protein, prot/creat ratio 4.4

– GN negative: ANCA, ANA, dsDNA, HBV SAG and SAB, HIV, GBM; C3 108, C4 41 (both normal)

– Cryocrit positive 5%; RF >6000

– SPEP/UPEP/IFE: monoclonal kappa chain

– Urine spot light chain: elevated kappa/lambda ratio

Case - continued

2 weeks after the labs are resulted, there is still no kidney ultrasound, no rheum

eval, she returns to my office feeling better.

Note:

-Will plan for admission to treat cryoglobulinemic vasculitis, given uncertain

outpatient followup and additionally, with impending change in insurance,

outpatient treatment is no longer feasible.

-She needs a multidisciplinary evaluation including rheum (vasculitis),

hepatology (HCV with cryoglobulinemia), and hematology (abnormal bmbx)

evaluations, but hasn't obtained these yet.

- Ideally needs urology f/u also for microhematuria, though this is likely to be a

glomerular source

Case, continued

• Admitted 2 months after intial presentation; the diagnosis was flare of cryoglobulinemic

vasculitis.

• Cr increased to 2.9 so she received SM 1g x 3d

• Renal Ultrasound: Right kidney measures 11.5 cm in length and left kidney 12.2 cm,

otherwise negative.

• Renal biopsy was performed

• She received PEX x 3 treatments, with Cr falling to 1.7; IVIG at the end of PEX to which she

had a flu-like reaction (infusion was delayed and SM had been given several hours before).

Then received rituximab 375mg/m2.

• Additional labs: HCV genotype 1b, viral load 6.77 x 10^6

• 24h urine free light chains: kappa 316 mg, lambda 21mg

Renal Biopsy

Are we done yet?

Case

• Dc’d home after 1 week with instructions to followup with me

• 3d after discharge, returned to the ER with fevers: – “ She states when she went home, she was feeling tired, she had fevers and

some rigors, and she came back to the Emergency Department. She denies any headache, no cough, no dyspnea, no chest pain, no hematuria, although she says her urine output had been decreased in the past 2 days. At this time, she is found to have gram-positive cocci growing in her blood stream. She has been started on broad-spectrum antibiotics.”

• Diagnosis: staph MSSA infection from the plasmapheresis catheter, which had been dc’d prior to discharge. Echo showed veggie on posterior MV. US of the chest wall showed no residual abscess, though the area had been tender on admission. She commenced 6 weeks of antibiotic therapy cefazolin. Prednisone decreased 60mg 20mg.

Post dc appointment: 2.5 months

after initial presentation • Recently hospitalized, found to have MSSA bacteremia and

endocarditis

• Has developed rash a few days ago which is increasing. Not pruritic or painful.

• Weak since leaving hospital, and retaining fluid, but otherwise, no other symptoms. Appetite ok.

• Sodium bicarb tabs not taken yet, not sure about lisinopril.

• Edema being controlled with lasix, but ongoing and she has a sense of bloating or fluid retention in her abdomen

The rash

Post dc appointment 2.5 months

after initial presentation: summary • 52F followup after hospitalization x2. Intially she was treated

with PEX x4, SM pulse, and rituximab 375mg/m2 for cryglobulinemic GN (MPGN pattern without crescents) but developed MSSA endocarditis, probably due to the line which had already been dc'd, and has now been on antibiotics for about 2 weeks. Blood cx became negative about 5d after starting antibiotics.

• Today she has a new rash which looks like cryo but has an atypical distribution. I discussed her case via telephone today with Dr. Landovitz who saw her while in hospital for endocarditis.

Case, continued

• Derm: cryo v drug reaction

• Skin biopsy:

- Leukocytoclastic vasculitis (See Comment) COMMENT: Vasculitis secondary to mixed cryoglobulinemia and drug/medication ingestion can have overlapping histologic features. Therefore, it is difficult to make this distinction based on histologic findings alone. Eosinophils are inconspicuous in the current biopsy arguing against a drug induced cause for the vasculitis; however, the aforementioned etiology cannot entirely be excluded. Clinical correlation is advised.

