Chronic graft-versus-host disease-associated muscle cramps: severity and response to immunomodulatory therapies

Abstract

Muscle cramps in patients with chronic graft-versus-host disease (cGVHD) are common and associated with impaired quality of life and symptom burden. Muscle cramps are not currently captured in the 2014 NIH response criteria and thus characterization and response to immunomodulatory therapies is lacking. The objective of this study was to characterize muscle cramp frequency, duration, and pain level in patients with steroid-refractory cGVHD undergoing extracorporeal photopheresis (ECP). A single-center cohort of patients initiating ECP for the indication of steroid-refractory cGVHD with muscle cramps at treatment initiation were followed from April 2021-April 2023. Of 22 patients receiving ECP for cGVHD during the study period, 9 (41%) had muscle cramps at ECP initiation (6/9 [66%] males, median age 59 years [range 25-66]). Seven (78%) had multiple organs involved and 7 (78%) had severe disease by NIH Global Severity. Over median 28 weeks (range 10-48) of treatment, 8/9 (89%) had improvement in frequency of muscle cramps from median 5 episodes/week (range 3/day-2/week) to median <1 episode/week (range 1/month – 3/week). Pain and duration of muscle cramps were not meaningfully changed. NIH Global Severity remained unchanged in 6 (67%) and improved in 3 (33%) patients. Muscle cramps are a morbid feature of cGVHD that may be sensitive to change with standard immunomodulatory therapies. Muscle cramp frequency should be further validated as a response measure in cGVHD.

Introduction:

Chronic graft-versus-host disease (cGVHD) is a leading cause of morbidity, non-relapse mortality, and impaired quality of life, and complicates up to 50% of allogeneic hematopoietic cell transplantations.^1–7 Chronic GVHD is a multisystem disorder that most commonly affects the skin, mucous membranes, gastrointestinal tract, liver, and lung.⁸ Musculoskeletal involvement is also common,^9–11 though clinical features and pathophysiology of this organ system are poorly understood. Musculoskeletal features are reported according to the 2014 National Institutes of Health (NIH) cGVHD Consensus Diagnostic and Response Criteria.^12,13 Diagnostic features include fasciitis, stiffness, and contractures, distinctive features include myositis and polymyositis, and ‘other’ features including edema, arthralgia/arthritis, and muscle cramps. These ‘other’ features are not captured in the response criteria and their response to therapy are not well understood. In an effort to improve the understanding of these atypical features of cGVHD, the NIH Consensus Task Force recently published an update calling for studies that help define the natural history, diagnostic, and grading criteria of these lesser known manifestations.¹⁴

Muscle cramps are a debilitating symptom of cGVHD characterized by rapid onset, painful visible or palpable contraction of single muscles or muscle groups, and residual soreness. The burden of muscle cramps was recently evaluated in a cross-sectional cohort of patients using the muscle cramping question of the GVHD-specific Lee Symptom Scale and was found to be common and associated with impaired health-related quality of life.¹⁰ Despite the prevalence and impact, the pathophysiology of muscle cramps is poorly understood and it is not clear whether they represent a primary manifestation of cGVHD or a secondary symptom to neurologic or non-immunogenic causes.^15,16 As a result, the current therapeutic approach to cGVHD-associated muscle cramps as recommended by the 2014 NIH cGVHD Consensus Ancillary Care working group is symptom-based, including muscle relaxers, elemental supplements, and neuropathic agents, with limited evidence and poor results.¹⁷ In-depth measurement of muscle cramps and the response to cGVHD-directed therapies remain unknown. Extracorporeal photopheresis (ECP) is a therapy for steroid-refractory cGVHD typically administered 1-2 times per week, allowing for frequent collection of cGVHD related clinical data. In this study, we evaluated frequency, duration, and pain intensity of muscle cramping in a cohort of patients receiving ECP for steroid-refractory cGVHD.

Methods:

A single center study was performed at the University of Pennsylvania from April 2021-April 2023. Patients were identified if they received treatment in the extracorporeal photopheresis (ECP) center during the study period. Patients were included if they had a diagnosis of cGVHD by 2014 NIH diagnostic criteria,¹² were receiving ECP (Therakos Cellex, Mallinckrodt Pharmaceuticals, Hampton, New Jersey, United States of America) for the indication of cGVHD, reported active muscle cramps at initiation of ECP, and remained on ECP for at least 8 continuous weeks during the study period.

