Colchicine is effective in controlling chroniccutaneous leukocytoclastic vasculitisJeffrey P. Callen, M.D. Louisville, KY

Chronic cutaneous leukocytoclastic vasculitis is commonly difficult to control.In an attempt to avoid potentially toxic therapy with corticosteroids and/orimmunosuppressives or to allow tapering of corticosteroid therapy, I institutedoral colchicine therapy in thirteen patients. Complete control of diseaseoccurred in nine patients, partial control (as evidenced by my ability to lowerthe corticosteroid dosage) was obtained in three patients, and one patient hadno demonstrable effects during a I-month period of colchicine therapy. Effectwas uniformly noted within 1 week after institution of therapy. Side effectswere uncommon but, when they occurred, consisted mainly of abdominalcramping and/or diarrhea. Seven patients had a relapse of their cutaneousvasculitis when colchicine was stopped, but reinstitution again led to a rapidcontrol of the disease manifestations. Therapy has been safely continuedfor up to 2Y2 years without evidence of toxicity. Thus colchicine appears to bea safe and effective therapy for chronic cutaneous leukocytoclastic vasculitis.(J AM ACAD DERMATOL 13:193-200, 1985.)

Hazen and Michel' were the first to report thatoral colchicine was an effective therapy for chroniccutaneous vasculitis. Despite their enthusiastic re­port, further reports with longer usage have notappeared. Cupps et aF suggest in their report ofthirteen patients that colchicine was not effectivefor chronic, recurrent cutaneous vasculitis. How­ever, their patients were referred because of a lackof response and therefore were selected as non­responders. Ekenstam and Callen3 reported agroup of eighty-two patients with cutaneous leu­kocytoclastic vasculitis, of whom roughly onethird had recurrent or chronic disease. Thuschronic disease is not uncommonly encountered

From the Department of Medicine (Dermatology), University ofLouisville.

Presented in part at the National Clinical Dermatology Conference,Chicago, IL, June, 1984.

Accepted for publication April 19, 1985.

Reprint requests to: Dr. Jeffrey P. Callen, 310 East Broadway, Louis­ville, KY 40202.

and, from the work of Cupps et aI, appears to bedifficult to treat.

Colchicine is an alkaloid with effects that couldtheoretically lead to a blockade of disease expres­sion in patients with vasculitis. Mackel andJordon4 demonstrated that circulating immunecomplexes have a role in the pathogenesis of cu­taneous leukocytoclastic vasculitis. Under appro­priate circumstances an inflammatory reaction canbe initiated by these circulating immune com­plexes. It is at this level that colchicine mightbe an effective agent, since it is known to in­hibit polymorphonuclear leukocyte chemotaxis,S

block lysosomal formation, and stabilize lysoso­mal membranes.

I have treated thirteen patients with cutaneousleukocytoclastic vasculitis with colchicine. Eval­uation of effectiveness was based on control ofdisease expression andlor the ability to withdrawconcomitant therapy. Furthermore, in several pa­tients in whom colchicine was stopped, relapsesoccurred, after which the patients again responded

193

Colchicine is effective in controlling chroniccutaneous leukocytoclastic vasculitisJeffrey P. Callen, M.D. Louisville, KY

Chronic cutaneous leukocytoclastic vasculitis is commonly difficult to control.In an attempt to avoid potentially toxic therapy with corticosteroids and/orimmunosuppressives or to allow tapering of corticosteroid therapy, I institutedoral colchicine therapy in thirteen patients. Complete control of diseaseoccurred in nine patients, partial control (as evidenced by my ability to lowerthe corticosteroid dosage) was obtained in three patients, and one patient hadno demonstrable effects during a I-month period of colchicine therapy. Effectwas uniformly noted within 1 week after institution of therapy. Side effectswere uncommon but, when they occurred, consisted mainly of abdominalcramping and/or diarrhea. Seven patients had a relapse of their cutaneousvasculitis when colchicine was stopped, but reinstitution again led to a rapidcontrol of the disease manifestations. Therapy has been safely continuedfor up to 2Y2 years without evidence of toxicity. Thus colchicine appears to bea safe and effective therapy for chronic cutaneous leukocytoclastic vasculitis.(J AM ACAD DERMATOL 13:193-200, 1985.)

Hazen and Michel' were the first to report thatoral colchicine was an effective therapy for chroniccutaneous vasculitis. Despite their enthusiastic re­port, further reports with longer usage have notappeared. Cupps et aF suggest in their report ofthirteen patients that colchicine was not effectivefor chronic, recurrent cutaneous vasculitis. How­ever, their patients were referred because of a lackof response and therefore were selected as non­responders. Ekenstam and Callen3 reported agroup of eighty-two patients with cutaneous leu­kocytoclastic vasculitis, of whom roughly onethird had recurrent or chronic disease. Thuschronic disease is not uncommonly encountered

From the Department of Medicine (Dermatology), University ofLouisville.

Presented in part at the National Clinical Dermatology Conference,Chicago, IL, June, 1984.

Accepted for publication April 19, 1985.

Reprint requests to: Dr. Jeffrey P. Callen, 310 East Broadway, Louis­ville, KY 40202.

and, from the work of Cupps et aI, appears to bedifficult to treat.

Colchicine is an alkaloid with effects that couldtheoretically lead to a blockade of disease expres­sion in patients with vasculitis. Mackel andJordon4 demonstrated that circulating immunecomplexes have a role in the pathogenesis of cu­taneous leukocytoclastic vasculitis. Under appro­priate circumstances an inflammatory reaction canbe initiated by these circulating immune com­plexes. It is at this level that colchicine mightbe an effective agent, since it is known to in­hibit polymorphonuclear leukocyte chemotaxis,S

block lysosomal formation, and stabilize lysoso­mal membranes.

