Bullous pemphigoid and glomerulonephritisReport offour cases

Claude A. Simon, M.D., and R. K. Winkelmann, M.D., Ph.D. Rochester, MN

We report on four patients with bullous pemphigoid and other autoimmunediseases who had or developed glomerulonephritis. The relationship betweenthese two immunologic disorders involving the basement membrane isdiscussed. Our data suggest a coincidental phenomenon in patients whosuccessively or concurrently have multiple diseases of autoimmunity.(J AM ACAD DERMATOL 14:456-463, 1986.)

Multiple associations

Table I. Other autoimmune diseasesassociated with bullolls pemphigoid

Alopecia universalis, Hashimoto's thyroiditis, rheu­matoid arthritis, autoimmune neutropenia20

Polymyositis, myasthenia gravis, Hashimoto'sthyroiditis21

Rheumatoid arthritis, pernicious anemia22Vitiligo, primary biliary cirrhosis23

copy revealed linear deposition of IgG, C3, and fibrin.Direct immunofluorescence microscopy of a peri­lesional area showed deposition of IgG, IgA, and C3along the basement membrane zone. The indirect im­munofluorescence titer was 1: 160 for bullous pemphi­goid antibodies. Bullous pemphigoid was diagnosed,and therapy with nicotinic acid, 100 mg three times a

NonclltaneollS

Factor V inhibitor~

Hashimoto's thyroiditis6

Multiple sclerosis7

Myasthenia gravisH

Pernicious anemia9

Polymyalgiarheumatica 10

Polymyositis II

Rheumatoid arthritis 12-15Systemic lupus

erythematosus l6-

1H

Ulcerative colitis 19

Single association

Cutaneous

Dermatitis herpetiformis I

Lichen planus2•3

Pemphigus4

Whereas bullous pemphigoid has been observedin association with several cutaneous and sys­temic autoimmune diseases during the last 20years (Table I), its association with glomerulo­nephritis has been reported in only a few isolatedcases, 19.24-26 and the relationship between these twodiseases in which basement membrane antibodieshave a major role27.28 has been the source of chal­lenging discussions.

We have observed the association of bullouspemphigoid and glomerulonephritis in four addi­tional cases that demonstrated various microscopicrenal changes, together with the bullous pemphi­goid and several other immunologic disorders.

CASE REPORTSCase 1

A 25-year-old woman had had idiopathic thrombo­cytopenic purpura in 1970. She was referred to theMayo Clinic in 1976 because of a burning and itchingskin rash with macular, papular-edematous, and vesic­ular-bullous lesions over her trunk and extremities thatwere unresponsive to prednisone (Fig. I). A skin bi­opsy specimen showed a subepidermal bulla with aperivascular infiltrate in the papillary dermis containingeosinophils, and direct immunofluorescence micros-

From the Department of Dermatology, Mayo Clinic and Mayo Foun­dation.

Accepted for publication Oct. 3.1. 1985.

Reprint requests to: Dr. R. K. Winkelmann, Mayo Clinic, 200 FirstSt. SW, Rochester, MN 55905.

456

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Bullous pemphigoid and glomerulonephritis 457

Fig. 1. A, Macular and vesicular bullous lesions on the trunk. B, Macular, papular­edematous, and vesicular-bullous lesions on the extremities.

day, was begun while the dose of oral prednisone wasreduced gradually. The patient's skin condition im­proved dramatically. Because of the patient's sleepyappearance, thyroid tests were performed, revealing alow thyroxine level, a greatly elevated thyroid-stimu­lating hormone level, and a positive titer to thyroglob­ulin antibodies (l: 1,600). The patient was consideredto have Hashimoto's thyroiditis, and replacement ther­apy with 0.15 mg of levothyroxine sodium daily wasstarted. Farther into the course of therapy, several at­tempts at reducing the prednisone dose were accom­panied by the recurrence of the skin lesions. The useof sulfapyridine, as much as 2 gm daily, did not help.

In March 1977 the patient developed a Coombs' test­positive hemolytic anemia and was treated with in­creased daily intake of prednisone for 6 months. InDecember 1977 the patient complained of headache,nausea, and dark urine. The erythrocyte sedimentationrate was 136 mm in 1hour, and results of the antinuclearantibody test and the lupus erythematosus clot test werenegative. The values for C3, C4, and native DNA werenormal. Results of the Raji test for circulating immunecomplexes were negative. Urinalysis revealed protein­uria and leukocyturia, but a urine culture was negative.

