Current recommendations

It seems that there are no strong data that support the use of corticosteroids in dermatomyositis, whether considering the muscle component, systemic disease such as pulmonary involvement or the skin disease. Despite this, most authorities state that corticosteroids are a mainstay of therapy. Therefore, it seems prudent to use corticosteroids for as short a period of time as is possible, substituting a steroid-sparing agent early in the course of treatment. Which of the agents to use is, in my view, dependent on the clinician's comfort level with the specific agent. Observations from individual case reports and small case series suggest that for skin disease, hydroxychloroquine, methotrexate and mycophenolate mofetil are effective corticosteroid-sparing agents.

IVIG has been the subject of a randomised controlled trial (RCT) and was found to be effective for both the muscle disease and the skin disease in patients with dermatomyositis refractory to corticosteroids and immunosuppressive agents. However, al least one open-label analysis reported that only seven of 19 patients treated with IVIG improved. Also, there has been the suggestion that patients with dermatomyositis have an increased risk of hydroxychloroquine reactions, which may be severe at times. This issue has not been adequately tested.

What about the therapy for juvenile dermatomyositis? This condition is complicated in two major ways. First, patients with juvenile dermatomyositis are more prone to calcinosis and second they may be permanently disabled by contractures. The results of retrospective

Agent/study

Treatments compared/studied

Type of study

Outcome

Comment(s)

Corticosteroids

Winkelmann et ai.3'-'

CS therapy

Retrospective review of DM and PM

Primary endpolnt: outcome of myositis

High-dose regimen (>50 mg/d) favoured

No statistical analysis Mixture of patients

Identified some with an acute, fulminant course

Carpenter et ai,45

Low- 1/high-dose prednisone

Retrospective CCS age-, sex-

No difference In survival

Doses selected to represent "high" dose may

(<10 mg/d v >20 mg/d)

matched PM patients

be too low to be clinically meaningful

Dally 50 mg 1/alternate day

Uchino et aI.46

100 mg prednisone

Retrospective review of patients

Alternate-day regimen more effective:

Groups not comparable groups

IVCS i/OCS

with PM

21/30 1/9/17

Some patients with cancer probably included

Kleln-Gitleman et ai.47

Retrospective comparison of 10 patients

IVCS more costly, but more effective

Small group of patients No statistical analysis

Immunosuppressives

Mosca et al.43

CS alone i/CSwlth immunosuppressive

Retrospective analysis

CS first-line therapy

Metzger et al.4-

MTX for CS-resistant DM/PM

Retrospective analysis of 22

17/22 had improvement In strength or

Minor, reversible toxicity

Initial dose 10-15 mg/wk,

patients (13 DM, 9 PM)

cutaneous lesions

raised to 30-50 mg/wk

Steroid-sparing

(IV or IM)

Al-Mayouf et air0

IV MP with MTX MTX given early i/ late

6 JDM In each group

0/6 1/2/6 developed calcinosis

Small trial

Fisher et ai.'A

CS and MTX for JDM

Retrospective analysis of open-label experience In 35 patients

Mild calcinosis In 5 patients

Calcinosis associated with longer time to diagnosis, longer duration of elevated muscle enzymes and longer disease duration

Table 46.2 (Continued)

Agent/study

Treatments compared/studied

Type of study

Outcome

Comment(s)

Bunch eia/.52

Prednisone 60 mg/d plus AZA 2 mg/kg/d 1/ prednisone plus placebo

3 month DB-PC trial 16 patients with PM

No significant differences

Bunch53

Long-term follow up of previous study

Unblinded continuance for 3 years

Significant benefit In AZA group

Often 8 weeks before affect of immunosuppressive agent noted

Villalba eia/.54

Oral weekly MTX and dally AZA 1/ IV MTX with leucovorin rescue

Randomised, open-label crossover study 18 PM and 11 DM

ITT analysis showed trend In favour of oral combination

Toxicity slightly more common in IV group

Joffe et al.--

Prednisone, MTX or AZA analysed

Retrospective analysis: 113 patients with a variety of types of MM

All agents effective In some patients Advantage of AZA v MTX could not be determined