I have treated thirteen patients with cutaneousleukocytoclastic vasculitis with colchicine. Eval­uation of effectiveness was based on control ofdisease expression andlor the ability to withdrawconcomitant therapy. Furthermore, in several pa­tients in whom colchicine was stopped, relapsesoccurred, after which the patients again responded

193

194 Callen

Table I. Summary of patient characteristics and response to therapy

Journal of theAmerican Academy of

Dermatology

Patient Age (yr), Location and type of Date of Cause or associated Date of startNo. sex, race vasculitic lesion onset condition Laboratory abnormalities of colchicine

1 44/W/F Legs: palpable 2/82 Hyperglobulinemia t Cryoglobulin 3/l/83purpura (normal bone PEG < 70

marrow) Conglutinin < 31

2 55/W/F Legs: generalized pal- 9/81 Food dye (probably Clq-8% (nl) 12120/82pable purpura FD&C yellow) tESR

3

4

5

6

45/W/M Fingers, toes, feet:purpura, periungualinfarctions

28/W/F Hands, arms: palpablepurpura

30/W/F Toes: periungual in-farction

78/W/M Legs: ulcers, andpurpura

10/80 SCLE-SLENephrotic syndromeArthritis

2/83 SCLE-SLEArthritis

4/82 Discoid LE

2/84 Idiopathic

+Anti-Ro and La an­tibodies

Leukopenia

+ Anti-Ro antibodiesLeukopenia

NoneCIC negative

THC, 62 (nl, 70-140)Cle, nl

12/82

7/83

10/83

6/84

erc: Circulating immune complexes; ESR: erythrocyte sedimentation rate; LE: lupus erythematosus; NSAID: nonsteroidal anti-inflammatory drug;PEG: polyethylene glycol; RF: rheumatoid factor; SCLE: subacute cutaneous lupus erythematosus; SLE: systemic lupus erythematosus; THe: totalhemolytic complement.

Methods: PEG: normal <30; Clq: normal < 13; conglutinin: nonnal <5.

to reinstitution of therapy. Thus the use of ag­gressive, more toxic therapies such as the use ofsystemic corticosteroids and/or immunosuppres­sives can often be avoided by using this agent.

MATERIALS AND METHODS

Thi.s article reports a prospective analysi.s of an opentrial of colchicine for cutaneous leukocytoclastic vas­culitis. All patients included in this study had clinicaland histopathologic evidence of leukocytoc1astic vas­culitis. Patients with systemic symptoms, collagen-vas­cular diseases, or abnormal laboratory findings were

not excluded from this study. All patients received oralcolchicine, 0.6 mg twice daily. This dose was thenvaried according to clinical response or the developmentof side effects. The dose was lowered and then stoppedat the time of clinical remission. If a relapse was ob­served, the colchicine was restarted in a dose of 1 or2 tablets (0.6 mg) per day.

At the onset of therapy, all patients were evaluatedby history, physical examination, and laboratory test­ing, including complete blood count and platelet count;serum multiphasic analysis; serum protein electropho­resis; determinations of cryoglobulins, antinucl'ear an­tibody (HEp-2 cells), rheumatoid factor, hepatitis B

194 Callen

Table I. Summary of patient characteristics and response to therapy

Journal of theAmerican Academy of

Dermatology

Patient Age (yr), Location and type of Date of Cause or associated Date of startNo. sex, race vasculitic lesion onset condition Laboratory abnormalities of colchicine

1 44/W/F Legs: palpable 2/82 Hyperglobulinemia t Cryoglobulin 3/l/83purpura (normal bone PEG < 70

marrow) Conglutinin < 31

2 55/W/F Legs: generalized pal- 9/81 Food dye (probably Clq-8% (nl) 12120/82pable purpura FD&C yellow) tESR

3

4

5

6

45/W/M Fingers, toes, feet:purpura, periungualinfarctions

28/W/F Hands, arms: palpablepurpura

30/W/F Toes: periungual in-farction

78/W/M Legs: ulcers, andpurpura

10/80 SCLE-SLENephrotic syndromeArthritis

2/83 SCLE-SLEArthritis

4/82 Discoid LE

2/84 Idiopathic

+Anti-Ro and La an­tibodies

Leukopenia

+ Anti-Ro antibodiesLeukopenia

NoneCIC negative

THC, 62 (nl, 70-140)Cle, nl

12/82

7/83

10/83

6/84

erc: Circulating immune complexes; ESR: erythrocyte sedimentation rate; LE: lupus erythematosus; NSAID: nonsteroidal anti-inflammatory drug;PEG: polyethylene glycol; RF: rheumatoid factor; SCLE: subacute cutaneous lupus erythematosus; SLE: systemic lupus erythematosus; THe: totalhemolytic complement.

Methods: PEG: normal <30; Clq: normal < 13; conglutinin: nonnal <5.

to reinstitution of therapy. Thus the use of ag­gressive, more toxic therapies such as the use ofsystemic corticosteroids and/or immunosuppres­sives can often be avoided by using this agent.

MATERIALS AND METHODS

Thi.s article reports a prospective analysi.s of an opentrial of colchicine for cutaneous leukocytoclastic vas­culitis. All patients included in this study had clinicaland histopathologic evidence of leukocytoc1astic vas­culitis. Patients with systemic symptoms, collagen-vas­cular diseases, or abnormal laboratory findings were

not excluded from this study. All patients received oralcolchicine, 0.6 mg twice daily. This dose was thenvaried according to clinical response or the developmentof side effects. The dose was lowered and then stoppedat the time of clinical remission. If a relapse was ob­served, the colchicine was restarted in a dose of 1 or2 tablets (0.6 mg) per day.