As part of routine clinical care, patients receiving ECP for the indication of cGVHD complete a cGVHD review of systems, which includes a detailed characterization of muscle cramping thus enabling longitudinal data collection. Muscle cramps were defined as sudden-onset, painful, involuntary muscle contraction. Patients with muscle cramps were asked to report frequency (cramping episodes per day, week, or month), pain severity (visual analogue scale 0-10), and duration of an average cramping episode in the last week.¹⁵ Patients also reported any prescribed or over the counter treatments for muscle cramps. Due to study timing, all patients initiated ECP prior to institutional collection of cramping information and were asked to recall muscle cramp characteristics at time of ECP initiation. Response was determined at the time of the last cramping assessment defined as ECP discontinuation or end of study period if patient remained on ECP. Demographic, transplant, and GVHD characteristics were collected via review of the electronic medical record. The University of Pennsylvania Institutional Review Board approved the study, and informed consent was waived because data were collected as part of routine clinical care, retrospective and deidentified.

Results:

During the study period, 22 patients were being treated with ECP for cGVHD, of which, 9/22 (41%) had muscle cramps at time of ECP initiation and met inclusion criteria. Six (66%) were males, with overall median age of 59 years (range 25-66). Table 1 reports patient characteristics. Six (66%) underwent myeloablative conditioning, 8 (89%) received peripheral blood stem cells, and all patients received methotrexate and tacrolimus GVHD prophylaxis. Organ cGVHD indication for ECP was skin in 8 patients (n=4 sclerotic only, n=2 nonsclerotic only, n=2 sclerotic and nonsclerotic), and lung in one patient (Table 2). Seven (78%) patients had multiple organ systems involved.

Table 1:

Patient Characteristics

Patient	Sex	Age (years)	Race	Underlying Disease	Conditioning Regimen	GVHD prophylaxis	Donor Match / Relation	Cell Source
1	M	58	White	AML	Fludarabine Busulfan	Tacrolimus Methotrexate	Matched Related	PBSC
2	F	66	White	AML	Fludarabine Cyclophosphamide TBI	Tacrolimus Methotrexate	None	Cord
3	F	66	White	MF	Fludarabine Busulfan TBI	Tacrolimus Methotrexate	Matched Unrelated	PBSC
4	M	59	White	MF	Fludarabine Busulfan TBI	Tacrolimus Methotrexate	Matched Unrelated	PBSC
5	M	63	White	AML	Fludarabine Busulfan	Tacrolimus Methotrexate	Matched Unrelated	PBSC
6	M	35	White	AML	Clofarabine Busulfan	Tacrolimus Methotrexate	Matched Unrelated	PBSC
7	F	25	White	AML	Busulfan Cyclophosphamide	Tacrolimus Methotrexate	Matched Unrelated	PBSC
8	M	55	White	AML	Busulfan Cyclophosphamide	Tacrolimus Methotrexate	Matched Related	PBSC
9	M	62	White	CML	Cyclophosphamide TBI	Tacrolimus Methotrexate	Matched Related	PBSC

Abbreviations: M:male, F:female, AML:acute myeloid leukemia, MF:myelofibrosis, CML: chronic myeloid leukemia, TBI:total body irradiation, PBSC:peripheral blood stem cell, GVHD:graft-versus-host disease

Table 2:

