Table 2.
Characteristics of literature review.
| Author(year/country) | Age of onset/gender/Age of diagnosis | HGVSc/ HGVSp | Skin lessions | Pulmonary involvement | Other Manifestations | JAK Inhibitors | Response to JAK Inhibitors and Prognosis |
|---|---|---|---|---|---|---|---|
| Shen D (2022/ China) (17) |
8m/M/19m | c.463G>A/ p.V155M (de novo) |
facial rash; chilblain-like rash on the auricles; recurrent oral ulcers | ILD | developmental delay (height <-3SD; weight <-2SD, >-3SD) | tofacitinib(2.5mg, bid) | Following a three-month course of tofacitinib therapy, the skin lesions resolved, and a high-resolution chest CT scan revealed an improvement in ILD. Despite these positive outcomes, recurrent oral ulcers and growth retardation remained unchanged, and there was no notable progress in serum immunoglobulins or immune phenotype. |
| Yu ZX (2018/ China) (18) |
After birth/M/14y | c.463G>A/ p.V155M (de novo) |
recurrent chilblain-like rash; telangiectasia; hair loss | ILD; PAH; hypoxemia; restrictive ventilatory dysfunction | right heart enlargement; developmental delay (height at P3-P10; weight < P3) | tofacitinib (5mg, bid) | Two weeks later, he no longer had hypoxemia, his activity tolerance increased, and he could sustain moderate-intensity exercise for more than 15 minutes. |
| Tang X (2020/ China) (19) |
3m/F/12m | c.463G>A p.V155M (de novo) | chilblain-like rash; telangiectasia | ILD | recurrent fever; myositis; developmental delay | tofacitinib(2.5mg,bid) | In the early stage, rash and respiratory symptoms showed improvement, yet recurrent fevers persisted. CT scans indicated progression of the disease, and ultimately, the patient succumbed to acute respiratory failure at the age of 20 months during an outbreak of influenza. |
| 54m/M/60m | c.463G>A/ p.V155M (de novo) |
telangiectasia; erythema; purpura; scaly rash | ILD | recurrent fever; arthritis; ureteral stones; cerebrovascular involvement | tofacitinib(2.5mg,bid) | During the initial four months of treatment, the patient experienced improvement in respiratory symptoms; however, CT findings deteriorated, while joint pain resolved. Following three months of therapy, the rash intensified, necessitating treatment with prednisone at 1mg/kg for its amelioration. Ten months later, tofacitinib was discontinued spontaneously, and the prednisone dosage was decreased. Notably, respiratory and joint symptoms remained stable, yet the rash worsened, and the patient continued to survive. | |
| Tokgun PE (2023/ Turkey) (21) |
U/F/45y (mother) |
c.580G>T/ p.V194L |
multiple skin swelling; bruises | --- | rheumatoid arthritis; psoriatic arthropathy | tofacitinib(5mg,bid) | All symptoms were reduced by approximately 70% within two weeks and completely disappeared after one month of treatment, and tofacitinib treatment has been continued for more than a year. |
| U/F/20y (daughter) | c.580G>T/ p.V194L (inherited from mother) |
multiple skin swelling; bruises | --- | rheumatoid arthritis; psoriatic arthropathy | tofacitinib(5mg,bid) | Within two weeks, all symptoms had decreased by roughly 70%, and they vanished entirely after a month of treatment. The patient has been continuously treated with tofacitinib for over a year now. | |
| Kim HR (2024/ Korea) (6) |
2m/M/29y | c.439G>A/ p.V147M (de novo) | multiple erythema and pustules; chilblain-like rash, pustular psoriasis; nasal septal perforation; foot gangrene |
ILD; hypoxemia; restrictive ventilatory dysfunction | proteinuria, class II lupus nephritis of kidney biopsy | tofacitinib(dosage not mentioned) | The patient’s lung condition did not improve after treatment with tofacitinib. The patient’s mobility was severely limited due to breathing difficulties and he eventually required a lung transplant. |
| Seo J (2017/ Korea) (7) |
