Abstract

Background

Morphea (morphoea) is an immune‐mediated disease in which excess synthesis and deposition of collagen in the skin and underlying connective tissues results in hardened cutaneous areas. Morphea has different clinical features according to the subtype and stage of evolution of the disease. There is currently no consensus on optimal interventions for morphea.

Objectives

To assess the effects of treatments for people with any form of morphea.

Search methods

We searched the following databases up to July 2018: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, LILACS, and five trial registers. We checked the reference lists of included studies for further references to relevant randomised controlled trials.

Selection criteria

Randomised controlled trials of topical, intralesional, or systemic treatments (isolated or combined) in anyone who has been clinically diagnosed by a medical practitioner with any form of morphea. Eligible controls were placebo, no intervention, any other treatment, or different doses or duration of a treatment.

Data collection and analysis

We used standard methodological procedures expected by Cochrane. The primary outcomes were global improvement of disease activity or damage assessed by a medical practitioner or by participants, and adverse effects. Secondary outcomes were improvement of disease activity and improvement of disease damage. We used GRADE to assess the quality of the evidence for each outcome.

Main results

We included 14 trials, with a total of 429 randomised participants, aged between 3 and 76 years. There were juvenile and adult participants; over half were female, and the majority had circumscribed morphea, followed by linear scleroderma. The settings of the studies (where described) included a dermatologic centre, a national laboratory centre, paediatric rheumatology and dermatology centres, and a university hospital or medical centre.

The studies evaluated heterogenous therapies for different types of morphea, covering a wide range of comparisons. We were unable to conduct any meta‐analyses. Seven studies investigated topical medications, two evaluated intralesional medications, and five investigated systemic medications. The study duration ranged from seven weeks to 15 months from baseline.

We present here results for our primary outcomes for our four key comparisons. All of these results are based on low‐quality evidence.

The included studies were at high risk of performance, detection, attrition, and reporting bias.

Global improvement of disease activity or damage after treatment may be higher with oral methotrexate (15 mg/m², maximum 20 mg, once a week, for 12 months or until disease flare) plus oral prednisone (1 mg/kg a day, maximum of 50 mg, in a single morning dose, for three months, and one month with gradually decreased dose until discontinuation) than with placebo plus oral prednisone in children and adolescents with active morphea (linear scleroderma, generalised morphea or mixed morphea: linear and circumscribed) (risk ratio (RR) 2.31, 95% confidence interval (CI) 1.20 to 4.45; number needed to treat for an additional beneficial outcome (NNTB) 3; 1 randomised controlled trial (RCT); 70 participants, all juvenile). This outcome was measured 12 months from the start of treatment or until flare of the disease. Data were not available separately for each morphea type. There may be little or no difference in the number of participants experiencing at least one adverse event with oral methotrexate (26/46) or placebo (11/24) (RR 1.23, 95% CI 0.75 to 2.04; 1 RCT; 70 participants assessed during the 12‐month follow‐up). Adverse events related to methotrexate included alopecia, nausea, headache, fatigue and hepatotoxicity, whilst adverse events related to prednisone (given in both groups) included weight gain (more than 5% of body weight) and striae rubrae.

One three‐armed RCT compared the following treatments: medium‐dose (50 J/cm²) UVA‐1; low‐dose (20 J/cm²) UVA‐1; and narrowband UVB phototherapy. There may be little or no difference between treatments in global improvement of disease activity or damage, as assessed through the modified skin score (where high values represent a worse outcome): medium‐dose UVA‐1 phototherapy versus low‐dose UVA‐1 group: MD 1.60, 95% CI −1.70 to 4.90 (44 participants); narrowband UVB phototherapy versus medium‐dose UVA‐1 group: MD −1.70, 95% CI −5.27 to 1.87 (35 participants); and narrowband UVB versus low‐dose UVA‐1 group: MD −0.10, 95% CI −2.49 to 2.29 (45 participants). This RCT included children and adults with active morphea (circumscribed morphea, linear scleroderma (with trunk/limb variant and head variant), generalised morphea, or mixed morphea), who received phototherapy five times a week, for eight weeks. Outcomes were measured at eight weeks from the start of treatment.