A kidney biopsy specimen showed a membranousglomerulonephropathy. Direct immunofluorescence mi­croscopy revealed granular deposits of IgG, IgM, andcomplement (Clg, C3, and C4). Findings on electronmicroscopy also were consistent with a membranousglomerulonephropathy because of chronic immunecomplex production. The dose of prednisone was in­creased to 40 mg daily, and a long-term tapering pro­gram was begun.

In February 1978, although the patient's skin did notshow any abnormality except cushingoid changes re­sulting from prolonged prednisone therapy, protein,erythrocytes, leukocytes, and occasional hyaline andgranular cysts were still present in her urine. In N0­

vember 1978 the patient was hospitalized because of arapidly spreading varicella, complicated by severepneumonitis with respiratory failure and deep-veinthrombosis in the left lower extremity. In June 1981the cessation of prednisone therapy was followed bythe development of uveitis in the left eye. This requiredprednisone treatment (40 mg daily) again. Despite oralsteroid therapy, a bulla appeared on the left knee, rap­idly followed by a severe clinical flare of bullous pem­phigoid. Biopsy was not performed. Indirect immu-

458 Simon and Winkelmann

nofluorescence was negative. Urinalysis showed pro­tein, erythrocytes, leukocytes, and waxy and granularcasts-findings suggestive of an increase in nephritisactivity. The serum creatinine level was normal. A sec­ond renal biopsy revealed morphologic and immuno­logic changes that were no different from those on thefirst biopsy in 1977. Hospital treatment consisted of 40mg of prednisone daily, and her skin and kidney con­dition improved. In September 1982 an acquired factorVIII inhibitor was discovered-the latest manifestationof this patient's complex series ofautoimmune diseases.

Case 2

A 29-year-old man was hospitalized in April 1976because of a 3-month history of a generalized itchyrash. He had had bullous impetigo, condylomata acu­minata, herpetic stomatitis, localized neurodermatitis,and alopecia areata involving the eyebrows and genitalregion. Physical examination revealed diffuse macu­lopapular, urticarial, and vesicular lesions on the trunkand extremities. The oral mucosa was eroded in severalareas. A skin biopsy specimen showed a subepidermalbulla with scattered eosinophils, and direct immunoflu­orescence microscopy showed a linear deposition of C3along the basement membrane zone. Results of indirectimmunofluorescence testing were positive (1: 640) forantibodies to the basement membrane zone. Laboratorytests were relevant for a marked blood eosinophilia(20,000 leukocytes/mm:1 with 15% eosinophils), andabnormal results on urinalysis (1.5 gm of protein ex­creted per 24 hours, erythrocytes, and occasional hya­line and granular casts). A urine culture was negative.Intravenous urography did not show any abnormalityexcept duplication of the collecting system in the rightkidney. Iothalamate clearance was normal. The levelsof C3 and C4 were normal. Results of the antinuclearantibody test were negative. Local therapy and 2 gmof sulfapyridine a day improved the patient's skin con­dition. The renal disease also improved, the amount ofurine protein decreasing to 0.86 gm/24 hr. A monthlater the patient had a flare of bullous pemphigoid onthe extremities. Direct immunofluorescence micros­copy showed linear deposition ofC3 along the basementmembrane zone. Sulfapyridine was replaced by 50 mgof dapsone daily, and the skin improved. In addition,the eyebrows began to regrow.

In December 1976 the urine protein was 3.6 gm124hr. A renal biopsy specimen demonstrated a chronicmembranous glomerulonephropathy, with diffuse fineand coarse granular deposits of IgG, IgA, and C3 alongwith segmental and diffuse granular deposits of Clq.Electron microscopy showed a generalized mild to mod-

Joumal of theAmerican Academy of

Dermatology

erate thickening of all capillary walls. Subepithelialelectron-dense deposits with numerous "spike" for­mations were found. During 1977 the patient's renalcondition and bullous pemphigoid improved on a reg­imen of dapsone, 50 to ISO mg daily. In January 1978a severe bullous pemphigoid flare was treated with pred­nisone. Biopsy and direct immunofluorescence micros­copy again showed bullous pemphigoid. The patient'scondition improved with local therapy, dapsone' (l00mg), nicotinic acid (300 mg daily), and cyproheptadinehydrochloride.

