Treating Pediatric Localized Scleroderma

What Happens After Your Child is Diagnosed?

After your child is diagnosed with localized scleroderma, he or she should be followed closely be a pediatric rheumatologist with the help of a pediatric dermatologist.

The work-up includes:

  • Evaluating if tissues besides the skin (extracutaneous) are affected.
  • Determining if there is inflammation, meaning that the disease is active

This will help determine what treatment is needed, and if other specialists should also be involved in your child’s care.

 

Treatment Goals

The overall goal of treatment and management is to minimize the impact of the disease on your child’s current and future life, weighing the risks and benefits of medication. If inflammation is untreated, then there is often at risk for abnormal growth of affected tissues that could result in that part of the body or head being smaller than the other side (hemiatrophy). There is also a potential risk for limited function and pain. So controlling inflammation is very important to avoid severe damage to skin, tissues, and bones, and thereby enable the child to grow and develop normally, and participate in all their normal activities.

If there is inflammation, then medication(s) are needed to suppress the activity.

For many children, controlling inflammation requires taking medications orally or as injections or infusions.

Inflammation is present at the earliest stages of jLS. If it is not controlled, then the disease progresses to a stage of fibrosis or hardening that results in loss of normal cells and structures. This can result in permanent damage. Because current medicines work on inflammation and not fibrosis, the window of opportunity for best outcome is to treat early in the disease course. Treating early and aggressively usually stops the inflammation and prevents the development of severe damage. Once inflammation is controlled, healing of damaged areas can often happen, improving function and sometimes restoring some of the lost tissue.

Working closely with occupational and physical therapy can help improve your child’s function if it has been impacted by the disease.

  • Decrease inflammation, pain, stiffness, itching and other discomfort
  • Reduce the severity of the disease
  • Prevent or minimize functional impairments (i.e., difficulty with grasping, reaching, walking, running, bending, chewing)
  • Prevent or minimize permanent cosmetic differences
  • Increase or maintain a child’s normal activity level and quality of life
  • Prevent permanent damage, such as limb length differences or permanent joint limitations (“contractures”)

It should be noted that the earliest stage of jLS lesions involve tissue inflammation, which if not treated, will progress to a stage of fibrosis or hardening that may cause irreversible changes. For this reason, it is important to treat early and aggressively to extinguish inflammation and try to prevent damage before it occurs.

 

Why is Treating the Disease Different for Different Patients?

Treatment regimens have been developed that are effective for most patients with juvenile localized scleroderma. However, because people differ in their pattern of disease and their response to treatment, the treatment can also vary for different patients.

  • Some children may have a single, superficial spot of circumscribed morphea in an area that doesn’t cause significant problems and treatment with creams such as topical steroids might be enough for them. However, some of these children may have disease affecting joints or other tissues remote from the skin lesion. If they do, then they need more than topical treatment.
  • Children with more extensive disease (i.e., generalized or pansclerotic morphea), or deeper lesions (linear scleroderma of limb, trunk, or head, or deep circumscribed lesions), are at higher risk of developing moderate to severe damage, pain, and impaired function and require a different treatment approach.
  • Lesions crossing joints may affect how the limb grows or cause problems with joint movement, and those on the trunk can cause breast, buttock, or other soft tissue loss. Lesions on the head, as in en coup de sabre or Parry Romberg Syndrome, could lead to dental, eye, or neurological issues. In these cases, a closer follow up is necessary and care by orthopedic surgeons, dentists, eye doctors or pediatric neurologists might be required.

How to Determine the Best Treatment Choice for Your Child?

To help determine the best treatment choice for your child, your pediatric rheumatologist and/or dermatologist may consider the following questions:

  1. Where are the lesions from localized scleroderma located? Is it near the head, joints, and/or cosmetically sensitive areas?
  2. How deep is its involvement?
  3. Is the disease affecting growth or causing symptoms in other areas outside of the skin?
  4. Does the disease appear active or inactive? Is it progressing?
  5. How long has this child had localized scleroderma?
  6. Is there new pain or discomfort? Have any symptoms recently changed?

Answering these questions may help determine if your child can be treated only with topical treatment such as creams or needs systemic therapy with oral or injected medicines.