Post-encounter labs also showed

• Urine protein increasing to 6.18

• Readmitted 2 weeks later for another attempt at PEX; received 4.8 sessions of PEX (the machine broke down with the 5th session); IVIG

• Urine Prot/cr did not improve

• Cr stable 1.6-1.9

• Completed 6 weeks of cefazolin, after stopping it, the rash did not improve

Case, continued

• Rituximab restarted, she has now received 4 doses of 375mg/m2 (in addition to the one dose in december)

• Follow note most recently: – Received rituximab 4 doses of 375mg/m2 which were well-tolerated.

– She has had somewhat increased pruritis, mainly at night; controlled with oatmeal baths

– Her energy is continuing to improve and she appears to be more alert and engaged.

– She has been taking HCV meds for about 2 weeks

– Reports home SBPs 130-140s

•

Current medications

• amlodipine (NORVASC) 10 mg tablet daily

• atovaquone (MEPRON) 1500mg daily

• ciprofloxacin (CIPRO) 500 mg tablet bid

• clonidine (CATAPRES) 0.2 mg tablet bid

• epoetin alfa (EPOGEN) 10000 units weekly

• ERGOCALCIFEROL 50000 units capsule weekly

• (FLONASE) 50 mcg/act nasal spray, 2 sprays by Each Nare route daily., Disp: 16 g, Rfl: 0

• furosemide (LASIX) 40 mg tablet prn edema (not needing to take)

• hydralazine 25 mg tablet q6h prn HTN, not needing to take

• levothyroxine 50 mcg daily

• Lisinopril 30 mg by mouth daily

• Nebivolol Take 40 mg by mouth daily.,

• prednisone 15 mg tablet PO daily

• Simeprevir Sodium (OLYSIO) 150 MG CAPS, Take 1 tablet by mouth daily,

• Sofosbuvir (SOVALDI) 400 MG tablet, Take 400 mg by mouth daily

• Aldactone (ALDACTONE) 50 mg tablet daily

Mixed cryoglobulinemia

• Type I – single monoclonal Ig, seen in monoclonal gammopathy disorders

• Type II – polyclonal IgG and monoclonal IgM

• Type III – polyclonal IgG and IgM

• Cryoglobulins precipitate on cooling below 37C and dissolve on rewarming

• A subset of patients with cryoglobulins develop immune complex diseases, which generally manifests as a small vessel vasculitis

• Well-characterized before the discovery of hepatitis C; originally thought to be due to HBV, then nAnB

• Most cases of type 2 and 3 are due to chronic HCV infection

• Type 2 and 3 cryogobulinemic vasculitis, MPGN, and other less common secondary GN are seen with chronic HCV infection (KI 1994;46:1255)

Epidemiology: HCV, cryo, MPGN overlap

• HCV incidence is 17000 new cases in the US in 2013, prevalence in the US is 3.2 million (www.cdc.gov).

• 15106 deaths caused by HCV in 2007 (Annals 2012;156:271). It is the most common indication for liver transplant (SRTR annual report 2011).

• Among patient with chronic HCV infection, cryoglobulins are detectable in 46% of patients

• The prevalence of cryoglobulinemic disease among all HCV patients is about 5-12% depending on the population studied (J Clin Gastro 1997;25:612; Clin Exp Rheum 2003;21:S78)

Epidemiology

• HCV-related glomerular disease is common; in a biopsy series of patients undergoing OLT, 25/30 had GN: MPGN-12, IgA-7, mesangial GN-6 (Annals 2006;144:735).

• MPGN is the most common glomerular disease seen in HCV, and is associated with cryoglobulinemia in the majority of cases (60-70%; KI 1994;46:1255).

• Renal disease has been shown to portend an increased mortality in patients with HCV-associated cryoglobulinemia (Am J Med 1980;69:287).

• The biggest cause of mortality in patients with mixed cryoglobulinemia is infection (NEJM 2013;369:1035). This should not be surprising when the immunomodulatory effects of chronic HCV are considered.

Epidemiology: like most autoimmune disease,

women are more commonly affected

Am J Med 1980;69:287

Epidemiology: risk factors for cryoglobulins among patients with HCV

This was a single-center study of liver biopsy patients

Not significant: duration of HCV infection, genotype, transaminase levels

Clinical manifestations of mixed

cryoglobulinemia

• Palpable purpura waxing and waning, GN,

neuropathy, polyarthritis, Raynaud

phenomenon; the tables below are from

one of the early case reports Am J Med

1980;69:287

Pathogenesis: cryoglobulinemia is due to clonal B-cell expansion in the

face of chronic antigenic stimulation

• Chronic HCV infection drives a clonal B-cell expansion, which then produces an IgM with RF activity, leading to immune complex disease.

