How to diagnose and treat pulmonary hypertension associated with connective tissue disease?

Pulmonary hypertension (PH) is one of the serious complications of connective tissue disease (CTD)

Pulmonary hypertension (PH) is one of the serious complications of connective tissue disease (CTD)

Pulmonary hypertension (PH) is one of the serious complications of connective tissue disease (CTD)

In recent years, research in the field of PAH has progressed rapidly.

01 Diagnostic criteria for CTD-PAH Diagnostic criteria for CTD-PAH

For patients suspected of CTD-PAH, after initial screening to support the diagnosis of PAH, right heart catheterization (RHC) should be completed as soon as possible, and if necessary, pulmonary function, pulmonary ventilation perfusion imaging, CT pulmonary angiography and other tests should be completed for accurate diagnosis and classification (see Fig.

For patients suspected of CTD-PAH, after initial screening to support the diagnosis of PAH, right heart catheterization (RHC) should be completed as soon as possible, and if necessary, pulmonary function, pulmonary ventilation perfusion imaging, CT pulmonary angiography and other tests should be completed for accurate diagnosis and classification (see Fig.

Figure 1.

Figure 1.

According to the 2015 ESC/ERS guidelines, PAH is defined as: mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg, PAWP ≤ 15 mmHg, and PVR > 3 WU measured by RHC at sea level and at rest

According to the 2015 ESC/ERS guidelines, PAH is defined as: mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg, PAWP ≤ 15 mmHg, and PVR > 3 WU measured by RHC at sea level and at rest

02 Treatment principles and goals of CTD-PAH Treatment principles and goals of CTD-PAH

The principle of CTD-PAH treatment is early and individualized treatment, which can delay disease progression to the greatest extent, reduce organ damage, and ultimately prolong patient survival, improve quality of life , and improve prognosis

The principle of CTD-PAH treatment is early and individualized treatment, which can delay disease progression to the greatest extent, reduce organ damage, and ultimately prolong patient survival, improve quality of life , and improve prognosis

Figure 2.

Figure 2.

03 Basic treatment of CTD-PAH Basic treatment of CTD-PAH

01 Diuretic

01 diuretic 01 diuretic

Decompensated right heart failure in CTD-PAH patients is often associated with water and sodium retention, manifested as increased central venous pressure, hepatic congestion, ascites, and peripheral edema.

Decompensated right heart failure in CTD-PAH patients is often associated with water and sodium retention, manifested as increased central venous pressure, hepatic congestion, ascites, and peripheral edema.

02 Oxygen 02 Oxygen

Studies have confirmed that for patients with PAH, long-term oxygen therapy can help reduce the mean pulmonary artery pressure and pulmonary vascular resistance.
When the peripheral blood oxygen saturation is less than 91% or the arterial blood oxygen partial pressure is less than 60mmHg, it is recommended to inhale oxygen to make the arterial blood gas oxygen content.
The pressure is maintained above 60mmHg
.

Studies have confirmed that for patients with PAH, long-term oxygen therapy can help reduce the mean pulmonary artery pressure and pulmonary vascular resistance.
When the peripheral blood oxygen saturation is less than 91% or the arterial blood oxygen partial pressure is less than 60mmHg, it is recommended to inhale oxygen to make the arterial blood gas oxygen content.
The pressure is maintained above 60mmHg
.

03 Digoxin

03 03 Digoxin

Digoxin can increase cardiac contractility, improve cardiac output, and control ventricular rate in patients with PAH, but the long-term efficacy is unclear
.
Patients with severe heart failure can be considered as appropriate
.

Digoxin can increase cardiac contractility, improve cardiac output, and control ventricular rate in patients with PAH, but the long-term efficacy is unclear
.
Patients with severe heart failure can be considered as appropriate
.

04 Iron

04 04 Iron

Iron deficiency is common in patients with PAH, especially in patients with CTD-PAH, which can reduce exercise tolerance and increase mortality in patients with CTD-PAH
.
The etiology of iron deficiency considers that there is iron metabolism disorder in PAH, and long-term chronic inflammation is also one of the important reasons.
Severe patients will develop iron deficiency anemia
.
Routine monitoring during follow-up is recommended, and iron supplementation should be used to correct if necessary
.

Iron deficiency is common in patients with PAH, especially in patients with CTD-PAH, which can reduce exercise tolerance and increase mortality in patients with CTD-PAH
.
The etiology of iron deficiency considers that there is iron metabolism disorder in PAH, and long-term chronic inflammation is also one of the important reasons.
Severe patients will develop iron deficiency anemia
.
Routine monitoring during follow-up is recommended, and iron supplementation should be used to correct if necessary
.