  • Active disease and
  • Lesions localized in the head or face, affecting deeper tissues (such as muscle or joints), and/or affect a large portion of the body, or are considered to have a moderate or severe risk for serious damage

If the disease is “inactive” and has remained in this state for at least 1 to 2 years, your child may no longer need systemic medications. The duration of treatment should always be individualized, so regular follow up with their pediatric rheumatologist and/or dermatologist is needed to assess if the disease is remaining inactive, and that no other problems have developed.

 

What is the Purpose/Goal of Different Medications and Therapies?

There is no single, perfect therapy for all localized scleroderma patients. However, from many studies, certain systemic immunosuppressant medications have been found to be effective for the majority of patients. These medications help control the ‘overactive’ immune system to get it functioning back to a more normal neutral state. This means that the immune system stops being focused on attacking the body’s normal tissues and can instead goes back to its normal role to fight germs.

Currently, the most commonly used medications are corticosteroids and “steroid-sparing” medications such as methotrexate, and mycophenolate mofetil. This may evolve over time as new research and studies identifies other therapies.

Systemic medications are prescribed for children and teens with localized scleroderma who have deep tissue involvement, including extracutaneous involvement, and widespread involvement. These children and teens are at risk for disability, disfigurement, or other complications. This includes children and teens with linear scleroderma either alone or as part of mixed morphea, lesions of the head, generalized morphea, and pansclerotic morphea.

  • Methotrexate
  • Corticosteroids:
  • Mycophenolate Mofetil (CellCept or Myfortic):

Methotrexate

An anti-inflammatory drug that is referred to as a Disease Modifying Anti-Rheumatic Drug (DMARD). Methotrexate is commonly used to treat a number of rheumatologic conditions, including juvenile idiopathic arthritis. At doses used in rheumatology, methotrexate is not significantly immunosuppressive, but rather acts as a powerful combatant of inflammation. Current research finds that methotrexate is effective in two-thirds of children with localized scleroderma, and is considered standard of care treatment for patients with a risk of moderate to severe localized scleroderma by pediatric rheumatologists (https://pubmed.ncbi.nlm.nih.gov/30826775/v; https://pubmed.ncbi.nlm.nih.gov/22505322/). Methotrexate can either be injected under the skin (subcutaneous injection) or administered orally. Generally, the subcutaneous form is recommended since it is more effective (none is lost in gut absorption).

Of note, methotrexate is also used in much, much higher doses as a chemotherapy for children with cancer. The doses used in pediatric rheumatology are several orders lower, so much safer and less likely to cause major side effects. The doses used in rheumatology are not associated with the same level of immunosuppression as when it is used for cancer treatment.

Corticosteroids

Steroids are a powerful anti-inflammatory treatment that work quickly and effectively to decrease inflammation. Side effects prevent the ability to use steroids in high doses for long durations, so their role is typically as a “bridge”, given in parallel with other medications to help gain control of jLS while waiting for other medications (with fewer side effects) to start working. For example, methotrexate can take up to 3 months to reach effectiveness, so is often combined with corticosteroids during the initial stages of treatment. Names of commonly used steroids include methylprednisolone, prednisolone and prednisone. Steroids can be given intravenously and/or orally.

Mycophenolate Mofetil (CellCept or Myfortic):

Another DMARD, like methotrexate, that modifies the immune system and does not necessarily suppress immune function. It is used to treat a number of autoimmune illnesses, including jLS. It can be used either alone or in combination with methotrexate or other medications, depending upon the stage and severity of disease. Mycophenolate is given orally, as a liquid or pill, typically twice a day.

 

Other Supplemental Therapies Include:

  • Topical agents (creams)
  • Light based therapy
  • Physical and Occupational therapy (shoe lifts or orthotics if there is a leg length discrepancy)

  • Topical agents, such as creams or ointments such as corticosteroids, derivatives of vitamin D, and tacrolimus, are applied to the skin and have anti-inflammatory effects (reduce inflammation) and can soften hard lesions.
  • They are commonly used to treat superficial, circumscribed isolated skin lesions,
  • They should not be the only treatment used in patients with deeper (such as linear scleroderma) and widespread lesions as they are only absorbed into the superficial skin.
  • They can be used in tandem with systemic medication therapy.
  • Light based therapy – UV-light treatment, UV-A or UV-B, may also be considered in a subset of patients depending on the disease extent, lesion depth. and lesion distribution
  • Light therapy is typically managed by a dermatologist in combination to following with a pediatric rheumatologist
  • This treatment is not recommended for patients with deep tissue involvement
  • Physical and occupational therapy – are important adjunct therapies for children who have functional impairment such as limited joint mobility, muscle weakness, or limb length differences from the disease.
  • PT can help teach your child exercises to increase the joint range of motion and strengthen their muscles. They can also be helpful with decreasing pain related to deep tissue involvement, and can improve the child’s gait and function by prescribing.