6m/M/9y | p.S102P +p.F279L (inherited from father) | telangiectasia with gangrenous lesions; nasal septal perforation | bronchiolitis obliterans with peribronchial inflammation; hypoxemia | acute cerebral infarction and subarachnoid hemorrhages | tofacitinib(5mg/day) | After three months of tofacitinib treatment, the patient's telangiectatic skin lesions showed improvement, while the lung damage remained unchanged. |
| Barry KK (2024/ America) (14) |
U/M/5y | p.R284T (de novo) | reddish-purple reticular plaques on the face and extremities; edema of the hands and feet; scarring of the toes; saddle nose deformity; sparse hair | --- | developmental delay (height and weight <P1), severe congenital neutropenia; perirectal abscesses; inflammatory polyarthritis | tofacitinib (3.2mg,bid) |
After six months of tofacitinib treatment, the patient showed clinical improvement in skin symptoms, with ulcers healing, hair regenerating, and weight gain observed. However, progressive destructive arthritis persisted, leading to a switch back to adalimumab, methotrexate, azathioprine, and hydroxychloroquine for further management. |
| Volpi S (2019/ Italy) (3) |
8m/F/9y | c.463G>A/ p.V155M (de novo) |
erythematosus-infiltrated skin lesions with pustular evolution; scarring; chilblains; nail dystrophy | ILD; mixed ventilatory dysfunction | recurrent fever, microscopic hematuria, mild proteinuria | ruxolitinib(0.65mg/kg/day) | Clinical symptoms showed improvement within a few weeks and markedly improved after three months. This progress was evident in the amelioration of lung disease, complete resolution of skin lesions, disappearance of microscopic hematuria, and the eventual discontinuation of steroids after two years. |
| 3m/F/7y | c.842G>A/ p.R281Q |
malar rash, livedo reticularis on lower limbs | ILD; PAH; hypoxemia | recurrent lower respiratory tract infections; developmental delay; hypertension | ruxolitinib(0.7mg/kg/day) | In the early stage of ruxolitinib treatment, skin symptoms improved, dyspnea was relieved, blood oxygen saturation increased (84% to 98%), echocardiography showed improvement in PAH, and pulmonary artery size returned to normal; hospitalization due to recurrent respiratory tract infection after 7 months of treatment; ILD lesions worsened after 18 months of treatment. | |
| 3d/F/3y | c.461A>G/ p.N154S (de novo) |
multiple erythematosus vesicular rash, pustules and scars | ILD | --- | ruxolitinib(1.25mg/kg/day) | In the early stage of ruxolitinib treatment, skin lesions and lung imaging improved; lung disease recurred after 10 months of treatment, requiring the addition of prednisone (2 mg/kg/day). | |
| Li W (2022/ China) (20) |
3m/M/1y3m | p.N154S | chilblain-like rash; ulcers; erythema | ILD; hypoxemia | recurrent fever; developmental delay (weight < -2SD) | tofacitinib (0.5mg/kg/day), ruxolitinib (0.5mg/kg/day) | After tofacitinib treatment, the fever subsided, the rash improved, which only appeared in winter and was mild in severity and duration, with little restriction in daily activities, and chest CT improved. Due to unsatisfactory control of CRP and ESR, tofacitinib was replaced with ruxolitinib after 15 months of treatment, and the median dose of prednisone was reduced to 0.20 (0.11-0.36) mg/kg/day, and the autoantibody level decreased. |
| 6m/M/12y10m | p.V155M | chilblain-like rash; telangiectasia | ILD; PAH; hypoxemia; severe restrictive lung dysfunction | right ventricular enlargement; developmental delay (weight < -2SD) | tofacitinib (0.38mg/kg/day) | The rash completely disappeared and steroids were discontinued. Daily activities were basically unrestricted, PAH improved, and anti-PAH treatment was still maintained. There was no significant change in chest CT, but the level of autoantibodies decreased. | |
| Saldanha RG (2018/ Australia) (22) |
