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Prognosis and treatment of mixed connective tissue disease

Prognosis and treatment of mixed connective tissue disease
Literature review current through: Jun 2023.
This topic last updated: Feb 23, 2022.

INTRODUCTION — Mixed connective tissue disease (MCTD) is a generalized connective tissue disorder that includes clinical features commonly seen in systemic lupus erythematosus (SLE), scleroderma, and polymyositis (referred to as overlap syndrome) (table 1) [1]. Almost any organ system can be involved in MCTD. There are, however, several clinical features that, taken together, suggest the presence of MCTD rather than another connective tissue disorder:

Raynaud phenomenon and swollen hands or puffy fingers

A high titer speckled pattern antinuclear antibody (ANA) (usually ≥1280)

The absence of severe renal and central nervous system (CNS) disease

More severe arthritis, which is sometimes deforming

The development of pulmonary arterial hypertension (PAH), which differentiates MCTD from both SLE and scleroderma [1,2]

Autoantibodies whose fine specificity is anti-U1 ribonucleoprotein (RNP), especially antibodies to the 70 kD protein

(See "Clinical manifestations and diagnosis of mixed connective tissue disease".)

The diagnosis of MCTD does not require the simultaneous presence of overlap features. It is, in fact, unusual for patients to exhibit overlapping features in the early stages of MCTD, but distinctive clinical characteristics of SLE, systemic sclerosis, and polymyositis commonly appear sequentially over time [2-6].

This topic will review the prognosis and treatment of MCTD. The typically better prognosis in this disorder than that in other connective tissue diseases is another of its characteristics.

PROGNOSIS — The original description of patients with mixed connective tissue disease (MCTD) emphasized the relatively good prognosis and excellent response to glucocorticoids [3]. As noted above, these patients have a low prevalence of serious renal disease and life-threatening neurologic problems [7-9]. Although both of these organ systems are involved in about 25 percent of patients, the renal disease is usually a fairly benign form of membranous nephropathy, while central nervous system (CNS) involvement is most commonly a bothersome, but not life-threatening, trigeminal neuropathy [10,11].

Patients initially diagnosed as having MCTD may morph into the clinical picture of another connective tissue disorder, especially systemic lupus erythematosus (SLE), rheumatoid arthritis, Sjögren’s syndrome, and vasculitis [12,13]. However, there are clearly subsets of patients who are at risk for significant morbidity and mortality. In a follow-up report of the original 25 patients, for example, nine (36 percent) required repeated courses of glucocorticoids [14]. In addition, in a second study of 47 patients followed for 3 to 29 years, pulmonary hypertension was the underlying cause of death in 6 of 11 patients who died [7]; five of the patients who died had IgG anticardiolipin antibodies, a possible risk factor for severe disease.

Mortality — Overall mortality is apparently lower in patients with MCTD than in those with classic SLE. Nevertheless, there is appreciable mortality associated with MCTD ranging, in different studies, from 16 to 28 percent at 10 to 12 years [14-17]. The highest mortality is seen in those patients with vascular involvement [18]. The largest study of mortality in MCTD patients reported survival rates of 98, 96, and 88 percent at 5, 10 and 15 years after diagnosis among 280 patients [19].

The major causes of death include:

Progressive pulmonary arterial hypertension (PAH) and its cardiac complications [7,19,20]. In some cases, PAH due to scleroderma-like vasculopathy can lead to death in a few weeks [21]. In a cohort of 147 MCTD patients followed for a mean of 5.6 years, 3.14 percent had established PAH [22]. In another study of 201 MCTD patients followed for a mean of 12.7 years, the prevalence of PAH was 56 percent [18].

Interstitial lung disease is increasingly recognized as a major cause of morbidity and mortality. In a Norwegian study on 120 MCTD patients (75 percent women), 52 percent had abnormal high-resolution computed tomography (HRCT) images at a mean disease duration of nine years. The fibrosis was concentrated in the lower regions of the lungs. After mean 4.2 years of follow-up, the overall mortality was 7.9 percent; patients with severe lung fibrosis had a mortality of 20.8 percent [23].

Myocarditis [24].

Renovascular hypertension and cerebral hemorrhage [25,26].

Morbidity — Morbidity is quite high in patients with MCTD. The quality of life may be reduced due to multiple factors including recurrent musculoskeletal pain, low energy levels, and the stress of living with a potentially fatal condition. Flares of polymyositis, pericarditis, pleurisy, and myocarditis are usually treated with fairly high-dose steroids for several months. As a result, patients may suffer from the many consequences of extended glucocorticoid use, including aseptic necrosis, vertebral compression fractures, cataracts, weight gain, accelerated atherosclerosis, nosocomial infections, and proximal myopathy. (See "Major side effects of systemic glucocorticoids".)