At the onset of therapy, all patients were evaluatedby history, physical examination, and laboratory test­ing, including complete blood count and platelet count;serum multiphasic analysis; serum protein electropho­resis; determinations of cryoglobulins, antinucl'ear an­tibody (HEp-2 cells), rheumatoid factor, hepatitis B

Volume 13Number 2, Part 1August, 1985

Colchicine in leukocytoclastic vasculitis 195

Additional therapy at Itime of start of therapy

Prednisone, 20 mgResponded as long

as dose is over 30mg/day

Prednisone, 20 mgHydroxychloroquine

(Plaquenil), 200mg

Prednisone, 80 mgevery other day

Hydroxychloroquine(Plaquenil), 200mg/day

Indocin, 25 mg bymouth, tid

Prednisone, 80 mgqd

DapsoneIntralesional cortico­steroids

None

Response

Complete taper andstop 5/83

Complete taper andremoval of othermedications

Hydroxych10roquine(Plaquenil),12120/82

Prednisone, 4112/83

CompleteIndomethacin (Indo-

cin) stopped 1/83Prednisone stopped

5/83

CompletePrednisone tapered

to 20 mg qid by10/83

PartialDapsone stopped11/83Intralesional notused furtherComplete

Relapse date

7/8312/84

Yes8/83

12/84

Yes4/83

10/84

Yes7/84

10/84

None

8/8411/84

Response to reinstitution IComplete

Complete

Excellent control withreinstitution of col­chicine

Prednisone neededfor SCLE in 10/84

Complete

CompleteNo additional therapy

used

Side effects

None

One episode of diar­rhea on 2 colchi­cine tablets perday

None

None

None

None

Continued

antigen, and erythrocyte sedimentation rate (Wintrobe);urinalysis; and chest roentgenogram. Selected patientshad determinations made for creatinine clearance, 24­hour urine protein, anti-Ro (SSA) antibodies, and cir­culating immune complexes. Follow-up examinationsincluded complete blood count, platelet count, and re­evaluation of any abnormalities found on initial testing.

Response to therapy was judged as follows. The term"complete response' , was used when the current lesionsdisappeared rapidly, no new lesions appeared, and ta­pering with cessation of other therapy occurred. Theterm "partial response" was used when lesions cleared,new lesions did not appear, but other medications couldnot be removed without reappearance of new lesions.Thus a partial response could be considered to haveoccurred if the patient's dosage of other medicationscould be lowered. Relapse was defined as reappearance

of lesions when colchicine was stopped or the dose waslowered.

RESULTS

Table I summarizes the characteristics of thepatients described in this report, as well as theirresponse to therapy. All thirteen patients wereadults ranging in age from 28 to 78 years. Therewere three white men, one black woman, and ninewhite women. The vasculitic lesions were clini­cally characterized by palpable purpura in ninepatients, purpura and ulcers in one patient, nodulesin two patients, and urticarial lesions in one pa­tient. All patients had biopsies that demonstratedcharacteristic changes of leukocytoclastic vascu­litis. Disease had been present from 1 month to 6

Volume 13Number 2, Part 1August, 1985

Colchicine in leukocytoclastic vasculitis 195

Additional therapy at Itime of start of therapy

Prednisone, 20 mgResponded as long

as dose is over 30mg/day

Prednisone, 20 mgHydroxychloroquine

(Plaquenil), 200mg

Prednisone, 80 mgevery other day

Hydroxychloroquine(Plaquenil), 200mg/day

Indocin, 25 mg bymouth, tid

Prednisone, 80 mgqd

DapsoneIntralesional cortico­steroids

None

Response

Complete taper andstop 5/83

Complete taper andremoval of othermedications

Hydroxych10roquine(Plaquenil),12120/82

Prednisone, 4112/83

CompleteIndomethacin (Indo-

cin) stopped 1/83Prednisone stopped

5/83

CompletePrednisone tapered

to 20 mg qid by10/83

PartialDapsone stopped11/83Intralesional notused furtherComplete

Relapse date

7/8312/84

Yes8/83

12/84

Yes4/83

10/84

Yes7/84

10/84

None

8/8411/84

Response to reinstitution IComplete

Complete

Excellent control withreinstitution of col­chicine

Prednisone neededfor SCLE in 10/84

Complete

CompleteNo additional therapy

used

Side effects

None

One episode of diar­rhea on 2 colchi­cine tablets perday

None

None

None

None

Continued

antigen, and erythrocyte sedimentation rate (Wintrobe);urinalysis; and chest roentgenogram. Selected patientshad determinations made for creatinine clearance, 24­hour urine protein, anti-Ro (SSA) antibodies, and cir­culating immune complexes. Follow-up examinationsincluded complete blood count, platelet count, and re­evaluation of any abnormalities found on initial testing.

Response to therapy was judged as follows. The term"complete response' , was used when the current lesionsdisappeared rapidly, no new lesions appeared, and ta­pering with cessation of other therapy occurred. Theterm "partial response" was used when lesions cleared,new lesions did not appear, but other medications couldnot be removed without reappearance of new lesions.Thus a partial response could be considered to haveoccurred if the patient's dosage of other medicationscould be lowered. Relapse was defined as reappearance

of lesions when colchicine was stopped or the dose waslowered.