Recurrent flares required the use of prednisone andazathioprine, which produced good control. Urinalysisshowed erythrocytes, and the total urine protein wasreduced to 0.66 gm124 hr. During 1980 and 1981, sev­eral attempts to stop the prednisone therapy failed, withflares of bullous pemphigoid. The patient required 30mg of prednisone a day for his bullous pemphigoid.The addition of methotrexate did not help. By 1982 thepatient responded to lower doses of prednisone, and hiscondition was in relative remission in January 1983 witha regimen of 10 mg of prednisone daily.

Case 3An 83-year-old man was seen in October 1979, com­

plaining of a 4-month history of a widespread, pruritic,burning, and painful eruption. He had suffered frombilateral painful ankle swelling with morning stiffnessand redness for 26 years. Symptoms were partially re­lieved by acetylsalicylic acid. Physical examination re­vealed generalized erythematous maculopapuies withlarge, tense bullae. A skin biopsy specimen showed asubepidermal bulla, and a dermal perivascular inflam­matory reaction containing eosinophils and direct im­munofluorescence microscopy showed a linear depo­sition of C3 on the basement membrane. The indirectimmunofluorescence titer was I :2,560 for bullous pem­phigoid antibodies. Results of an antinuclear antibodytest were negative, and thyroid test results were normal.Urinalysis showed microhematuria. The serum creati­nine level was normal. Stool analysis revealed occultblood, and rectosigmoidoscopy showed a thickened,friable mucosa with abscesses in the crypts. A rectalbiopsy specimen demonstrated ulcerative colitis. Thepatient was treated with prednisone, 40 mg daily, andsulfapyridine, 500 mg four times a day, and his con­dition improved. In February 1980, new blisters formedon the upper portion of the right arm. The patient hadstopped taking the prednisone a month earlier. Halcin­onide cream was given, and by March 1980 the blistershad disappeared.

In September 1982 the patient experienced a new

Volume 14Number 3March, 1986

blistering eruption on the upper extremities. The blis­tering became rapidly generalized, and the patient washospitalized and treated with oral prednisone (60 mgdaily). Laboratory findings revealed severe proteinuria(protein excretion, 7.4 gm124 hr) with hyaline, gran­ular, leukocytic, and waxy casts in the urine. Iothala­mate clearance was decreased to 28 ml/min. A urineculture, antinuclear antibody test results, and rheuma­toid factor were all negative. Renal lithiasis was ruledout by radiologic study. The patient refused a renalbiopsy. The diagnosis of membranous or membra­noproliferative glomerulonephritis was clinically as­sumed, and the patient was given a low protein diet forhis renal condition.

In June 1984 the prednisone therapy was stopped,and in December 1984 a new flare of erythematous,infiltrated, vesicular lesions developed on the trunk andback. A skin biopsy specimen demonstrated dennaledema and eosinophilia, and direct immunofluores­cence microscopy showed linear deposition of IgO andC3 along the basement membrane. The indirect im­munofluorescence basement-membrane-zone antibodytiter was I: 640. The antinuclear antibody titer was1:40, and the complement level was normal. Mild pro­teinuria, leukocyturia, and hematuria were present,along with occasional hyaline and granular casts. Thepatient was treated with prednisone, 40 mg daily. Whenseen in January 1985, he was taking 40 mg of pred­nisone daily and denied having any new skin lesionduring this treatment.

Case 4

A 63-year-old man had suffered from microscopichematuria and hypertension since 1970. In December1972 a renal biopsy specimen demonstrated mesangialthickening, increased cellularity of the glomeruli, andperiglomerular fibrosis with complete hyalinization ofmost glomeruli. The tubules contained scattered eosin­ophilic casts with some flattening of epithelial cells andminimal atrophy. Minimal patchy interstitial chronicinflammation and fibrosis were also present, along witha slight thickening of the walls of the arterioles-find­ings consistent with chronic glomerulonephritis. Renalinsufficiency rapidly developed, and hemodialysis wasstarted a few months later.