2m/M/3y | c.850A>G/ p.R284G (de novo) |
erythematous papules, blisters, and livedo reticularis on the limbs | ILD; PAH | global developmental delay | ruxolitinib(5mg/day) | After 8 weeks of ruxolitinib combined oral prednisolone (2 mg/kg/day) and anti-pulmonary hypertension treatment, respiratory symptoms and mobility improved, and gross motor and fine motor skills and language improved rapidly; 5 months after treatment, body weight increased from <P3 to P20; however, the lividinous rash persisted, and the nasal septum was completely lost 6 months after ruxolitinib treatment. |
| Wang Y (2021/ China) (8) |
36y8m/M/37y (father) | c.841G>A/ p.R281Q (de novo) |
nail dystrophy | ILD; PAH; hypoxemia;severe restrictive lung dysfunction | --- | ruxolitinib(0.2mg/kg/day) | The escalation of the ruxolitinib dose was poorly tolerated, and the patient died 4 months later due to ILD progression and heart failure. |
| 2y/M/13y (son) | c.841G>A/ p.R281Q(AD) |
--- | ILD; restrictive lung dysfunction | polyarthritis, joint pain, developmental delay (height and weight < P3) | ruxolitinib(0.16mg/kg/day) | The escalation of ruxolitinib dose was poorly tolerated, with no improvement in arthritis, arthralgia, or chest CT. | |
| Berrada KR (2023/ France) (23) |
5y/M/12y | p.V155M (AD) |
chilblain-like rash; telangiectasia | ILD; hypoxemia; | recurrent fever | ruxolitinib(0.4mg/kg/day) | Despite treatment with ruxolitinib, his respiratory status continued to deteriorate until he had recurrent pneumothoraces, requiring bilateral lung transplant (BLT) at age 17. He was still alive 2.6 years after BLT. |
| 1y/F/12y | p.V155M (de novo) |
--- | ILD; hypoxemia; | arthritis; developmental delay | ruxolitinib(0.3mg/kgday) | In spite of treatment with ruxolitinib, the patient's respiratory status progressed, with worsening ILD on CT and hypoxemia, requiring lung transplantation at age 13.9 years, and died 4 years after BLT due to left bronchial rupture. | |
| 0.7y/M/14y | p.V155M (de novo) |
chilblain-like rash; telangiectasia | ILD;PAH; hypoxemia | --- | ruxolitinib(0.3mg/kgday) | Despite treatment with ruxolitinib, the patient's respiratory status progressively deteriorated, requiring lung transplant, and he died 33 days after the second transplant at the age of 16 due to multiorgan failure and hemorrhagic shock. | |
| Alghamdi MA (2021/ Saudi Arabia) (24) |
U/M/15y (brother) |
c.841C>T/ p.R281W (AR) | nasal rash and nasal deviation; acrocyanosis; nail dystrophy; dorsal hyperpigmentation; alopecia areata | ILD;PAH; hypoxemia | Severe right ventricular dilatation with moderate right ventricular dysfunction | ruxolitinib (5mg, bid) | The patient's pulmonary and skin symptoms improved significantly after ruxolitinib treatment. After 6 months, he no longer had dyspnea at rest. He did not require oxygen therapy with decreased immunoglobulin levels and acute phase reactants, a reduction in the size of the area of hair loss with hair regrowth, and a decrease in the hypopigmentation. |
| U/F/7y (sister) | c.841C>T/ p.R281W (AR) | malar rash with Raynaud’s phenomenon | ILD; PAH | arthritis | ruxolitinib(5mg, bid) | The patient's pulmonary and skin symptoms improved significantly after ruxolitinib treatment, and after 6 months, she no longer had dyspnea at rest. |
SD, standard deviation; P, percentage; U, unmentioned; bid, bisindie; m, month; y, year; ---: no other involvement.
HGVSc, human genome variation society coding; HGVSp, human genome variation society protein; AD, autosomal dominant inheritance; AR, autosomal recessive inheritance.
The abbreviations of HGVSc/ HGVSp variants: V, valine; M, methionine; S, serine; P, proline; F, phenylalanine; L, leucine; T, threonine; N, aspartic acid; S, serine; R, arginine; Q, glutamine; W, tryptophan; ILD, interstitial lung disease; PAH, pulmonary arterial hypertension.