Certain subsets of patients respond less well: IBM, those with MSAs PM responds less well than DM, some patients crossed over from AZA to MTX and vice versa; equal numbers responded to each agent

Ramirez et al.'"1

Prednisone Initially In 23, AZA (23), MTX (4), CYT (7), TBI (1)

Retrospective analysis of 25 patients with DM (17) or PM (1) or overlap (6) or PM with Ca (1)

15/22 treated with AZA and prednisone had excellent response 1 with prednisone alone and one with no treatment responded

Stepwise approach to treatment with prednisone and early AZA then other immunosuppressive If there is failure suggested

Tausche and Meurer57

MMF alone or with IVIG

Open-label 4 patients

Three-quarters Improved

One patient had cancer-associated DM

Sinoway and Callen53

Chlorambucil for DM

Open-label 5 patients

Steroid sparing

Assessment of myositis primarily

Adams et ai.'J-

Fludarablne 20 mg/m2/for 3 days per month for 6 months recalcitrant PM or DM

Open-label 7 PM, 9 DM patients

Improved: 4 Unchanged:7 Failures: 5

A subset of patients respond to this agent

Table 46.2 (Continued)

Agent/study

Treatments compared/studied

Type of study

Outcome

Comment(s)

Heckmatt et al.m

CYA for JDM

Open-label, retrospective analysis

All had a lower steroid dose, and

AZA failed In 10 patients

(2-5-7-5 mg/kg/d)

of 14 patients

Increased strength

Qushmaq et al"

CYA mean dose 3-5 mg/kg/d

Retrospective analysis of 6 patients (4 PM, 2 DM)

Steroid sparing

No controls

Vencovsky et al.'12

CYA 3-3-5 mg/kg/d i/MTX

Randomised, but not masked

Improvement equal

7-5-15 mg/wk with folic acid

Mixture of PM and DM patients

Steroid sparing

Analysis of reports In the literature Small group Mixture of patients

Plasmapheresis

Dau"

Plasmapheresis with

Open-label retrospective analysis

Increased strength In 32 patients

All patients received the procedure and drugs

prednisone and CYT or

of 35 patients with disease

No comment on effect on skin disease

that might be expected to be effective without

chlorambucil: 15 PM, 11 DM,

recalcitrant to prednisone and

pheresls

7 SDM, 1 each with RA or SS

various Immunosuppressive

and myositis

agents

Miller etaiM

Plasma exchange or leukapheresls 1/placebo

RCT of 39 patients with PM/DM

Equal effect to sham pheresls

Prior open-label trails had been positive

Cherln efa/.£5

Plasma exchange

Retrospective, multicentre

Significant Improvement In acute

PE given with albumin replacement In this

analysis of 24 PM and 33 DM

myopathy only

study

patients In France

Must be combined with an Immunosuppressive agent

Cherln et ai.£,£

IVIG for PM/DM 1 g/kg/d for

Open-label of 14 PM and 6 DM

Statistically significant Improvement In

Toxicity In 4 patients consisted of fever,

2 days each month (n = 3) or

patients

strength and decrease In dose of

sweating, headaches, delirium or vomiting

0-4 g/kg/d for 5 days each

steroids In 15 patients

month (n = 7)

Dalakas et al.67

IVIG v placebo for 3-6

DB-PC trial with crossover of 15

Statistically significant benefit for IVIG

Skin disease, strength, muscle biopsy

months

patients with DM

Improved

Table 46.2 (Continued)

Agent/study

Treatments compared/studied

Type of study

Outcome

Comment(s)

Al-Mayouf et a/.63

IVIG for JDM

Open label 18 JDM patients

Multiple regimens used

Gottfried etai0-

IVIG for DM

Open-label trial of 19 patients (4 with cancer)