Changes in muscle cramping characteristics before and after ECP treatment

Patient	ECP Indication	Other cGVHD organ involvement	ECP Frequency (sessions per week)	Duration between pre and post-ECPa assessment (weeks)	cGVHD Treatment		Muscle Cramp Frequency (episodes per week)		Muscle Cramp Pain (0-10)		Muscle Cramp Duration (minutes)		NIH Global Severity Score
					Pre-ECP	Post-ECPa	Pre-ECP	Post-ECPa	Pre-ECP	Post-ECPa	Pre-ECP	Post-ECPa	Pre-ECP	Post-ECPa
1	Nonsclerotic skin	Eyes, Mouth, Liver	1	29	Prednisone 2.5mg QD	Prednisone 7.5mg QD	4	1b	10	10	10	10	Moderate	Moderate
2	Nonsclerotic skin	None	1	14	Prednisone 30mg QD, Tacrolimus 1.5mg QD	Prednisone 30mg QD, Tacrolimus 1.5mg QD	7	0.5	8	9	0.5	1.5-2	Severe	Mild
3	Sclerotic skin	Joints	2	10	Prednisone 5mg / 7.5mg alternating QD	Prednisone 40mg QD	4	2	7	8	30	30	Severe	Severe
4	Sclerotic skin	Lungs, Liver	2	13	Prednisone 5mg QD, Ruxolitinib 10mg BID	Prednisone 12.5mg QD, Ruxolitinib 10mg BID	21	3	8	7	15	15	Severe	Severe
5	Sclerotic skin	None	0.5	48	Prednisone 40mg QD, Ruxolitinib 10mg BID	None	2	0.5	4	4	2	2	Severe	Moderate
6	Sclerotic skin	Eyes, Joints, Liver	2	30	Prednisone 10mg QD, Ruxolitinib 10mg BID	Prednisone 12.5mg QD, Ruxolitinib 10mg BID, Belumosudil 200mg QD	14	1	7	7	5	3	Severe	Moderate
7	Nonsclerotic and sclerotic skin	Eyes, Joints, Liver	2	28	Prednisone 20mg QD, Belumosudil 200mg QD	Prednisone 12.5mg QD, Belumosudil 200mg QD	4.5	2	5	5	15	5	Severe	Severe
8	BOS	Eyes, Mouth, Liver	2	11	Prednisone 25mg QD, Ruxolitinib 10mg BID, Belumosudil 200mg dQD	Prednisone 20mg QD, Ruxolitinib 10mg BID, Belumosudil 200mg QD	0.25	2	6	6	<1	<1	Severe	Severe
9	Nonsclerotic and sclerotic skin	Lungs Joints	Twice	44	Prednisone 7.5mg Ruxolitinib 10mg twice daily	Ruxolitinib 5mg twice daily Belumosudil 200mg daily	4	0.25	7	4	15	10	Moderate	Moderate

Abbreviations: M:male, F:female, ECP:extracorporeal photopheresis, cGVHD=chronic graft-versus-host disease, wk:week, d:day, m:month, NIH:National Institutes of Health

^aPost-ECP refers to the assessment done at the ECP discontinuation or end of study period if patient remained on ECP.

^bPatient reported < 1 muscle cramp per week.

The duration from ECP initiation to discontinuation or end of study was median 28 weeks (range 10-48 weeks). Eight (89%) patients noted a decrease in frequency of muscle cramps over this time period. Of patients who experienced improvement, the frequency of muscle cramps decreased from pre-ECP median 4 episodes/week (range 0.25-21) to post-ECP median 1 episode/week (range 0.25-3) with no patients experiencing daily symptoms. No patients had complete resolution of muscle cramps. Pain intensity change ≥2 points was improved in 1/8 (13%) and duration of cramping episodes were improved in 3/8 (38%). The one non-responder was receiving ECP for lung cGVHD, and notably had no skin, joint, or fascial involvement.

All patients were on concurrent immunosuppressive therapies at ECP initiation (Table 2). Immunosuppression was increased (n=4), stable (n=3), decreased (n=1), and discontinued (n=1) between the pre-ECP and post-ECP muscle cramp assessments. Of the 4 patients who had increased immunosuppression, 2 increased prednisone by <7.5mg/day and 2 were started on belumosudil. No other treatments directed at muscle cramps were being used, except intermittent topical magnesium in one patient. Chronic GVHD severity by NIH Global Severity remained unchanged in 6 (67%) and improved in 3 (33%) patients. Two patients improved from NIH Global Severity severe to moderate and one patient from severe to mild.

Discussion:

In this study, we characterized cGVHD-associated muscle cramps in a cohort of patients receiving ECP and systemic immunosuppression for the treatment of steroid-refractory cGVHD. We found that muscle cramps were commonly reported and that 89% of patients experienced reduction in muscle cramping frequency while receiving ECP treatment.