RESULTS

Table I summarizes the characteristics of thepatients described in this report, as well as theirresponse to therapy. All thirteen patients wereadults ranging in age from 28 to 78 years. Therewere three white men, one black woman, and ninewhite women. The vasculitic lesions were clini­cally characterized by palpable purpura in ninepatients, purpura and ulcers in one patient, nodulesin two patients, and urticarial lesions in one pa­tient. All patients had biopsies that demonstratedcharacteristic changes of leukocytoclastic vascu­litis. Disease had been present from 1 month to 6

196 Callen

Table I. Cont'd

Journal of theAmerican Academy of

Dermatology

Patient IAge (yr), INo. sex, race

'Location and type ofvasculitic lesion I

Date of Ionset

Cause or associatedcondition

Date of startLaboratory abnormalities 'of colchicine

7

8

39/W/F Legs: nodules

29/B/F Generalized urticaria

1181 Idiopathic arthralgias None

4/78 Idiopathic None

1183

4/84

9 60/W/F Legs: palpable 4184 Idiopathic (arthritis) None 5/14184purpura

10 78/W/F Legs: palpable 1980 Idiopathic (nephritis CIC + PEG 160 5/27/83purpura arthritis) (nl, 30)

Clq = 46 (nl, 13)RF = 1:5,120

11 54/W/F Legs (feet); palpable 1183 Idiopathic None 3/3183purpura

12 29tW/M Legs: livedo reticu- 8/83 Hyperglobulinemia +Cryoglobulin 8/83laris No crc

13 67/W/F Legs, arms; nodules 1182 Rheumatoid arthritis RF-conglutinin 20 12/7/82PEG 640Clq, 65

years before institution of colchicine therapy(mean, 18.4 months).

The vasculitis was unassociated with a recog­nized etiologic factor or disease in six patients,two patients had hyperglobulinemia, three patientshad lupus erythematosus, one patient had rheu­matoid arthritis, and one patient's disease wasthought to be related to a food dye. Arthritis orsevere arthralgias complicated the cutaneous dis­ease in five patients: two with lupus erythemato­sus, the one with rheumatoid arthritis, and twowith idiopathic leukocytoclastic vasculitis. Onepatient had hematuria and two had proteinuria tran­siently, but renal biopsies were not done.

Laboratory abnormalities were common butgenerally nonspecific. Four patients had an ele­vated erythrocyte sedimentation rate. The two pa­tients with subacute cutaneous lupus erythemato­sus had a positive test for the Ro (SS-A) antibody,but no other patient had an abnormal antinuclearantibody titer. One patient, in addition to the pa­tient with rheumatoid arthritis, had an abnormalrheumatoid factor titer. Circulating immune com­plexes were tested in twelve patients, but only fourhad abnormal levels.

Therapy prior to the use of colchicine includedthe use of oral prednisone in seven patients. In allseven it was effective; however, at initiation of

196 Callen

Table I. Cont'd

Journal of theAmerican Academy of

Dermatology

Patient IAge (yr), INo. sex, race

'Location and type ofvasculitic lesion I

Date of Ionset

Cause or associatedcondition

Date of startLaboratory abnormalities 'of colchicine

7

8

39/W/F Legs: nodules

29/B/F Generalized urticaria

1181 Idiopathic arthralgias None

4/78 Idiopathic None

1183

4/84

9 60/W/F Legs: palpable 4184 Idiopathic (arthritis) None 5/14184purpura

10 78/W/F Legs: palpable 1980 Idiopathic (nephritis CIC + PEG 160 5/27/83purpura arthritis) (nl, 30)

Clq = 46 (nl, 13)RF = 1:5,120

11 54/W/F Legs (feet); palpable 1183 Idiopathic None 3/3183purpura

12 29tW/M Legs: livedo reticu- 8/83 Hyperglobulinemia +Cryoglobulin 8/83laris No crc

13 67/W/F Legs, arms; nodules 1182 Rheumatoid arthritis RF-conglutinin 20 12/7/82PEG 640Clq, 65

years before institution of colchicine therapy(mean, 18.4 months).

The vasculitis was unassociated with a recog­nized etiologic factor or disease in six patients,two patients had hyperglobulinemia, three patientshad lupus erythematosus, one patient had rheu­matoid arthritis, and one patient's disease wasthought to be related to a food dye. Arthritis orsevere arthralgias complicated the cutaneous dis­ease in five patients: two with lupus erythemato­sus, the one with rheumatoid arthritis, and twowith idiopathic leukocytoclastic vasculitis. Onepatient had hematuria and two had proteinuria tran­siently, but renal biopsies were not done.

Laboratory abnormalities were common butgenerally nonspecific. Four patients had an ele­vated erythrocyte sedimentation rate. The two pa­tients with subacute cutaneous lupus erythemato­sus had a positive test for the Ro (SS-A) antibody,but no other patient had an abnormal antinuclearantibody titer. One patient, in addition to the pa­tient with rheumatoid arthritis, had an abnormalrheumatoid factor titer. Circulating immune com­plexes were tested in twelve patients, but only fourhad abnormal levels.

Therapy prior to the use of colchicine includedthe use of oral prednisone in seven patients. In allseven it was effective; however, at initiation of

Volume 13Number 2, Part 1August, 1985

Colchicine in leukocytoclastic vasculitis 197

Additional therapy attime of start of therapy Response Relapse date Response to reinstitution Side effects

Triamcinolone (Ken- Complete steroids Unknown (lost to NoneaIog), 40 mg q3 and NSAIDs follow-up)wk stopped (2/83)

Tolmetin (Toiectin)Dapsone, 150 mg Partial response to Continued activity Not applicable NoneIndomethacin (Indo- colchicine but no need to

cin), 25 mg tid Taper prednisone to t dose ofPrednisone, 30 mg 10 mg qid prednisone

qd Other medicationsstopped 5/84

None (antihistamine) Complete control of 6/14/84 (skin le- Complete response to Noneskin and joint sions only) 1 tablet per dayproblems

Prednisone, 40 mg/ Complete 2/84 Complete response of Diarrhea with threeday Prednisone stopped 9/84 skin to colchicine colchicine tablets

11/25/83 1/85 on 9/84 per day, 9/84Indomethacin (lndo-

cin) used for ar-thritis

None Complete control Relapses 8/83, Complete None12/83, 3/84

None No effect Eventually treated Nonewith prednisoneand azathio-prine

Hydroxych1oroquine Partial prednisone Died Diarrhea on 4 col-(Plaquenil), 200 decreased to 10 chicine tablets permg mg day 1/18/85

Prednisone, 40 mg Hydroxychloroquine Resolved with doseIndocin, 25 mg tid (Plaquenil) reduction

stopped 12/17/82

colchicine therapy, these patients were taking 20to 40 mg of prednisone per day. Other agentsthat had been used included hydroxychloroquinein three patients, nonsteroidal anti-inflammatorydrugs in four patients (indomethacin in three, tol­metin sodium [Tolectin] in one), and dapsone intwo patients. These drugs, other than the predni­sone, were not effective in controlling diseaseexpression in any of the individuals in whom theywere used.