In January 1973, transient intravascular hemolysiswith positive Donath-Landsteiner test results devel­oped-findings suggestive of paroxysmal cold hemo­globinuria. In February and July 1977, transplantationof a cadaver donor kidney was carried out; both trans­plants were rejected. The patient was redialyzed andthen put on long-term ambulatory peritoneal dialysis

Bullous pemphigoid and glomerulonephritis 459

from 1979 onward. At the end of 1981 a severely pru­ritic, generalized rash with blisters developed on theextremities. A skin biopsy specimen showed a subepi­dennal bulla containing eosinophils and a papillary der­mal perivascular infiltrate of eosinophils, with positivedirect immunofluorescence microscopy (linear C3 de­position along the basement membrane). The indirectimmunofluorescence titer was 1: 80 for bullous pem­phigoid antibodies. Oral prednisone therapy was started(30 mg daily), and the bullous pemphigoid was fairlywell controlled by this treatment. In November 1984the patient was still taking 10 mg of prednisone a dayand had not had a recurrence of the bullous pemphigoidduring this period.

DISCUSSION

In 1953, Lever7 established bullous pemphigoidas an individual entity. A decade later, Jordonet aF9 demonstrated its autoimmune nature by dis­covering antibodies bound along the skin basementmembrane and circulating antibodies in patientswith bullous pemphigoid. The antigen responsiblefor this blistering disease was later purified by Diazet apo and called bullous pemphigoid antigen.

Our four patients had their clinical diagnosis ofbullous pemphigoid confirmed by a typical his­tologic picture-the presence of linear depositionof IgO or C3 (or both) along the basement mem­brane zone (positive direct immunofluorescence)and the presence of circulating bullous pemphi­goid antibodies (positive indirect immunofluores­cence).

In two patients, glomerulonephritis developedshortly after the onset of the bullous disease, 3years later in one patient and 11 years before inthe other (Table II). Prior to the first renal symp­toms, neither had been receiving nephrotoxicagents or drugs reported to induce glomerulone­phritis. 31 Urine cultures were negative, and radio­logic study did not show any significant urinarytract abnormality. Systemic lupus erythematosus,known as one of the major causes of glomerulo­nephritis, was excluded by the absence of fulfill­ment of the American Rheumatism Associationcriteria, by the absence of circulating antinuclearantibodies, and by negative results of a lupus-bandtest on direct immunofluorescence.

In our cases the chronologie relationship be­tween glomerulonephritis and bullous pemphigoid

460 Simon and Winkelmann

Table II. Data on four patients with bullous pemphigoid and glomerulonephritis

Journal of theAmerican Academy of

Dermatology

Bullous pemphigoid Glomerulonephritis

Year, Year,Case Sex, age (yr) Duration age (yr) DurationNo. age (yr) at onset (yr) at onset (yr) Associated immunologic disorders

F,25 1976,25 6 1977,26 5 Idiopathic thrombocytopenic purpura; Coombs'test-positive hemolytic anemia; Hashimoto'sthyrOiditis; uveitis; acquired factor VIIIinhibitor

2 M,29 1976,29 7 1976, 29 4 Alopecia areata3 M,83 1979, 83 6 1982, 86 6 Rheumatoid arthritis; ulcerative colitis4 M,63 1981,63 1 1970, 52 2 Paroxysmal cold hemoglobinuria; two consecu-

tive renal transplant rejections

and the kidney biopsy findings varied considerablyfrom one patient to another. In Case 1 the firstclinical and microscopic renal changes were notedwhen the blistering disease was under fair control,and although the kidney biopsy findings were con­sistent with chronic deposition of circulating im­mune complexes on the glomerular basementmembrane, we failed to detect these complexes inthe serum. It is of interest that the increase innephritis activity in 1981 was concomitant not onlywith a flare of bullous pemphigoid but also withthe development of uveitis. In Case 2, proteinuriaincreased while the skin was healing, and althoughnumerous spikes were found on the glomerularbasement membrane, consistent with immunecomplex deposition, a fine, diffuse deposition of19G, IgA, and C3 was also noted. The strikingfeature in Case 3 was the development of protein­uria and renal insufficiency during the severe flareof bullous pemphigoid in 1982, 3 years after itsbeginning. The patient was 86 years old and re­fused to have a renal biopsy specimen taken. Glo­merulonephritis in Case 4 preceded the bullousdisease by 11 years, and the renal biopsy disclosednot only glomerular mesangial thickening and in­creased cellularity but also flattening of the tubularepithelial cells with atrophy and patchy interstitialchronic inflammation and fibrosis.