05 Anticoagulation

05 05 Anticoagulation

The risk-benefit ratio of oral anticoagulation in CTD-PAH is not clear, and anticoagulation strategies should be formulated according to the degree of thrombosis risk of patients
.
Usually CTD patients with positive antiphospholipid antibodies, or the results of radionuclide pulmonary ventilation/perfusion imaging suggest that there is a moderate or high suspicion of pulmonary embolism, etc.
, long-term anticoagulation with oral vitamin K antagonist drugs is recommended, and the international normalized ratio (INR) target is 2.
0 -3.
0
.
The efficacy of novel oral anticoagulants in CTD-PAH is unclear
.

The risk-benefit ratio of oral anticoagulation in CTD-PAH is not clear, and anticoagulation strategies should be formulated according to the degree of thrombosis risk of patients
.
Usually CTD patients with positive antiphospholipid antibodies, or the results of radionuclide pulmonary ventilation/perfusion imaging suggest that there is a moderate or high suspicion of pulmonary embolism, etc.
, long-term anticoagulation with oral vitamin K antagonist drugs is recommended, and the international normalized ratio (INR) target is 2.
0 -3.
0
.
The efficacy of novel oral anticoagulants in CTD-PAH is unclear
.
thrombus

06Calcium ion antagonists (CCBs)

06 06 Calcium Antagonists (CCBs)

Only patients with idiopathic PAH with a positive acute vascular response test may benefit from CCBs treatment, while the benefit of CCBs treatment in patients with positive CTD-PAH is unclear; if CCBs are used, the treatment response needs to be assessed every 3 months.
Patients with poor efficacy should be transferred to PAH-targeted drug therapy as soon as possible
.

Only patients with idiopathic PAH with a positive acute vascular response test may benefit from CCBs treatment, while the benefit of CCBs treatment in patients with positive CTD-PAH is unclear; if CCBs are used, the treatment response needs to be assessed every 3 months.
Patients with poor efficacy should be transferred to PAH-targeted drug therapy as soon as possible
.

04Treatment for CTD

04 Treatment for CTD The treatment for CTD is different from idiopathic pulmonary arterial hypertension.
CTD-PAH is considered to be a "causal" pulmonary arterial hypertension, which is a manifestation of the primary disease involving the pulmonary blood vessels
.
Therefore, at the same time or before the targeted drugs "symptomically" reduce pulmonary hypertension, the "cause" treatment for the primary disease is the top priority
.
Control of the primary disease can not only prevent the continued progression of pulmonary hypertension, but may even "reverse" pulmonary hypertension
.

01Treatment goals

01 01 Treatment Goals

CTD remission should be actively pursued
.
Overall, PGA<1 points indicated that CTD was in clinical remission
.

CTD remission should be actively pursued
.
Overall, PGA<1 points indicated that CTD was in clinical remission
.

Take three common CTDs as examples:

Take three common CTDs as examples:

①SLE low disease activity: SLE activity score (SLEDAI-2K) ≤ 4 points, BILAG grades C/D/E in each system, PGA < 1 point, prednisone dose ≤ 7.
5 mg per day, no immunosuppressive use
.
SLE remission: SLEDAI is 0 points, PGA<0.
5 points, only taking antimalarial drugs
.

①SLE low disease activity: SLE activity score (SLEDAI-2K) ≤ 4 points, BILAG grades C/D/E in each system, PGA < 1 point, prednisone dose ≤ 7.
5 mg per day, no immunosuppressive use
.
SLE remission: SLEDAI is 0 points, PGA<0.
5 points, only taking antimalarial drugs
.
immunity

② pSS low disease activity: SS European League Against Rheumatism Disease Activity Index (ESSDAI) <4 points
.
pSS treatment response target: ESSDAI score reduction ≥3 points
.

② pSS low disease activity: SS European League Against Rheumatism Disease Activity Index (ESSDAI) <4 points
.
pSS treatment response target: ESSDAI score reduction ≥3 points
.

③SSc: Although there is no exact activity assessment system, no progressive skin or pulmonary fibrotic lesions or vascular lesions (digital ulcers, PAH) in the short term can be used as a treatment target
.

③SSc: Although there is no exact activity assessment system, no progressive skin or pulmonary fibrotic lesions or vascular lesions (digital ulcers, PAH) in the short term can be used as a treatment target
.

02Treatment plan

02 02 Treatment Program

Intensive immunosuppressive therapy helps to improve the condition of CTD-PAH
.
An individualized immunosuppression regimen should be developed according to the type of CTD, disease activity, disease course, organs involved, and severity
.
Compared with IPAH, the treatment of CTD-PAH is more complicated.
In the treatment of PAH, it is necessary to actively control the condition of CTD, so as to achieve "double compliance", in order to improve the long-term prognosis and improve the quality of life of patients
.
Determining whether the primary disease is active is the first step in treatment
.

Intensive immunosuppressive therapy helps to improve the condition of CTD-PAH
.
An individualized immunosuppression regimen should be developed according to the type of CTD, disease activity, disease course, organs involved, and severity
.
Compared with IPAH, the treatment of CTD-PAH is more complicated.
In the treatment of PAH, it is necessary to actively control the condition of CTD, so as to achieve "double compliance", in order to improve the long-term prognosis and improve the quality of life of patients
.
Determining whether the primary disease is active is the first step in treatment
.