Colchicine therapy initially consisted of 0.6 mgtaken orally twice daily. It was judged to be ef­fective in twelve patients. Effects were uniformlyseen within 7 to 10 days of the start of therapy.

Complete control of disease expression with ces­sation of other therapy (Figs. 1 and 2) was ob­served in nine patients. Partial control, which wasevidenced by a tapering of other therapy (generallyprednisone), occurred in three patients. Of thesethree patients, one (Patient 8) was able to stopindomethacin and dapsone and to lower the pred­nisone dosage from 30 mg/day to 10 mg everyother day, the second (Patient 5) was able to stopdapsone, and the prednisone dosage of the third(Patient 13) was lowered from 40 mg/day to 10mg/day and her hydroxychloroquine was stopped.

Only one patient (Patient 12) failed to respondto oral colchicine. His clinical disease was man-

Volume 13Number 2, Part 1August, 1985

Colchicine in leukocytoclastic vasculitis 197

Additional therapy attime of start of therapy Response Relapse date Response to reinstitution Side effects

Triamcinolone (Ken- Complete steroids Unknown (lost to NoneaIog), 40 mg q3 and NSAIDs follow-up)wk stopped (2/83)

Tolmetin (Toiectin)Dapsone, 150 mg Partial response to Continued activity Not applicable NoneIndomethacin (Indo- colchicine but no need to

cin), 25 mg tid Taper prednisone to t dose ofPrednisone, 30 mg 10 mg qid prednisone

qd Other medicationsstopped 5/84

None (antihistamine) Complete control of 6/14/84 (skin le- Complete response to Noneskin and joint sions only) 1 tablet per dayproblems

Prednisone, 40 mg/ Complete 2/84 Complete response of Diarrhea with threeday Prednisone stopped 9/84 skin to colchicine colchicine tablets

11/25/83 1/85 on 9/84 per day, 9/84Indomethacin (lndo-

cin) used for ar-thritis

None Complete control Relapses 8/83, Complete None12/83, 3/84

None No effect Eventually treated Nonewith prednisoneand azathio-prine

Hydroxych1oroquine Partial prednisone Died Diarrhea on 4 col-(Plaquenil), 200 decreased to 10 chicine tablets permg mg day 1/18/85

Prednisone, 40 mg Hydroxychloroquine Resolved with doseIndocin, 25 mg tid (Plaquenil) reduction

stopped 12/17/82

colchicine therapy, these patients were taking 20to 40 mg of prednisone per day. Other agentsthat had been used included hydroxychloroquinein three patients, nonsteroidal anti-inflammatorydrugs in four patients (indomethacin in three, tol­metin sodium [Tolectin] in one), and dapsone intwo patients. These drugs, other than the predni­sone, were not effective in controlling diseaseexpression in any of the individuals in whom theywere used.

Colchicine therapy initially consisted of 0.6 mgtaken orally twice daily. It was judged to be ef­fective in twelve patients. Effects were uniformlyseen within 7 to 10 days of the start of therapy.

Complete control of disease expression with ces­sation of other therapy (Figs. 1 and 2) was ob­served in nine patients. Partial control, which wasevidenced by a tapering of other therapy (generallyprednisone), occurred in three patients. Of thesethree patients, one (Patient 8) was able to stopindomethacin and dapsone and to lower the pred­nisone dosage from 30 mg/day to 10 mg everyother day, the second (Patient 5) was able to stopdapsone, and the prednisone dosage of the third(Patient 13) was lowered from 40 mg/day to 10mg/day and her hydroxychloroquine was stopped.

Only one patient (Patient 12) failed to respondto oral colchicine. His clinical disease was man-

198 CallenJournal of the

American Academy ofDermatology

Figs. 1 and 2. The hand of a 45-year-old man (Patient 3) had purpuric, erosive lesions inthe nail fold area (Fig. 1). The lesions resolved within 10 days and by I month (Fig. 2)were totally healed.Figs. 3 and 4. The foot of a 78-year-old man (Patient 6) developed palpable purpuriclesions and an ulceration (Fig. 3). After I week of therapy with colchicine, 0.6 mg takenorally twice daily, his ulcer was reepithelialized (Fig. 4). Total resolution occurred within1 month.

ifested by mild purpura, a livedo pattern, and alarge ulceration. In addition, he had hyperglobu­linemia. Each of these characteristics were presentin other patients, although not jointly. Patient 1,with hyperglobulinemia and purpura, respondeddramatically, and Patient 6, who had purpura anda moderate ulceration, also had a dramatic re­sponse. This latter patient received only colchicineas monotherapy in an outpatient setting. Within 1

week he was observed to have had a resolution ofhis purpura and reepithelialization of his ulceration(Figs. 3 and 4).

In addition to the cutaneous disease, nine pa­tients had some evidence of systemic disease, asmanifested by abnormal physical findings or anabnormal laboratory test. Five patients had arthritisor severe arthralgias, and in four, their symptomsor signs were relieved by colchicine therapy alone.