Kida et aP5 described a 39-year-old woman inwhom edema and proteinuria abruptly developed6 months after the onset of bullous pemphigoid.A renal biopsy specimen, taken 5 months later,showed deposition of IgG and C3 along the glo-

merular basement membrane, together with aslight thickening of the basement membrane anddense deposits on electron microscopy. The lightmicroscopic findings were normal. During thecourse of the bullous disease, proteinuria fluc­tuated in proportion to the level of circulating bul­lous pemphigoid antibodies. Despite these find­ings, the authors failed to obtain direct evidencefor an immune complex-mediated glomerulone­phritis because deposition in vitro of fluoresceinisothiocyanate-stained serum gamma globulinsand kidney immunoglobulins onto normal skin,normal kidney tissue, and kidney tissue from thepatient was negative. In addition, there was noanticomplementary activity in the serum of thispatient, and results of the Clq binding test werenegative.

More recently, Merot et aF6 described two el­derly patients (one described earlier by Glassonet aP2) in whom hematuria, proteinuria, and amoderate renal insufficiency developed shortly af­ter the onset of bullous pemphigoid. Renal bi­opsy revealed diffuse proliferative and exudativechanges with humplike deposits along the glo­merular basement membrane and granular depositsof C3. Systemic steroids were given, leading to arapid resolution of the skin and kidney problems.All these findings suggested to the authors evi­dence for deposition of bullous pemphigoid im­mune complexes on the glomerular basementmembrane.

Deposition of circulating immune complexesalong the glomerular basement membrane is a pos-

Volume 14Number 3March, 1986

sible mechanism responsible for glomerulone_phritis in patients with bullous pemphigoid, be­cause the presence of circulating immune com­plexes has been recognized in several studies. 33·35Jordon et aP6 developed a method with which theyfound these complexes in as many as 68% of theirserum samples and discovered that they were largeenough (l9S or greater) to deposit in the kidneys.

In some respects, our data suggest the deposi­tion of immune complexes on the glomerular base­ment membrane (proteinuria after a severe bullousflare in Case 3, granular deposits and/or spikes inCases 1 and 2), whereas in other respects, they donot (absence of detectable circulating immunecomplexes in Case 1; fine deposition of IgG, IgA,and C3 in Case 2; chronology and tubulointerstitialinvolvement in Case 4).

The case reported by Esterly et aJ24 is of specialinterest because the renal symptoms preceded (by9 months) bullous pemphigoid, as in our fourthpatient. Moreover, in spite of this time discrep­ancy, occasional spikes were found on the glo­merular basement membrane, along with a slightdiffuse thickening of the capillary walls and de­position of IgG, and beta1c globulins were foundin discontinuous and continuous linear pattern, asin our second patient. The patient died shortlyafterward, and at autopsy a thrombus was notedto be occluding the right renal vein. The authorsbelieved that the thrombus was an epiphenomenonand could not have been the cause of the renalimpairment. Recently, Kaplan et aP7 reviewed thissubject and concluded that renal vein thrombosiswas the result, rather than the cause, of the ne­phrotic syndrome. The data on our four patients,in addition to those obtained by Esterly et al,24raise the question of another mechanism that leadsto glomerulonephritis in patients with bullous pem­phigoid.

An antigenic cross-reactivity between the base­ment membrane of the skin and the glomeruli ishighly unlikely because the bullous pemphigoidantigen is known to be synthesized in the epider­mal basal cells. 38 Further, although the antigen ispresent in the skin basement membrane of almostall vertebrates,39 it has not been found in the base­ment membrane of other tissues.40