Muscle cramps are a frequent complication of cGVHD and are associated with significant morbidity. Muscle cramps, however, are not currently captured in the 2014 NIH response criteria, which are used as the primary outcome for therapy approval in randomized controlled trials.¹³ Muscle cramps are captured by a single question in the Lee Symptom Scale, which is a validated patient-reported outcome measure of symptom bother in cGVHD.¹⁸ In a cross-sectional study of 334 patients, 74% reported muscle cramps on the Lee Symptom Scale, 37% of which categorized their muscle cramps as severe (score >3/5).¹⁰ In this study, we further characterized muscle cramping by frequency, duration, and pain intensity. Frequency of cramping was the feature that was most responsive to change, observed in all treatment responders, while only one patient experienced meaningful improvement in pain and 3 patients experienced improvement in duration of episodes. We also found that many patients had improvement in muscle cramp frequency despite no change in NIH Global Severity score. In patients with highly morbid forms of cGVHD (e.g. joint contractures, sclerosis), ceiling scores are often reached on the current NIH organ-specific measures and subtle improvement on therapy is also difficult to ascertain. Muscle cramps might be more sensitive to change than our current measures and assist in determining therapeutic benefit.

The pathophysiology of cGVHD-associated muscle cramps is poorly understood, which presents a diagnostic and therapeutic challenge. Kraus et al. demonstrated that muscle cramps were associated with increased high-frequency attenuation on nerve conduction studies, a marker of subtle demyelination, and raise the possibility that muscle cramps are subclinical neuropathies that precede severe axonal damage.¹⁵ Others demonstrate that muscle cramps are highly correlated to joint and skin manifestations, suggesting that muscle cramps may be related to these compartments.¹⁰ Interestingly, 3/9 (33.3%) of this cohort had muscle cramping without clinical or laboratory evidence of myofascial involvement (n=2 nonsclerotic skin, n=1 bronchiolitis obliterans), though evaluation with muscle biopsy was not performed. Lehky et al found muscle cramps were similarly prevalent in autologous and allogeneic hematopoetic cell transplantation survivors, suggesting that other non-cGVHD related factors including dehydration, electrolyte imbalances, neuropathy, and immunosuppression and chemotherapy toxicity, may play a role.¹⁹ Non-cGVHD factors should be considered and excluded.¹⁶

The current treatment approach of cGVHD-associated muscle cramps as proposed by the 2014 NIH cGVHD Consensus Ancillary Care working group is symptom-based and includes stretching exercises, pharmacotherapy intended to minimize hyperexcitability of peripheral nerves, and muscle relaxers.¹⁷ Kraus et al. evaluated response (binary yes / no) to muscle cramps of supportive therapies including magnesium, quinine, gabapentin, pregabalin, carbamazepine and found moderate response rates, though this did not control for concurrent immunosuppressive medication.¹⁵ We evaluated the response of muscle cramps to cGVHD-directed therapy primarily through ECP and found an 8/9 patients experienced reduction in muscle cramp frequency. No patients were taking ancillary treatments for muscle cramps. While it is difficult to disentangle treatment effect from the natural history of muscle cramping, consistency across patients and correlation of improvement with stable to improved global scores is reassuring. The positive effect of ECP and other immunosuppressive medication on muscle cramping suggests that immune-based therapies might be preferable to the current standard.

This study is hypothesis generating and is limited by lack of control group and small sample size. Patients were included who had muscle cramping and therefore regression to the mean cannot be excluded. Patients had the potential for recall bias of baseline severity, although consistent findings across 8 subjects supports the observed trend of improvement. In conclusion, this study demonstrates improvement in the frequency of cGVHD-associated muscle cramps in 8/9 patients receiving immunomodulatory therapy and identifies frequency as a feature of muscle cramps that may be responsive to change. Muscle cramping characteristics should be collected prospectively in therapeutic trials as an exploratory outcome to verify these findings and validate formal diagnostic and response criteria.

Highlights:

• Muscle cramps are an atypical feature of chronic GVHD that is not well understood

• Muscle cramp frequency was reduced in patients receiving extracorporeal photopheresis for chronic GVHD

• Muscle cramp pain and duration of episodes did not meaningfully change

• Muscle cramp frequency should be further evaluated as a response measure for chronic GVHD