198 CallenJournal of the

American Academy ofDermatology

Figs. 1 and 2. The hand of a 45-year-old man (Patient 3) had purpuric, erosive lesions inthe nail fold area (Fig. 1). The lesions resolved within 10 days and by I month (Fig. 2)were totally healed.Figs. 3 and 4. The foot of a 78-year-old man (Patient 6) developed palpable purpuriclesions and an ulceration (Fig. 3). After I week of therapy with colchicine, 0.6 mg takenorally twice daily, his ulcer was reepithelialized (Fig. 4). Total resolution occurred within1 month.

ifested by mild purpura, a livedo pattern, and alarge ulceration. In addition, he had hyperglobu­linemia. Each of these characteristics were presentin other patients, although not jointly. Patient 1,with hyperglobulinemia and purpura, respondeddramatically, and Patient 6, who had purpura anda moderate ulceration, also had a dramatic re­sponse. This latter patient received only colchicineas monotherapy in an outpatient setting. Within 1

week he was observed to have had a resolution ofhis purpura and reepithelialization of his ulceration(Figs. 3 and 4).

In addition to the cutaneous disease, nine pa­tients had some evidence of systemic disease, asmanifested by abnormal physical findings or anabnormal laboratory test. Five patients had arthritisor severe arthralgias, and in four, their symptomsor signs were relieved by colchicine therapy alone.

Volume 13Number 2, Part IAugust, 1985

In the remaining patient who had long-standing,severe, deforming rheumatoid arthritis, we did notobserve any change in her symptoms, despitedoses as high as 0.6 mg taken four times a day.The two patients with hyperglobulinemia hadsplenomegaly, and both failed to demonstrate anychange in either the spleen size or the immuno­globulin level, even after 2 months of colchicinetherapy. Lesions of cutaneous lUpus erythematosuswere seemingly unaffected by colchicine therapyin the three patients who had this abnormality de­spite the beneficial effects noted on their vasculiticlesions. I was able to retest two patients who re­sponded to colchicine therapy who initially hadabnormal levels of circulating immune complexes.In both cases, on retesting, the levels had droppedback into the normal range. Thus the only param­eters observed to benefit from colchicine therapywere inflammatory joint disease and the level ofcirculating immune complexes.

I have been able to follow ten of the twelveresponders. One patient was lost to follow-up, andone patient died of an acute myocardial infarction.

Colchicine therapy was tapered and eventuallystopped in ten patients who had responded to ther­apy. Of these ten patients who stopped oral col­chicine therapy, three have not had recurrent dis­ease. Fifteen episodes of disease relapse occurredin the remaining seven patients. At the time ofrelapse, none of the patients were taking any othertherapy. Biopsies were not reperformed, but theclinical disease was unchanged from its initialcharacter. In all fifteen instances, the relapse waseffectively treated and controlled solely by thereinstitution of oral colchicine.

Toxicity in this group of patients has been min­imal. In most patients the dosage of 0.6 mg twicedaily did not result in any gastrointestinal symp­toms; however, two patients had intermittent diar­rhea at this dosage, and one patient developed diar­rhea at 0.6 mg taken four times daily. The use ofcolchicine has been continued for an average of11.7 months (range, 3 to 24 months). Despite thislong-term usage, no side effects have been ob­served. Routine blood counts, platelet counts, andserum multiphasic analysis have been performedon a regular basis at least every 3 months. Onlyone patient, with subacute cutaneous lupus ery-

Colchicine in leukocytoclastic vasculitis 199

thematosus, has had an abnormality involvingthrombocytopenia and leukopenia. This abnor­mality was thought to be related to his lUpus er­ythematosus, rather than to colchicine, and hasresponded to a short course « 1 month) of oralprednisone therapy.

DISCUSSION

Twelve of my thirteen patients had a measurableresponse to colchicine therapy. There were no uni­fying characteristics of this group that can be usedto predict their response. Our ,group contained pa­tients with varying etiologic or associated fac­tors-patients with associated systemic diseaseand patients with only cutaneous disease. The vas­culitis was urticarial in some, purpuric in some,and ulcerative in some. Thus it seems unreason­able to exclude a patient from receiving colchicineas a primary or adjunctive therapy unless the dis­ease seems rampant.

This is not the first report of colchicine therapyfor leukocytoclastic vasculitis. Hazen and Michel'reported that four of four patients with cutaneousvasculitis had a good response to oral colchicinetherapy. In addition, a fifth patient with leukocy­toclastic vasculitis associated with cryoglobuline­mia showed no effects from colChicine therapy. Intheir four responders, all had relapse after cessa­tion of therapy and again responded to reinstitutionof colchicine. Furthermore, three of these patientshad arthralgias and responded to colchicine. Theirtrial was for 3 months with a I-month rest period,followed by 2 to 3 months of therapy.

My findings of beneficial effects from colchicinetherapy are similar to those of Hazen and Michel J

with the foHowing exceptions. I treated a largergroup of patients and have continued their therapyfor up to 2 years. We noted similar results witharthralgias in our patients, but in addition, two ofthe patients with objective findings of arthritis alsohad a benefit from colchicine therapy. My groupdiffers in its inclusion of patients with cutaneousleukocytoclastic vasculitis who have "rheumaticdiseases." These patients' vasculitis lesions alsoresponded to colchicine therapy. Last, we had twopatients with dysproteinemias, one of whom re­sponded well. Although the hyperglobulinemia didnot involve a cryoglobulin, the response of our one

Volume 13Number 2, Part IAugust, 1985

In the remaining patient who had long-standing,severe, deforming rheumatoid arthritis, we did notobserve any change in her symptoms, despitedoses as high as 0.6 mg taken four times a day.The two patients with hyperglobulinemia hadsplenomegaly, and both failed to demonstrate anychange in either the spleen size or the immuno­globulin level, even after 2 months of colchicinetherapy. Lesions of cutaneous lUpus erythematosuswere seemingly unaffected by colchicine therapyin the three patients who had this abnormality de­spite the beneficial effects noted on their vasculiticlesions. I was able to retest two patients who re­sponded to colchicine therapy who initially hadabnormal levels of circulating immune complexes.In both cases, on retesting, the levels had droppedback into the normal range. Thus the only param­eters observed to benefit from colchicine therapywere inflammatory joint disease and the level ofcirculating immune complexes.