Safety data, measured throughout treatment, from the same RCT (62 participants) showed that treatment with UVA‐1 phototherapy may cause mild tanning compared to narrowband UVB: narrowband UVB versus medium‐dose UVA‐1: RR 0.03, 95% CI 0.00 to 0.42; 35 participants; narrowband UVB versus low‐dose UVA‐1: RR 0.03, 95% CI 0.00 to 0.41; 45 participants. However, there may be no difference in the number of participants reporting mild tanning when comparing medium and low dose UVA‐1 phototherapy (RR 1.00, 95% CI 0.91 to 1.10; 44 participants). Transient erythema was reported in three participants with narrowband UVB and no participants in the low‐ or medium‐dose UVA‐1 groups.

Authors' conclusions

Compared to placebo plus oral prednisone, oral methotrexate plus oral prednisone may improve disease activity or damage in juvenile active morphea (linear scleroderma, generalised morphea or mixed morphea: linear and circumscribed), but there may be a slightly increased chance of experiencing at least one adverse event.

When medium‐dose UVA‐1 (50 J/cm²), low‐dose UVA‐1 (20 J/cm²), and narrowband UVB were compared against each other in treating children and adults with active morphea (circumscribed morphea, linear scleroderma, generalised morphea and mixed morphea), there may be little or no difference between these treatments on global improvement of disease activity or damage. UVA‐1 phototherapy may cause more mild tanning than narrowband UVB, but there may be no difference between medium‐ and low‐dose UVA‐1 phototherapy. These results are based on low‐quality evidence.

Limitations of data and analyses include risk of bias and imprecision (small number of participants or events and wide confidence intervals). We encourage multicentre RCTs to increase sample size and evaluate, with validated tools, different treatment responses according to the subtypes of morphea and age groups.

Author(s)

Julia V de Albuquerque, Brenda NG Andriolo, Monica RA Vasconcellos, Vinicius T Civile, Anne Lyddiatt, Virginia FM Trevisani

Abstract

Plain language summary

Interventions for morphea

Review question

The aim of this Cochrane Review was to assess the effects of treatments, either given in isolation or combination, for people with morphea (morphoea), when compared with an inactive substance (placebo), no intervention, any other treatment, or different doses or duration of a treatment. We collected and analysed all relevant studies published up to July 2018.

Background

Morphea is a rare disease that causes skin hardening. It affects adults and children equally, and is more common in females. There are different subtypes of morphea, with different characteristics: circumscribed morphea is generally less severe than the other subtypes; linear scleroderma can cause significant body differences, possibly affecting growth in children; generalised morphea is a severe type involving multiple areas of the body; pansclerotic morphea is a severe and progressive type of generalised morphea; and mixed morphea is the presence of two or more disease types. Recurrence rates are high, and even when disease activity reduces, a person can be left with permanent effects. This review intended to assess the safety and effectiveness of different treatments for morphea.

Study characteristics

We found 14 relevant studies, with a total of 429 participants, including children and adults aged from three to 76 years. Over half of the participants were female. Most participants had circumscribed morphea, followed by linear scleroderma. Six studies did not describe their setting, but the rest were set in university hospital, medical centre, or national laboratory centre. Seven studies received funding from either universities, government or association scholarships, or the pharmaceutical industry. Six studies had no funding, and one study did not report this information.

Seven studies compared topical medications: phototherapy; an immunosuppressive (suppresses immune system activity); an antiallergic drug; and a corticosteroid (an anti‐inflammatory). Two studies compared medications within the lesion itself: collagen, and an immunomodulator (modifies the immune response). Five studies compared systemic medications (meaning they affect the whole body): an immunosuppressive; traditional Chinese medicine therapies; and a vitamin D analogue (a form of vitamin D). These treatments were compared with either no treatment; placebo; differing doses of phototherapy; hydroxychloroquine (an immune system regulator); emollient petrolatum (moisturising treatment); corticosteroids; an anticoagulant agent (blood thinner) taken with a medicinal plant extract and vitamin E tablet; or antibiotic with base cream. The studies lasted between seven weeks and 15 months.

Key results

The results we present in this summary are based on low‐quality evidence.

Children and teenagers with active morphea (linear scleroderma, generalised morphea and mixed morphea: linear and circumscribed) may experience greater improvement of disease activity or damage with oral methotrexate plus prednisone than with placebo plus prednisone. We would expect that out of 100 children and teenagers, 67 would experience improvement with methotrexate, compared with 29 given placebo; this is based on results measured either 12 months after start of treatment or until flare of the disease. In addition, there may be little or no difference in the number of participants experiencing at least one side effect during treatment (such as hair loss, headache, sickness, tiredness, or liver damage) between those given methotrexate and those given placebo. Side effects from prednisone (given in both groups) included weight gain and stretch marks. We would expect that out of 100 children and teenagers, 56 would experience at least one side effect with methotrexate, compared with 46 given placebo.