① If the primary disease activity is obvious, or other important organs are clearly involved, the plan should be formulated according to the treatment principles of the primary disease
.

① If the primary disease activity is obvious, or other important organs are clearly involved, the plan should be formulated according to the treatment principles of the primary disease
.

② If there is evidence of activity in the primary disease (such as: decreased complement and significantly increased anti-ds-DNA in patients with SLE; or obvious purpura and increased IgG in patients with pSS), but no other organs are seriously involved except PAH, active immunosuppression should also be performed treatment
.
Previous studies have found that in SLE, pSS and MCTD-PAH patients, PAH can be effectively controlled by high-dose glucocorticoid combined with immunosuppressive therapy to induce remission
.
Stronger immunosuppressants such as cyclophosphamide (CTX) and mycophenolate mofetil (MMF) should be selected
.
If some patients have obvious primary disease activity, or are in the early stage of the disease course, after assessing the relevant risks, they can add hormonal pulse therapy as appropriate, so as to strive for the hope of "reversing" PAH
.

② If there is evidence of activity in the primary disease (such as: decreased complement and significantly increased anti-ds-DNA in patients with SLE; or obvious purpura and increased IgG in patients with pSS), but no other organs are seriously involved except PAH, active immunosuppression should also be performed treatment
.
Previous studies have found that in SLE, pSS and MCTD-PAH patients, PAH can be effectively controlled by high-dose glucocorticoid combined with immunosuppressive therapy to induce remission
.
Stronger immunosuppressants such as cyclophosphamide (CTX) and mycophenolate mofetil (MMF) should be selected
.
If some patients have obvious primary disease activity, or are in the early stage of the disease course, after assessing the relevant risks, they can add hormonal pulse therapy as appropriate, so as to strive for the hope of "reversing" PAH
.

③ If the primary disease is stable and the pulmonary hypertension is still progressing: the focus of treatment may be slightly biased towards "targeted therapy"
.
In terms of primary disease, the dose of the original hormone can be maintained, or it can be increased to half or full dose of hormone therapy according to the actual situation, but the dose should be gradually reduced as soon as possible; it is recommended to strengthen the immunosuppressant appropriately, because the appearance of PAH indicates that the intensity of the original treatment plan is not enough to suppress PAH, combined with its condition, can be intensified into CTX, MMF, azathioprine,
etc.

③ If the primary disease is stable and the pulmonary hypertension is still progressing: the focus of treatment may be slightly biased towards "targeted therapy"
.
In terms of primary disease, the dose of the original hormone can be maintained, or it can be increased to half or full dose of hormone therapy according to the actual situation, but the dose should be gradually reduced as soon as possible; it is recommended to strengthen the immunosuppressant appropriately, because the appearance of PAH indicates that the intensity of the original treatment plan is not enough to suppress PAH, combined with its condition, can be intensified into CTX, MMF, azathioprine,
etc.

④ Both the primary disease and pulmonary hypertension are stable: it is recommended to adopt a treatment plan for maintaining remission, that is, low-dose glucocorticoids and long-term immunosuppressants, such as calcineurin inhibitors (cyclosporine, tacrolimus, etc.
) ), mycophenolate mofetil, azathioprine, methotrexate, or hydroxychloroquine
.

④ Both the primary disease and pulmonary hypertension are stable: it is recommended to adopt a treatment plan for maintaining remission, that is, low-dose glucocorticoids and long-term immunosuppressants, such as calcineurin inhibitors (cyclosporine, tacrolimus, etc.
) ), mycophenolate mofetil, azathioprine, methotrexate, or hydroxychloroquine
.

⑤ For patients with SSc-PAH, existing studies have shown that hormones and immunosuppressants cannot improve the symptoms, hemodynamics and prognosis of patients.
Therefore, whether to add hormones and immunosuppressants is recommended according to SSc disease staging and other organ involvement.
Circumstances decide
.

⑤ For patients with SSc-PAH, existing studies have shown that hormones and immunosuppressants cannot improve the symptoms, hemodynamics and prognosis of patients.
Therefore, whether to add hormones and immunosuppressants is recommended according to SSc disease staging and other organ involvement.
Circumstances decide
.

In particular, it should be pointed out that although the disease activity scores of SLE, SS and SSc do not include PAH in the evaluation, PAH cannot be completely isolated and evaluated individually.
PAH should be considered as a part of CTD system involvement.
Individualized treatment in clinical practice
.

In particular, it should be pointed out that although the disease activity scores of SLE, SS and SSc do not include PAH in the evaluation, PAH cannot be completely isolated and evaluated unilaterally, and PAH should be considered as a part of CTD system involvement.
Individualized treatment in clinical practice
.


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