I have been able to follow ten of the twelveresponders. One patient was lost to follow-up, andone patient died of an acute myocardial infarction.

Colchicine therapy was tapered and eventuallystopped in ten patients who had responded to ther­apy. Of these ten patients who stopped oral col­chicine therapy, three have not had recurrent dis­ease. Fifteen episodes of disease relapse occurredin the remaining seven patients. At the time ofrelapse, none of the patients were taking any othertherapy. Biopsies were not reperformed, but theclinical disease was unchanged from its initialcharacter. In all fifteen instances, the relapse waseffectively treated and controlled solely by thereinstitution of oral colchicine.

Toxicity in this group of patients has been min­imal. In most patients the dosage of 0.6 mg twicedaily did not result in any gastrointestinal symp­toms; however, two patients had intermittent diar­rhea at this dosage, and one patient developed diar­rhea at 0.6 mg taken four times daily. The use ofcolchicine has been continued for an average of11.7 months (range, 3 to 24 months). Despite thislong-term usage, no side effects have been ob­served. Routine blood counts, platelet counts, andserum multiphasic analysis have been performedon a regular basis at least every 3 months. Onlyone patient, with subacute cutaneous lupus ery-

Colchicine in leukocytoclastic vasculitis 199

thematosus, has had an abnormality involvingthrombocytopenia and leukopenia. This abnor­mality was thought to be related to his lUpus er­ythematosus, rather than to colchicine, and hasresponded to a short course « 1 month) of oralprednisone therapy.

DISCUSSION

Twelve of my thirteen patients had a measurableresponse to colchicine therapy. There were no uni­fying characteristics of this group that can be usedto predict their response. Our ,group contained pa­tients with varying etiologic or associated fac­tors-patients with associated systemic diseaseand patients with only cutaneous disease. The vas­culitis was urticarial in some, purpuric in some,and ulcerative in some. Thus it seems unreason­able to exclude a patient from receiving colchicineas a primary or adjunctive therapy unless the dis­ease seems rampant.

This is not the first report of colchicine therapyfor leukocytoclastic vasculitis. Hazen and Michel'reported that four of four patients with cutaneousvasculitis had a good response to oral colchicinetherapy. In addition, a fifth patient with leukocy­toclastic vasculitis associated with cryoglobuline­mia showed no effects from colChicine therapy. Intheir four responders, all had relapse after cessa­tion of therapy and again responded to reinstitutionof colchicine. Furthermore, three of these patientshad arthralgias and responded to colchicine. Theirtrial was for 3 months with a I-month rest period,followed by 2 to 3 months of therapy.

My findings of beneficial effects from colchicinetherapy are similar to those of Hazen and Michel J

with the following exceptions. I treated a largergroup of patients and have continued their therapyfor up to 2 years. We noted similar results witharthralgias in our patients, but in addition, two ofthe patients with objective findings of arthritis alsohad a benefit from colchicine therapy. My groupdiffers in its inclusion of patients with cutaneousleukocytoc1astic vasculitis who have "rheumaticdiseases." These patients' vasculitis lesions alsoresponded to colchicine therapy. Last, we had twopatients with dysproteinemias, one of whom re­sponded well. Although the hyperglobulinemia didnot involve a cryoglobulin, the response of our one

200 Callen

patient suggests that this finding may not be acontraindication of a positive effect.

Although it is possible that cutaneous vasculitiscan spontaneously resolve, the response noted inmost of these patients is inconsistent with a chanceoccurrence. In particular, the response noted wasrapid. Usually within 2 days and at most 1 week,the patient noted a decrease in appearance of le­sions, and resolution had often occurred by 7 to10 days. Furthermore, many of the patients hadrelapses of disease when the colchicine dose waslowered or stopped. These relapses uniformly re­sponded to reinstitution of colchicine as the soletherapeutic agent. Thus this cycle of rapid re­sponse, a relapse with cessation of therapy, andrapid remission again with reinstitution of colchi­cine suggests that suppression of the clinicalexpression is a real phenomenon associated withcolchicine therapy.

Cupps et aF reported a group of patients withchronic cutaneous vasculitis who were seen at theNational Institutes of Health. Several of these pa­tients had previously been treated unsuccessfullywith colchicine, among other forms of therapy.They thus suggest that this therapy may not bebeneficial in this type of patient but conclude thatthe adequacy of the therapeutic trials given wasunknown. This group of patients, however, areselected for nonresponse to other therapy. Onlyone of my thirteen patients was unresponsive.

Colchicine therapy in this group of patients wasremarkably well tolerated. Only a few patients ex­perienced diarrhea or abdominal cramping. Thesesymptoms could be altered with cessation of ther­apy. When the colchicine was reinstituted at alower dose, the side effects would generally notrecur. Long-term toxicity has not been seen in thisgroup of patients.

Hazen and MicheJi and, subsequently, Malkin­sons have reviewed the possible mechanisms ofaction in colchicine therapy. Of particular impor­tance is its effect on the expression of the immuneresponse. Colchicine interferes with the motility,phagocytosis, chemotaxis, and lysosomal degran­ulation of neutrophils. Italso blocks kinin release

Journal of theAmerican Academy of

Dermatology

and histamine release and is inhibitory to micro­tubule formation. Thus it is likely that these mech­anisms would alter the expression of disease. Myobservations of two patients who had evidence ofcirculating immune complexes at the onset of ther­apy are of interest in this regard. Both patients hada return to normal of their circulating immunecomplex levels after therapy. Another responderto therapy had hyperglobulinemia that failed tochange after therapy. It is possible that colchicinewas responsible for the suppression of measurablecirculating immune complexes; on the other hand,it is possible that the cause of the vasculitis spon­taneously resolved and with it the formation ofimmune complexes. The latter consideration is notlikely, since relapse of disease occurred in bothpatients when colchicine therapy was stopped.Thus the mechanism of effect is still not known.