Children and adults with active morphea (circumscribed morphea, linear scleroderma, generalised morphea, or mixed morphea) may present similar reduction in disease activity or damage with medium‐dose (50 J/cm²) UVA‐1, low‐dose (20 J/cm²) UVA‐1, or narrowband UVB phototherapy. Those treated with medium‐dose (50 J/cm²) UVA‐1 or low‐dose (20 J/cm²) UVA‐1 phototherapy may have mild tanning after the treatment compared to those treated with narrowband UVB phototherapy. However, there may be no difference in the number of participants reporting mild tanning when comparing medium‐ and low‐dose UVA‐1 phototherapy. Temporary redness was reported in three participants given narrowband UVB and none of the participants in either the low‐ or medium‐dose UVA‐1 groups.

Quality of the evidence

We considered the quality of evidence as low because most studies included few participants and there were concerns over the design of some studies, such as no treatment masking and incomplete analysis.

Author(s)

Julia V de Albuquerque, Brenda NG Andriolo, Monica RA Vasconcellos, Vinicius T Civile, Anne Lyddiatt, Virginia FM Trevisani

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

There is a lack of high‐certainty evidence for the treatment of morphea, and more studies are necessary to establish the optimal treatment, dosage and period of treatment for each morphea subtype. Although the studies were too heterogeneous for a meta‐analysis, the results of this systematic review help to confirm current understandings regarding the effectiveness of different treatments which are used in practice to varying degrees, and identify opportunities for future research. It is important to analyse and balance the risks and benefits of the available treatments, considering the preferences and needs of each individual.

Low‐certainty evidence demonstrates that oral MTX plus prednisone may be more effective than placebo plus prednisone in the global improvement of disease activity or damage for treating active juvenile morphea (linear scleroderma, generalised morphea and mixed morphea: linear and circumscribed). There may be little or no difference in the number of participants experiencing at least one adverse event (e.g. alopecia, nausea, headache, fatigue) when comparing oral methotrexate with placebo.

Low‐certainty evidence indicates that there may be a similar effectiveness between treatment with low‐dose UVA‐1 (20 J/cm²), medium‐dose UVA‐1 (50 J/cm²) and narrowband UVB phototherapy in terms of reduction of disease activity or damage in children and adults with active morphea (circumscribed morphea, linear scleroderma (with trunk/limb variant and head variant), generalised morphea or mixed morphea). UVA‐1 phototherapy may cause mild tanning compared to narrowband UVB phototherapy, but there may be no difference when comparing medium‐ and low‐dose UVA‐1 phototherapy. Transient erythema was reported in three participants with narrowband UVB and in none of the participants in either the low‐ or medium‐dose UVA‐1 groups.

Implications for research 

Future studies could consider investigating the treatment of:

• morphea characterised by superficial and multiple lesions with phototherapy combined with initial systemic corticosteroid treatment versus phototherapy alone;
• linear scleroderma, generalised morphea, pansclerotic morphea or mixed subtype with MTX in combination with initial systemic corticosteroid treatment versus MTX alone;
• refractory morphea previously treated with MTX: phototherapy in combination with MTX versus phototherapy alone; and
• circumscribed morphea with topical tacrolimus versus topical corticosteroid versus placebo.

Different doses and regimens of phototherapy also need assessing. We encourage multicentre studies of national and international collaborative networks to increase sample sizes, which need to be much larger (e.g. 100 to 200). The report of RCTs must follow the CONSORT 2010 statement (Schulz 2010), and include a registered protocol. Studies ideally should have a triple‐blind design (participants, personnel, and outcome assessors), a long‐term follow‐up (more than one year), and use validated outcome measures such as the LoSCAT. Other technical procedures to access outcome measures should also be included, as well as quality of life and psychosocial outcomes. The development of a core outcomes set on morphea in international platforms such as the Cochrane Skin Core Outcome Set Initiative (CS‐COUSIN) may enable greater potential for studies to be pooled in future updates. Global individual assessments are preferable than intra‐individual comparisons. Considering the heterogeneity of the disease, it is important to evaluate, with validated tools, different treatment responses according to the subtypes of morphea and age groups. Studies should report both combined and separate data in case of multiple morphea subtypes or age groups.

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