• The IgM with RF activity binds HCV antigen and anti-HCV IgG (Arthritis Rheum 2002;46:2252) and acts as a cryoglobulin (Autoimm Rev 2011;11:48).

• The immune complexes are good acceptors of C1q, and then bind to C1q receptor on endothelial cells (NEJM 2013). The ET becomes activated, additional reactions of the complement cascade take place, and small-vessel vasculitis can result.

• HCV RNA can be detected in immunecomplex lesions (Clin Exp Rheum 2003;21:S78)

Pathogenesis: evidence for B-cell activation

in patients with HCV infection

• HCV infects lymphocytes (Blood 1993;82:3701)

• The HCV-envelope protein E2 binds to (in addition to hepatocytes) CD81, a transmembrane receptor on human B cells (Science 1998;282:938)

• CD81 forms a costimulatory complex with CD19 and CD21; this complex interacts with the BCR to lower the threshold for B-cell proliferation; however, stimulation of CD81 can also trigger a BCR-independent survival/proliferation pathway known as JNK (Proc Natl Acad Sci USA 2005;102:18544).

• Oncogenic alteration: Compared to patients HCV+/Cryo-, patients HCV+/cryo+ have increased amounts of lymphocytes with the antiapoptotic t14;18 translocation with Bcl-2 activation (Ann Int Med 2002;137:571)

• Transgenic mice expressing the full HCV genome in B cells develop spontaneous lymphomas (Blood 2010;116:4926).

• BAFF (B-cell activating factor) or BlyS (B lymphocyte stimulator), a powerful B-cell survival factor and a product of dendritic – Bcell interactions, is increased in HCV patients, higher in those with CV (Rheumatology (Oxford) 2007;46:37) .

• Changes in microRNA in PBMC are seen in HCV patients with MC compared to no MC (Plos ONE 2013;8:e62965).

Effects of HCV on B-cells, continued

• The monoclonally expanded marginal zone B cells express the VH1-69-encoded heavy chain variable region gene (Autoimm Rev 2013;12:430). This type of B cell is also preferentially seen in Ab-producing responses to influenza A and HIV.

• This population of B cells accumulates substantially in HCV, and can replace the B-cell population almost completely. These cells have characteristics which make them more “innate-like”, including preferential trafficking to sites of inflammation, instead of LNs and germinal centers.

• They have multiple attributes of function impairment (the term “exhaustion” has been used to describe them), they are prone to anergy. They may respond subnormally to BCR activation. Genetic profiling has demonstrated a transcriptional profile of anergy, defective proliferation, and reduced survival.

Diagnosis

• Cryocrit: the blood must be allowed to clot at 37C; then the plasma is collected, it is cooled, then spun, then a solid component if there, is quantified. Turnaround time for UCLA lab is 2-7d.

• Other labs: low complements; high RF; elevated CRP and ESR

• Clinical: look for typical symptoms (eg palpable purpura) or syndromes (eg MPGN) in a susceptible patient

• Skin biopsy: leukocytoclasic vasculitis

• Renal biopsy: MPGN pattern is the most common

Treatment of HCV-

cryoglobulinemic vasculitis • Options: 1-treat the cause (HCV); 2-treat the cause of

the CV (B cells); 3-treat vasculitis directly (steroids, PEX); 4-do nothing

• Depends on the severity of manifestations. Patients with positive cryocrit but no symptoms or signs vasculitis are generally treated like other patients with chronic HCV infection

• Underlying HCV must be treated whenever possible

Antiviral therapy

• Interferon: multiple ways

• Ribavirin: inhibits viral replication, not

specific to HCV

• New agents are specific to HCV non-

structural proteins

Treatment: antiviral therapy

• interferon alpha was first shown to be useful in the treatment of mixed cryoglobulinemia before the discovery of HCV, in a 7-patient case series in Italy (Am J Med 1987;83:726).

• Subsequent investigators established it as a useful agent, with response rates of 40-60%, though relapses shortly after completion of therapy were common (NEJM 2013;369:1035).

Treatment: antiviral therapy

• When pegylated interferon and ribavirin became the standard of treatment for HCV infection, open-label studies demonstrated their efficacy in relieving MC as well.