What Other Medications or Therapies Could be Used?

A smaller proportion of children with localized scleroderma that require systemic medications may have inadequate response to standard treatment or develop significant side effects. Alternative medications are now being studied for these patients, most of which are given as infusions (through an intravenous line) or as subcutaneous (under the skin) injections. More study is needed to determine if and when to use these medicines.

  • Biologics
  • Immunomodulators

 

Biologics

These drugs are being explored for the management of many rare diseases. In localized scleroderma, these are the “new kids on the block”, therefore limited studies exist to date. However, some promising drugs have emerged for their potential use in patients that are resistant to, or do not tolerate other therapies:

  • Abatacept (or Orencia)
  • Tocilizumab (or Actemra)
  • Tumore Necrosis Factor inhibitors (TNFi). Includes Infliximab (or Remicade/Renflexis/Inflectra), adalimumab (humira), etanercept (Enbrel)

Abatacept (or Orencia) targets and disrupts the way inflammatory T cells communicate. It can be effective for certain types of localized scleroderma with deep tissue involvement, specifically for those with joint involvement. It is an FDA approved medication for juvenile arthritis and has a good safety profile.

Tocilizumab (or Actemra) blocks an inflammatory protein called interleukin-6 (IL-6). This medicine was effective as rescue therapy in a group of children with different types of localized scleroderma that had failed other therapies. It is an FDA approved medication for juvenile arthritis.

Tumore Necrosis Factor inhibitors (TNFi). Includes Infliximab (or Remicade/Renflexis/Inflectra), adalimumab (humira), etanercept (Enbrel)

This group of medicines works by targeting a protein in the body, TNF-alpha, that regulates inflammation. These are FDA approved medications for juvenile arthritis.

 

Immunomodulators

The term “immunomodulators” refers to certain medicines that help regulate or normalize the immune system. Some are relatively new (JAK inhibitors) while others have been used for decades to treat different autoimmune conditions. For most of these medicines, there are only limited case reports about their efficacy for localized scleroderma.

  • Cyclophosphamide (Cytoxan)
  • Cyclosporine
  • Hydroxychloroquine (plaquenil)
  • Intravenous Immunoglobulin (IVIG)
  • Janus Kinase (JAK) inhibitors
  • Tacrolimus
  • Rituximab (Rituxan)

Cyclophosphamide (Cytoxan) is a very strong anti-cancer chemotherapy drug that at reduced doses helps treat autoimmune diseases that are more severe in presentation or are difficult to treat. Cyclophosphamide has been rarely used to treat very severe forms of localized scleroderma such as severe pansclerotic morphea.

Cyclosporine is part of a family of medicines called calcineurin inhibitors most commonly used to prevent rejection in people who have received an organ transplant. By reducing the function of certain cells of the immune system called T-lymphocytes it also helps treating autoimmune diseases including localized scleroderma.

Hydroxychloroquine (plaquenil) It is considered a disease-modifying anti-rheumatic drug fro inflammatory arthritis, and also has been found to be beneficial for patients with systemic lupus erythematosus. It is not an immunosuppressant but is thought to interfere with communication of cells in the immune system, and has been reported to be of benefit for localized scleroderma.

Intravenous Immunoglobulin (IVIG) a blood product obtained from thousands of donors that contain antibodies (immunoglobulins) which your body naturally produces to fight infections or eliminate foreign bodies. IVIG may help modulate the immune system in localized scleroderma by neutralizing or blocking autoantibodies that damage and produce inflammation of the tissues. Most studies show efficacy in treating systemic sclerosis but reported cases of patients with localized scleroderma also showed some benefit. It is FDA approved in juvenile dermatomyositis.

Janus Kinase (JAK) inhibitors with certain signals needed for activation of the immune system. Case reports show efficacy of tofacitinib (a specific type of JAK-inhibitor) in treating severe forms of localized scleroderma. It is FDA approved for children with juvenile arthritis.

Tacrolimus cyclosporine, tacrolimus is a calcineurin inhibitor used to prevent transplant rejection and treat certain autoimmune conditions.

Rituximab (Rituxan).