In conclusion, colchicine seems to have a placein the therapy of vasculitis. The findings of thisgroup, as well as previous reports, suggest thatcolchicine is effective in a high percentage of pa­tients with cutaneous leukocytoclastic vasculitis.It may benefit associated arthritis but does notseem to have effects on other associated laboratoryor clinical characteristics. It can be used safely forat least up to 2 years. Colchicine can be a steroid­sparing agent in these patients. Since I believe thatcolchicine is less toxic, particularly over the longterm, than corticosteroids or immunosuppressives,it has been my recent policy to use colchicine asa first-line agent.

REFERENCES1. Hazen PG, Michel B: Management of necrotizing vas­

culitis with colchicine: Improvement in patients with cu­taneous lesions and Behget's syndrome. Arch Dermatol115:1303-1306, 1979.

2. Cupps TR, Springer RM, Fauci AS: Chronic, recurrentsmall-vessel cutaneous vasculitis: Clinical experience in13 patients. JAMA 247:1994·1998, 1982.

3. Ekenstam E, Callen JP: Cutaneous 1eukocytoclastic vas·culitis: Clinical and laboratory features of 82 patients seenin private practice. Arch Dermatol 120:484-489, 1984.

4. Mackel S, Jordon RE: Leukocytoclastic vasculitis. ArchDermatoI1l8:296-301, 1982.

5. Malkinson FM: Colchicine. Arch DermatoI1l8:453-457,1982.

200 Callen

patient suggests that this finding may not be acontraindication of a positive effect.

Although it is possible that cutaneous vasculitiscan spontaneously resolve, the response noted inmost of these patients is inconsistent with a chanceoccurrence. In particular, the response noted wasrapid. Usually within 2 days and at most 1 week,the patient noted a decrease in appearance of le­sions, and resolution had often occurred by 7 to10 days. Furthermore, many of the patients hadrelapses of disease when the colchicine dose waslowered or stopped. These relapses uniformly re­sponded to reinstitution of colchicine as the soletherapeutic agent. Thus this cycle of rapid re­sponse, a relapse with cessation of therapy, andrapid remission again with reinstitution of colchi­cine suggests that suppression of the clinicalexpression is a real phenomenon associated withcolchicine therapy.

Cupps et aF reported a group of patients withchronic cutaneous vasculitis who were seen at theNational Institutes of Health. Several of these pa­tients had previously been treated unsuccessfullywith colchicine, among other forms of therapy.They thus suggest that this therapy may not bebeneficial in this type of patient but conclude thatthe adequacy of the therapeutic trials given wasunknown. This group of patients, however, areselected for nonresponse to other therapy. Onlyone of my thirteen patients was unresponsive.

Colchicine therapy in this group of patients wasremarkably well tolerated. Only a few patients ex­perienced diarrhea or abdominal cramping. Thesesymptoms could be altered with cessation of ther­apy. When the colchicine was reinstituted at alower dose, the side effects would generally notrecur. Long-term toxicity has not been seen in thisgroup of patients.

Hazen and MicheJi and, subsequently, Malkin­sons have reviewed the possible mechanisms ofaction in colchicine therapy. Of particular impor­tance is its effect on the expression of the immuneresponse. Colchicine interferes with the motility,phagocytosis, chemotaxis, and lysosomal degran­ulation of neutrophils. Italso blocks kinin release

Journal of theAmerican Academy of

Dermatology

and histamine release and is inhibitory to micro­tubule formation. Thus it is likely that these mech­anisms would alter the expression of disease. Myobservations of two patients who had evidence ofcirculating immune complexes at the onset of ther­apy are of interest in this regard. Both patients hada return to normal of their circulating immunecomplex levels after therapy. Another responderto therapy had hyperglobulinemia that failed tochange after therapy. It is possible that colchicinewas responsible for the suppression of measurablecirculating immune complexes; on the other hand,it is possible that the cause of the vasculitis spon­taneously resolved and with it the formation ofimmune complexes. The latter consideration is notlikely, since relapse of disease occurred in bothpatients when colchicine therapy was stopped.Thus the mechanism of effect is still not known.

In conclusion, colchicine seems to have a placein the therapy of vasculitis. The findings of thisgroup, as well as previous reports, suggest thatcolchicine is effective in a high percentage of pa­tients with cutaneous leukocytoclastic vasculitis.It may benefit associated arthritis but does notseem to have effects on other associated laboratoryor clinical characteristics. It can be used safely forat least up to 2 years. Colchicine can be a steroid­sparing agent in these patients. Since I believe thatcolchicine is less toxic, particularly over the longterm, than corticosteroids or immunosuppressives,it has been my recent policy to use colchicine asa first-line agent.

REFERENCES1. Hazen PG, Michel B: Management of necrotizing vas­

culitis with colchicine: Improvement in patients with cu­taneous lesions and Behget's syndrome. Arch Dermatol115:1303-1306, 1979.

2. Cupps TR, Springer RM, Fauci AS: Chronic, recurrentsmall-vessel cutaneous vasculitis: Clinical experience in13 patients. JAMA 247:1994·1998, 1982.

3. Ekenstam E, Callen JP: Cutaneous 1eukocytoclastic vas·culitis: Clinical and laboratory features of 82 patients seenin private practice. Arch Dermatol 120:484-489, 1984.

4. Mackel S, Jordon RE: Leukocytoclastic vasculitis. ArchDermatoI1l8:296-301, 1982.

5. Malkinson FM: Colchicine. Arch DermatoI1l8:453-457,1982.