• The smaller, earlier case series (Arthitis Rheum 2005;52:911) showed that most patients with virologic response had clinical remission; the only patient without a clinical remission did not have a virologic response.

• In the larger series (published in 2011), 88% of patients with a virologic response also had a clinical remission.

• The usefulness of ribavirin and peginterferon is particularly limited in GN patients because they are renally cleared and dose reductions are needed if the GFR <50 or Cr >2.0 (contraindicated according to the pegetron package insert), and they are extremely difficult to use in patients on dialysis.

Antiviral treatment: new agents

• Newer antiviral agents are several “STAT-C” (specifically-targeted-antiviral-therapy-Hep C” drugs:

– Telepravir: NS3/4A HCV protease inhibitor, and also hepatic enzyme cytochrome P450 3A inhibitor

– Bocepravir: same mechanism; CYP 3A/4 inhibitor

– Simeprevir: same mechanism as t/b, but “2nd generation” less anemia

– Daclatasvir: NS5A replication complex inhibitor

– Asunaprevir: NS3 protease inhibitor

– Sofosbavir: NS5B polymerase inhibitor

• These drugs have higher risk of HCV resistance and one mechanism of action cannot be used alone; so far, FDA-approved regimens are for triple-drug therapy including interferon. However, IFN-free regimens are under development and are expected to be approved soon. Triple drug regimens have better response rates than IFN/riba but are less efficacious in cirrhotics and there are more side effects. T&B have substantial drug-drug interactions (NEJM 2013;368:1907).

Antiviral treatment: schematic

• IFN+riba+t or b used in open label study of 28 pts with HCV and cryo. The treatment endpoints were viral load, cryocrit, and C4 level, although proteinuria did fall in statically significant manner. There was a high rate (44%) of grade 3-4 hematologic side effects and rash or pruritis in the telepravir group

Trial design

Trials results

Immunosuppressive therapy

• Steroids can be used for severe vasculitis flares

but otherwise are not typically used.

• Methylprednisoline 16mg/d, when added to IFN,

showed a marginal benefit in symptoms but was

associated with increased HCV RNA levels

(Blood 1994;84:3336).

Rituximab

• The fact that the underlying pathogenesis of HCV-associated MC syndrome is due to clonal B-cell expansion has led to interest in rituximab.

• Between 1999 and 2012, about 360 cases reported with high response rates

• Prospective cohort studies in 2010 showed improved clinical outcomes in patients receiving ritux/ifn/riba v ifn/riba alone (Blood 2010;116:326-34 and 343-53)

• in 2012, two open label trials comparing rituxib v steroids/aza/ctx about 83 patients were also reported. These two trials showed markedly superior outcomes for rituximab with complete responses in most cases.

Rituximab trial 1

Ritux trial 1

• 12 patients in ritux arm, 12 in “best available treatment arm”; 6-month followup

• Primary endpoint: patient in remission (BVAS scrore of 0) at month 6

• 10 (83%) in ritux arm v 1 (8%) in control arm had a complete response. GN outcomes were not reported, but 4 patients in each group had GN

• Relapse: 3 patients relapsed (and 1 responder was lost to f/u)

Rituxan trial 1- results

HCV RNA levels rose in ritux treated patients but the mean

difference was NS; otherwise, therapy was well-tolerated

Rituximab trial 2

Ritux trial 2

• 59 patients randomized to receive rituximab 1g days 1,14; versus standard therapy which could include steroids, CTX, AZA, PEX

• Patients were allowed to switch arms if there was a lack of response

• Primary endpoint: proportion of patients in the same arm at end of study; 64.3% in rituximab group v 3.5% for standard group

• Followup was 18 months

Ritux trial 2: secondary endpoints

Rituximab misc

• Relapses after treatment do occur

• Doses of 375mg/m2 weekly x 4, 1g every other week x2, and 250mg/m2 x2 1 week apart

• HCV viral load has increased in some studies but evidence for progression of cirrhosis is lacking

Summary

• HCV- associated cryoglobulinemia and MPGN occur in a subset of HCV victims

• Aberrant B cell proliferation and subsequent production of rheumatoid factor are key steps in the pathogenesis

• The prognosis depends upon the presence of renal disease

• Diagnosis of CV is clinical, confirmed by path

• The two most effective treatment strategies are antiviral medications and anti-B cell treatment (rituximab)