7 responders

Non-responders had severe skin and muscle disease, presence of MSA or cancer

IVIG monotherapy In some patients, used after Immunosuppressive agents In some and with Immunosuppressive In some slL-2R levels decreased with response

Miscellaneous

Hollingsworth et ai.70

"Intensive

Immunosuppression" Initial phase ALG: 15 dally Infusions of 750 mg, plus prednisone 150 mg/d tapering to 20 mg/d over 10 days and AZA 2-5 mg/kg/d (max. 150 mg) Maintenance phase: AZA and prednisone adjusted to disease activity

Open-label study of 12 patients

9/12 Improved

Mixed group of patients Included, Including perhaps 3 with malignancy Toxicity was common

Treatments of cutaneous disease of DM

Woo et al.71

Hydroxychloroquine for cutaneous lesions of DM

Retrospective, multicentre analysis of 7 patients

Steroid sparing In 2 patients. CR In 3 patients

No toxicity noted In these patients

Zleglschmld-Adams et al.72

MTX for DM (7) or ADM (3), Initial dose 7-5 or 9-2 mg/wk raised to 14-2 or 20 mg/wk for DM or ADM

Retrospective analysis

9/10 had Improvement of skin disease

Mild, reversible toxicity In 7 patients Liver biopsy In 4 patients, 2 had hepatic fibrosis (grade IIIA)

Table 46.2 (Continued)

Agent/study Treatments

Type of study

Outcome

Comment(s)

compared/studied

Kasteler and Callen75 MTX for DM

Retrospective analysis

CR-4

Minimal toxicity

Eventual dose 2.5-30 mg/wk

13 patients

PR-9

Steroid-sparing

Gelber et al.7A MMF for recalcitrant DM

Open label

Steroid sparing

-

4 patients

ALG, antilymphocyte globulin; ADM, amyopathlc dermatomyositls; AZA, azathioprlne; CA, Calcium; CCS, clinical case series; CR, complete response; CS, corticosteroids; CYA, Ciclosporin; CYT, cyclophosphamide; DB-PC, double-blind, placebo-controlled; DM, dermatomyosltis; IBM, inclusion body myositis; MM, Idiopathic inflammatory myopathy; ITT,

ALG, antilymphocyte globulin; ADM, amyopathlc dermatomyositls; AZA, azathioprlne; CA, Calcium; CCS, clinical case series; CR, complete response; CS, corticosteroids; CYA, Ciclosporin; CYT, cyclophosphamide; DB-PC, double-blind, placebo-controlled; DM, dermatomyosltis; IBM, inclusion body myositis; MM, Idiopathic inflammatory myopathy; ITT,

Intention-to-treat; JDM, juvenile dermatomyosltis; MSA, myosltis-speclfic antibodies; OCS, oral CS; IM, Intramuscular; IV, intravenous; IVCS, intravenous corticosteroids; IVIG, Intravenous immunoglobulin; MMF, mycophenolate mofetil; MP, methylprednlsolone; MTX, methotrexate; PM, polymyositis; RCT, randomised controlled trial; RA, rheumatoid arthritis; SDM, sclerodermatomyosltis; SIL-2R, soluble lnterluekln-2 receptor; SS, Sjogren's syndrome; PR, partial response; TBI, total body irradiation case series suggest that the use of early "aggressive" therapy will limit the possibility of calcinosis. However, there are no studies that clearly demonstrate the veracity of this statement. Klein-Gitleman et a/.47 believe that high-dose, intravenous pulsed methylprednisolone limits the risk and severity of calcinosis. However, adequate RCTs have not yet corroborated this belief. It does appear that whatever the treatment, combination with physical therapy will prevent contractures from developing and that even if contractures occur, the use of physical therapy might improve the long-term disability. Once established, calcinosis may resolve spontaneously after a period of months to years; however, there are multiple individual case reports and some small series suggesting that various therapies, including warfarin, diltiazem and probenecid, are effective in reversing the calcinosis.

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