 

Working to Identify “Best” Therapies

Many studies have identified methotrexate as an effective treatment for active disease. This treatment works in about 70% of patients the first time it is given. Pediatric rheumatologists and many other physicians agree that methotrexate should be used to treat active disease in jLS patients at risk for moderate or higher levels of damage.

Ongoing efforts are directed towards identifying the most effective, “best”, treatment regimen(s), especially identifying factors that are associated with poorer/better response to treatment, use of corticosteroids, including type, dose, and duration, and how long to treat.

More studies are also needed to figure out how to treat patients whose disease is not controlled by methotrexate with or without corticosteroids.

  • In LS, because there are no laboratory tests, clinical tools or measures are used to assess disease status, especially disease activity. To be able to study different treatments in LS, physicians need to agree on the tools to use, and how to standardize their use.
  • Clinical measures for evaluating level of skin activity and disease morbidity were developed by the LS working group of CARRA (Childhood Arthritis and Rheumatology Research Alliance), the North American pediatric rheumatology research network. This group also developed other tools needed for conducting treatment studies.
  • While methotrexate has been identified as an effective treatment, there are differences between pediatric rheumatologists and other physicians on the “best” dose, need for concomitant corticosteroids, and duration. CARRA members have been working to answer some of these questions. Once a “best” methotrexate regimen is identified, then more studies would be done to compare this regimen against other medications and regimens in an iterative process to identify “best” regimen for patients with different LS problems. These types of studies, called comparative effectiveness (CE) studies, will allow us to evaluate new medications as they become available, with studies carried out as an extension of routine care.
  • CARRA members recently completed a pilot CE study of 50 children and teens beginning methotrexate with one of 3 regimens, showing that this approach is feasible. (https://pubmed.ncbi.nlm.nih.gov/31615917/)
  • A recent study by pediatric rheumatologists and dermatologist support following these consensus treatment plans as this was associated with a lower need for other treatments. (https://onlinelibrary.wiley.com/doi/abs/10.1111/pde.14074)
  • CARRA members also used some of the clinical tools they developed in a retrospective study that evaluated abatacept treatment of 18 patients who had had an inadequate response to methotrexate. Most of the patients showed improvement, with some also have improvement in their muscle and joint involvement (doi: 10.1093/rheumatology/keaa873).

LINKS

https://onlinelibrary.wiley.com/doi/full/10.1002/acr.21687

https://ard.bmj.com/content/78/8/1019.long

 

Do Children and Adolescents with LS ever Require Surgery?

Orthopedic surgical interventions may be considered in children with localized scleroderma that have developed problems with their joints or limbs. Plastic surgery may be considered for those who have lost tissue in cosmetic sensitive areas such as the face, head or scalp. Surgical procedures should be individualized for every patient and be considered based on your child’s needs.

Orthopedic surgeons can help improve problems such as joint contractures (a fixed flexed position of the joints), joint angulation defects, and limb length differences. They can perform surgery that can help straighten the joints by releasing stiff tendons or other tissues around the joints, and procedures to lessen the difference in length between the two legs.

Plastic surgeons can help reconstruct depressed areas in the head or face, and in improving appearance if there is breast or buttock asymmetry. This might be done by fat grafting techniques, or by injecting or inserting artificial fillers intended for this purpose. Sometimes reconstructive surgery involves altering bony tissues of the face.

Although the optimal time for surgery has not been established, it should be undertaken with caution and ideally with at least 6 months of disease inactivity.

 

Monitoring During Ongoing Treatment

You child’s pediatric specialists will ensure that the treatment matches the child’s specific case of localized scleroderma. It is important to see your doctors regularly during treatment, which may mean visits every 1-3 months when the disease is active, and less when the disease is considered to be in remission. If you are on systemic treatment, your doctor will be periodically doing laboratory studies on you to be sure there are no side effects related to the medications. It is also important to see your doctors at least once per year after stopping treatment to check if there are any signs of relapse (when the disease returns after a period of improvement).

A child with localized scleroderma often needs to be examined by other physicians including a pediatric ophthalmologist, neurologist, orthopedist, or other specialist. For children that have LS involvement of their head, it is strongly recommended that they get an initial and routine eye and dental checks.

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Where to Start Find Your Path

No two scleroderma journeys are the same, but there are common experiences along the way. No matter where you, your child, or a loved one are in your journey, or the type of scleroderma, the National Scleroderma Foundation can help you find your best path.