Other problems can also be debilitating:

As in patients with SLE, it is not uncommon for patients with MCTD to develop the widespread pain syndrome of fibromyalgia. This can often become more debilitating than the primary disease [27,28]. (See "Clinical manifestations and diagnosis of fibromyalgia in adults".)

Patients with severe Raynaud phenomena can develop ischemic ulcers and even outright gangrene of the fingers. Such patients generally have a higher mortality [16].

A small subset of patients with MCTD develops a deforming arthritis and even arthritis mutilans [29-31].

Esophageal dysmotility can progress over time; as a result, some patients must undergo regular bougie dilatation. Gastroesophageal acid reflux may lead to Barrett's esophagus and, eventually, to carcinoma.

A minority of patients with renal disease develops end-stage renal failure [32].

Patients diagnosed with MCTD may also evolve into a clinical picture more consistent with SLE, scleroderma, or rheumatoid arthritis [16,33,34]. Such an evolution is, in part, genetically predetermined. Particular human leukocyte antigen (HLA)-DR alleles have been associated with a propensity to develop one connective disease as opposed to another. As an example, SLE is more likely in patients with HLA-DR3, scleroderma with HLA-DR5, and MCTD with HLA-DR4 or HLA-DR2 [16].

TREATMENT — Although mixed connective tissue disease (MCTD) was originally described as being extremely responsive to glucocorticoids, it is thought to be incurable. In addition, no controlled trials have been performed to guide therapy. Instead, the management of patients with MCTD generally rests upon the known effectiveness of specific therapies for similar problems seen in systemic lupus erythematosus (SLE), systemic sclerosis (SSc), or polymyositis [35].

General principles — The following discussion outlines some specific management issues and empiric observations concerning therapy:

In general, those features of MCTD also observed among patients with SLE (eg, pleurisy, pericarditis) respond to prednisone at a dose of 0.25 to 1.0 mg/kg per day. By comparison, scleroderma-like features (eg, Raynaud phenomenon, pulmonary hypertension) are usually less responsive to therapy. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults" and "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults".)

Since pulmonary arterial hypertension (PAH) is the main cause of death among patients with MCTD, early diagnosis with routine echocardiography is recommended for all patients. The MCTD Research Committee or the European Society of Cardiology has recommended that the threshold for the estimated pulmonary arterial systolic pressure for the diagnosis of PAH be set at 36 mmHg [36]. The timely diagnosis of PAH will hopefully lead to its early treatment with the administration of therapies which have shown some promise in this disorder [37]. These therapies include a calcium channel blocker (usually long-acting nifedipine), anticoagulation, intravenous prostacyclin, prolonged immunosuppression (beginning with glucocorticoids and combining with cyclophosphamide if necessary), and angiotensin-converting enzyme inhibitors [38-45]. In end-stage disease, a heart-lung transplant needs to be considered [46].

Advances in the treatment of pulmonary arterial hypertension have led to reduced morbidity and mortality. Long-term treatment with intravenous epoprostenol or prostacyclin improves exercise capacity, hemodynamics, and survival in most patients. Bosentan, an oral endothelin-1 antagonist, and phosphodiesterase inhibitors such as sildenafil are proving useful in the management of this complication [47,48]. Treatment of pulmonary hypertension in patients with connective tissue disease is discussed in more detail elsewhere. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Many of the clinical manifestations of MCTD associated with significant morbidity tend to be intermittent and responsive to glucocorticoids (prednisone 0.5 to 1.0 mg/kg per day); these disorders include aseptic meningitis, myositis, pleurisy, pericarditis, and myocarditis. By comparison, nephrotic syndrome, Raynaud phenomenon, deforming arthropathy, acrosclerosis, and peripheral neuropathies are usually steroid resistant.

Many gastrointestinal problems can be managed according to the treatment guidelines established for similar disorders in scleroderma [49] (see "Treatment of gastrointestinal disease in systemic sclerosis (scleroderma)"). Prednisone, however, may be effective in the treatment of esophageal involvement. As an example, a longitudinal study of 10 patients with MCTD evaluated the effectiveness of prednisone (an average dose of 25 mg/day) in the treatment of esophageal dysmotility [50]. Significant improvement was demonstrated in lower esophageal sphincter pressure, and a trend toward improvement was noted in proximal esophageal peristaltic waves.

As in SLE, it is worthwhile considering the use of rituximab in patients with steroid resistant thrombocytopenia or autoimmune hemolytic anemia. (See "Hematologic manifestations of systemic lupus erythematosus".)

IVIG may also have a role in the treatment of severe, eruptive skin disease [51] and of steroid resistant myositis. (See "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults".)

Patients with severe hand deformities may be helped by soft tissue release operations and selected joint fusions.

As in SLE and other autoimmune disorders, the combination of systemic inflammation, antiendothelial antibodies, and hyperlipidemia (often aggravated by glucocorticoid therapy) may lead to long-term morbidity or mortality from accelerated atherosclerosis [52].