The association of bullous pemphigoid and glo-

Bullous pemphigoid and glomerulonephritis 461

merulonephritis could occur through coincidence;however, the presence of three or more immuno­logic disorders in our patients is a clinical andimmunologic fact currently designated as "mul­tiple autoimmune disease." Our first patient illus­trates a unique state of "self-intolerance" througha never previously reported sequence of autoim­mune diseases: idiopathic thrombocytopenic pur­pura, Coombs' test-positive hemolytic anemia,Hashimoto's thyroiditis, uveitis, acquired factorVIII inhibitor, bullous pemphigoid, and glomer­ulonephritis. The second patient had alopeciaareata, as well as bullous pemphigoid and glo­merulonephritis. Patient 3 suffered from rheuma­toid arthritis and ulcerative colitis when he wasseen for bullous pemphigoid and, later, for glo­merulonephritis. Patient 4 not only presented withparoxysmal cold hemoglobinuria, bullous pem­phigoid, and glomerulonephritis but also experi­enced two consecutive renal transplant rejections.This immunologic host response to the "nonself"is not entirely foreign to the rejection of the' 'self"because both conditions are known to require sim­ilar immunologic pathways.4t Bullous pemphigoidhas been recently reported in a 12-year-old girlduring chronic rejection of her second kidneytransplant. It is of interest that graft nephrectomywas rapidly followed by the disappearance of theskin lesions. 42

Many observations support the concept that au­toimmune diseases are closely related host re­sponses whether or not they involve different tis­sues. 43 Although the link they share is still poorlyunderstood,44 these autoimmune diseases are be­lieved to occur under the influence of the sameetiologic agent-that is, genetic,45 viral,46 ortoxic. 47

Glomerulonephritis is an inflammatory renaldisease in which the glomerular basement mem­brane is immunologically injured, mainly throughthree major mechanisms: antibodies directed a­gainst the glomerular basement membrane, de­position of circulating immune complexes, andformation of immune complexes in situ.48 How­ever, these immunologic mechanisms are not mu­tually exclusive and can occur simultaneouslyin vivo, being artificially separated for didacticreasons. 31 This may explain why bullous pemphi-

462 Simon and Winkelmann

gold and glomerulonephritis were not always con­current in our cases and why the renal changeswere not uniform. Some conditions, such as lupuserythematosus, thymoma,4'1 and penicillamine-in­duced reactions;t1 can lead to expression of mul­tiple autoimmune reactions. We believe that ourpatients-as well as the young patient describedin 1970 by Bean et al,19 who had ulcerative colitisfollowed by acute hemolysis of unclear origin andproteinuria with minimal mesangial changes on thekidney biopsy-fulfill such a description and thatthe occurrence of bullous pemphigoid and glo­merulonephritis, although partially causal, is a co­incidental phenomenon in patients who succes­sively or concurrently demonstrate multiple dis­eases of autoimmunity.

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ABSTRACTS

Toxoplasma antibodies in morbus Beh~et (Germantext)

Breustedt W, Audring H, Brenke A, Jacobza D:Dermatol Monatsschr 171:324-328, 1985

Changing titers of Toxoplasma-specificantibodies, frompositive at the onset of the disease to negative 12 weeks later,point to the possibility of a causal connection between toxo­plasmosis and Behs;et's disease. Treatment with colchicine,fifteen to twenty drops three to four times daily, seems to besuccessful, particularly for the acute disease stage.

Alfred Hal/ander, M.D.

Lupus vulgaris; clinical findings and therapy,past and present (German text)

Simon N: Z Hautkr 60:1295-1306, 1985

The number of lupus vulgaris patients has greatly de­creased in both West and East Germany during the last decade.Regardless of the type of sldn tuberculosis, all patients un­dergo monotherapy with isonicotinic acid hydrazide (INH),5-7 mg/kg daily. After clinical cure therapy is continued forone-half year. Clinical resistance was found in only one of100 patients. In clinically resistant patients a combined treat­ment of INH, rifampin, and ethambutol is recommended.

Alfred Hollander, M.D.

Antenatal therapy with corticosteroids andpostpartum complications

Curet LB, Morrison lC, Rao AV: Am J ObstetGynecol 152:83-84, 1985

In another comparative study, using placebo and steroid,careful evaluations show that moderate doses of corticosteroidcan be used safely in pregnancy, in this situation for manyweeks, to control fetal distress.

P. C. Anderson, M.D.

Cutaneous blisters and carbon monoxidepoisoning

Myers RA, Snyder SK, Majerus TC: Ann EmergMed 14:603-606, 1985

A reminder to emergency room staffers that skin findingscan be crucial in making a correct diagnosis and doing sorapidly enough to give therapy to the patient while he needsit.

P. C. Anderson, M.D.