Concerns with glucocorticoids — Since MCTD was initially considered to be a steroid-responsive disease, there is often a tendency to assume that all patients with MCTD should be treated with long-term glucocorticoids. This mistake is compounded by the assumption that all medical problems are related to MCTD. As an example, apparent flares of discomfort and pain in MCTD may instead be due to myofascial pain syndrome or to fibromyalgia and are therefore unresponsive to glucocorticoids [27,28]. In addition, malaise and easy fatigability may be due to a reactive depression or to a lack of conditioning. As a result, the management of patients with MCTD requires continuing reassessment of the changing pattern of disease activity and a constant alertness to the emergence of new problems.

As with other connective tissue diseases, the onset of an iatrogenic illness needs to be considered in the differential diagnosis of any new clinical problem. Over time, concern usually mounts over the total glucocorticoid burden and the possibility of inducing an iatrogenic steroid myopathy, nosocomial infection, aseptic necrosis of bone, or accelerated osteoporosis. Thus, among patients requiring long-term glucocorticoids, the use of antimalarials (400 mg of hydroxychloroquine per day) or methotrexate (7.5 to 15 mg/week) may be reasonable in an attempt to minimize the cumulative steroid burden. In one study of patients with SLE, for example, withdrawing hydroxychloroquine in stable patients was associated with a 2.5-fold increase in the risk of a clinical flare compared with those maintained on hydroxychloroquine [53]. On the other hand, long-term antimalarial therapy has been associated with a fatal cardiomyopathy [54].

Unless contraindicated, all steroid-treated patients should take calcium and vitamin D supplements. Postmenopausal women or others at high risk for osteoporosis may benefit from assessment of bone mineral density and use of bisphosphonates or other prophylactic or therapeutic interventions (see "Prevention and treatment of glucocorticoid-induced osteoporosis"). Anecdotal experience suggests that estrogen/progesterone therapy is not associated with flares of MCTD.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Mixed connective tissue disease".)

SUMMARY AND RECOMMENDATIONS

Patients with mixed connective tissue disease (MCTD) have a quite variable prognosis. Some features (eg, pleurisy, aseptic meningitis) are responsive to glucocorticoids, while scleroderma-like features, especially pulmonary hypertension, are steroid-unresponsive. There is a low prevalence of serious renal disease and life-threatening neurologic problems. Although the kidneys or nervous system are affected in about 25 percent of patients, the renal disease is usually a fairly benign form of membranous nephropathy, and the most common central nervous system (CNS) manifestation is trigeminal neuropathy. Anticardiolipin antibodies may be a risk factor for more severe disease, including pulmonary hypertension. (See 'Prognosis' above.)

Estimates of mortality in patients with MCTD range from 16 to 28 percent at 10 to 12 years. Patients with more features of scleroderma and polymyositis have a worse prognosis. The major causes of death include progressive pulmonary hypertension and its cardiac complications, interstitial lung disease, myocarditis, renovascular hypertension, and cerebral hemorrhage. (See 'Mortality' above.)

There is a high level of morbidity in patients with MCTD. Contributing factors include recurrent musculoskeletal pain, low energy levels, psychological stress, and the multiple adverse effects of periodic and relatively high doses of glucocorticoids. Other problems include fibromyalgia, severe Raynaud phenomena with ischemic changes, deforming arthritis, esophageal dysmotility, gastroesophageal reflux (sometimes resulting in Barrett esophagus), and, infrequently, end-stage kidney disease. Patients with MCTD may also evolve into a clinical picture more consistent with systemic lupus erythematosus (SLE), scleroderma, or rheumatoid arthritis. (See 'Morbidity' above.)

MCTD is thought to be incurable, and no randomized trials have been performed to guide therapy. The management is largely guided by the known effectiveness of specific therapies for similar problems seen in SLE, scleroderma, or polymyositis. Many of the clinical manifestations of MCTD associated with significant morbidity, such as aseptic meningitis, myositis, pleurisy, pericarditis, and myocarditis, tend to be intermittent and responsive to glucocorticoids. Glucocorticoids may occasionally be effective in MCTD for esophageal involvement. (See 'Treatment' above and 'General principles' above.)

We give particular attention to the avoidance of adverse effects related to the use of glucocorticoids. For example, features of fibromyalgia, a mood disorder, or deconditioning should be distinguished from manifestations of active MCTD that may require glucocorticoids. Appropriate measures should be taken to prevent glucocorticoid-induced osteoporosis. Antimalarials or methotrexate should be used in patients requiring repeated or ongoing treatment with glucocorticoids. (See 'Concerns with glucocorticoids' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert M Bennett, MD, FRCP, MACR, now deceased, who contributed to an earlier version of this topic review.

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